annex i list of the names, pharmaceutical forms, … · products, routes of administration,...

1

ANNEX I

LIST OF THE NAMES, PHARMACEUTICAL FORMS, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION

HOLDERS IN THE MEMBER STATES

2

Member State EU/EEA

Marketing Authorisation Holder

(Invented) name Strength Pharmaceutical Form

Route of administration

Content (concentration)

Augmentin intravenös 550 mg – Trockenstechampullen

500/50 mg

Powder for solution for injection or infusion

Intravenous use

500mg : 50mg/ vial

Augmentin intravenös 1,1 g - Trockensubstanz zur Infusionsbereitung

1000/100 mg

Powder for solution for infusion

Intravenous use

1000mg : 100mg/ vial

Augmentin intravenös 2,2 g - Trockensubstanz zur Infusionsbereitung

2000/200 mg

Powder for solution for infusion

Intravenous use

2000mg : 200mg/ vial

Augmentin 625 mg - lösliche Tabletten

500/125 mg

Dispersible tablet

Oral use

Augmentin 625 mg – Filmtabletten

500/125 mg

Film-coated Tablet

Oral use

Augmentin 1 g – Filmtabletten 875/125 mg

Film-coated Tablet Oral use

GlaxoSmithKline Pharma GmbH, Albert Schweitzer-Gasse 6, A-1140 Wien

Augmentin 457 mg/5 ml – Trockensaft

400/57mg/ 5ml

Powder for oral suspension

Oral use

400mg : 57mg/ 5ml

Clavamox intravenös 550 mg –Trockenstechampullen

500/50 mg

Powder for solution for injection or infusion

Intravenous use 500mg : 50mg/ 10.5ml

Clavamox intravenös 1,1 g - Trockensubstanz zur Infusionsbereitung

1000/100 mg Powder for solution for infusion

Intravenous use 1000mg : 100mg/ 100ml

Clavamox intravenös 2,2 g - Trockensubstanz zur Infusionsbereitung

2000/200 mg Powder for solution for infusion


Clavamox 625 mg - lösliche Tabletten

500/125mg Dispersible tablet Oral use

Austria

Sandoz GmbH, Biochemiestr. 10, A - 6250 Kundl

Clavamox 625 mg – Filmtabletten

500/125mg Film-coated Tablet Oral use

3

Member State EU/EEA





Clavamox 1 g – Filmtabletten 875/125 mg Film-coated Tablet Oral use

Clavamox 156,25 mg/5 ml – Trockensaft

125/31.25mg/ 5ml Powder for oral suspension

Oral use

125/31.25mg/ 5ml

Clavamox 312,5 mg/5 ml – Trockensaft

250/62.5mg/ 5 ml Powder for oral suspension

Oral use

250/62.5mg/ 5 ml

Clavamox Duo – Trockensaft 400/57mg/ 5 ml Powder for oral suspension

Oral use

400/57mg/ 5 ml

Augmentin P

500/50 mg

Powder for injection or infusion

Intravenous use

500mg : 50mg/ 10.5ml or 25ml

Augmentin P

1000/100 mg Powder for infusion Intravenous use 1000mg :100mg/ 50ml

Augmentin 1000/200 mg Powder for injection


Augmentin 2000/200 mg Powder for infusion Intravenous use 2000mg : 200mg/ 100ml

Augmentin 500/125mg Film-coated tablet Oral use Augmentin 875/125 mg Film-coated tablet Oral use Augmentin 125/31.25mg/ 5ml Powder for oral

suspension Oral use 125mg : 31.25mg/

5ml Augmentin 250/62.5mg/ 5ml Powder for oral

suspension Oral use 250mg : 62.5mg/ 5ml

Augmentin 500/125mg


Oral use

Belgium

GlaxoSmithKline s.a. / n.v. Rue du Tilleul 13 1332 Genval

Augmentin Retard 1000/62.5 mg Modified release tablet

Oral use

Augmentin 250/125mg Film-coated tablet Oral use Augmentin 500/125mg Film-coated tablet Oral use

Bulgaria GlaxoSmithKline EOOD Ivan Vasov Complex Dimitar Manov street, Augmentin 875/125 mg Film-coated tablet Oral use

4

Member State EU/EEA





Augmentin

125/31.25mg / 5 ml


Oral use 125mg : 31.25mg/ 5ml

Augmentin

250/62.5mg/ 5ml



Augmentin

400/57mg/ 5ml


Oral use 400mg : 57mg/ 5ml

Augmentin ES

600/42.9mg/ 5ml



bl.10, 1408 Sofia, Bulgaria

Augmentin SR 1000/62.5mg Prolonged release tablet

Oral use

Augmentin

500/100 mg Powder for injection or infusion

Intravenous use

500mg : 100mg/ 10.5ml or 60ml

Augmentin 1000/200 mg Powder for injection or infusion

Intravenous use

1000mg : 200mg/ 20.9ml or 120ml


suspension Oral use

250mg : 62.5mg/ 5ml

Augmentin 400/57mg/ 5ml Powder for oral suspension

Oral use

400mg : 57 mg/ 5ml

SmithKline Beecham plc 980 Great West Road Brentford Middlesex TW8 9GS UK

Augmentin ES 600/42.9mg/ 5ml Powder for oral suspension

Oral use

600mg : 42.9mg/ 5ml

Augmentin SR 1000/62.5mg Film-coated tablet Oral use Noprilam 500/125 mg Film-coated tablet Oral use Noprilam DT 875/125 mg Film-coated tablet Oral use Noprilam 156.23 mg/ 5 ml Powder for oral

suspension Oral use 125 mg : 31.23 mg/ 5

ml

Cyprus

Laboratórios BIAL À Av. da Siderurgia Nacional – 4745-457 S. Mamede do Coronado Portugal

Noprilam 250/62.5 mg/ 5 ml Powder for oral suspension

Oral use 250 mg : 62.5 mg/ 5 ml

5

Member State EU/EEA





Noprilam DT 400/57mg/ 5ml Powder for oral suspension


Augmentin 600 mg

500/100 mg


Intravenous use

500mg : 100mg/ 10.5ml or 60 ml

SmithKline Beecham plc trading as SmithKline Beecham Pharmaceuticals 980 Great West Road, Brentford, Middlesex TW8 9GS United Kingdom

Augmentin 1,2 g 1000/200 mg Powder for injection or infusion

Intravenous use

1000mg : 200mg/ 20.9ml or 120ml

Augmentin 375 mg 250/125mg Film-coated tablet Oral use Augmentin 625 mg 500/125mg Film-coated tablet Oral use Augmentin 1 g 875/125 mg Film-coated tablet Oral use Augmentin 156 mg/5 ml 125/31.25mg / 5

ml Powder for oral suspension


Augmentin 312 mg/5ml 250/62.5mg/ 5ml Powder for oral suspension


Augmentin Duo 400/57mg/ 5ml Powder for oral suspension


Czech Republic

SmithKline Beecham plc trading as SmithKline Beecham Pharmaceuticals 980 Great West Road, Brentford, Middlesex TW8 9GS United Kingdom

Augmentin SR 1000/62.5mg modified-release tablet

Oral use

Spektramox 500/125 mg Film-coated tablet Oral use Spektramox 125/31.25mg/ 5ml Powder for oral


5ml Spektramox 250/62.5mg/ 5ml Powder for oral


Spektramox 2 :1 250/125 mg Film-coated tablet Oral use

Denmark

Meda AS Solvang 8 DK-3450 Allerød Denmark

Spektraforte 875/125 mg Film-coated tablet Oral use Augmentin

1000/200 mg


Intravenous use

1000mg : 200mg/ 20.9ml or 120ml

Estonia

SmithKline Beecham plc. 980 Great West Road, Brentford Middlesex TW8 9GS Augmentin 500/125mg Film-coated tablet Oral use

6

Member State EU/EEA





Augmentin 875/125 mg Film-coated tablet Oral use United Kingdom Augmentin 400/57mg/ 5ml Powder for oral

suspension Oral use

400mg : 57 mg/ 5ml

Augmentin 875/125 mg Film-coated tablet Oral use SmithKline Beecham plc 980 Great West Road Brentford, Middlesex TW8 9GS UK

Augmentin (80 /11.97 mg/ml) 400/57mg/ 5ml Powder for oral suspension


Clavurion 875/125 mg Film-coated tablet Oral use Clavurion 200/28.5mg/ 5ml Powder for oral

suspension Oral use 200mg:28.5mg/ 5ml

Finland

Orion-yhtymä Oyj, Orionintie 1, 02200 Espoo

Clavurion 400/57mg/ 5ml Powder for oral suspension


Augmentin IV ENFANTS NOURRISSONS

500/50 mg

Powder for solution for injection AND Powder and solvent for solution for injection

Intravenous use

500mg : 50mg

Augmentin IV ADULTES

500/100 mg Powder for solution for injection

Intravenous use

500mg :100mg

Augmentin IV ENFANTS

1000/100 mg Powder for solution for injection

Intravenous use

1000mg : 100mg


1000/200 mg Powder for solution for injection AND Powder and solvent for solution for injection

Intravenous use

1000mg : 200mg


2000/200 mg

Powder for solution for injection

Intravenous use

2000mg : 200mg

Augmentin ADULTES

500/62.5mg Film-coated tablet

Oral use

France

Laboratoire GlaxoSmithKline 100, route de Versailles – 78163 Marly-le-Roi Cedex

Augmentin ENFANTS

100/12.5mg/ ml Powder for oral suspension

Oral use 100mg : 12.5mg/ ml

7

Member State EU/EEA





Augmentin NOURRISSONS


Oral use 100mg / 12.5mg/ ml

Augmentin NOURRISSONS

250/31.25mg Powder for oral suspension

Oral use

Augmentin ENFANTS

500/62.5mg Powder for oral suspension

Oral use

Augmentin ADULTES

1000/125 mg Powder for oral suspension

Oral use

Duamentin ADULTES

1000/62.5mg Film-coated tablet Oral use

Augmentan i.v. pro infantibus 275mg

250/25mg Powder for solution for infusion

Intravenous use

250mg : 25mg

Augmentan i.v. 600mg 500/100 mg Powder for solution for injection or infusion

Intravenous use

500mg : 100mg

Augmentan i.v. 1,2g 1000/200 mg Powder for solution for infusion or infusion

Intravenous use

1000mg : 200mg

Augmentan i.v. 2,2g 2000/200 mg Powder for solution for infusion

Intravenous use 2000mg : 200mg

Augmentan Tabs Tabletten 500/125mg Dispersible tablet Oral use Augmentan Filmtabletten 875/125mg

875/125 mg Film-coated tablet Oral use

Augmentan Tropfen 50 mg/ 12,5 mg pro ml für Säuglinge


Oral use

50mg : 12.5mg/ ml

Augmentan Trockensaft 25 mg/6,25 mg pro ml


Oral use

125mg : 31.25mg/ 5ml

Augmentan forte Trockensaft 50 mg/12,5 mg pro ml


Oral use

250mg : 62.5mg/ 5ml

Germany

GlaxoSmithKline GmbH & Co. KG Theresienhöhe 11 80339 München

Augmentan Kindersaft 400/57mg/ 5ml Powder for oral suspension

Oral use

400mg : 57mg/ 5ml

Greece

GlaxoSmithKline a.e.b.e, Leof. Kifissias 266,

Augmentin

500/100 mg

Powder for injection

Intravenous use

500mg : 100mg/ 10.5ml

8

Member State EU/EEA






Intravenous use

1000mg : 200mg/ 20.9ml

Augmentin 500/125mg Film-coated tablet Oral use Augmentin 875/125 mg Film-coated tablet Oral use Augmentin 500/125mg Dispersible tablet Oral use Augmentin 125/31.25mg / 5


Oral use

125mg : 31.25mg/ 5ml

Augmentin 250/62.5mg/ 5ml Powder for oral suspension

Oral use

250mg : 62.5mg/ 5ml


Oral use

400mg : 57mg/ 5ml

Augmentin SR 1000/62.5mg Film-coated tablet

Oral use

152 32 Halandri, Athens


Oral use

600mg : 42.9 mg/5ml

Augmentin

500/100 mg


Intravenous use

500mg : 100mg/ 10.5ml



Augmentin 250/125mg Film-coated tablet Oral use Augmentin 500/125mg Film-coated tablet Oral use Augmentin 125/31.25mg / 5


Oral use

125mg : 31.25mg/ 5ml

GlaxoSmithKline Kft. 1124 Bp, Csörsz u. 43 Hungary


Oral use

250mg : 62.5mg/ 5ml

Augmentin Duo 875/125 mg Film-coated tablet Oral use Augmentin Duo 500/125mg Film-coated tablet Oral use Augmentin Duo 400/57mg/ 5ml Powder for oral

suspension Oral use

400mg : 57mg/ 5ml

Hungary

GlaxoSmithKline Kft. 1124 Bp, Csörsz u. 43.

Augmentin Extra 600/42.9mg/ 5ml Powder for oral suspension

Oral use

600mg : 42.9 mg/ 5ml

9

Member State EU/EEA





Augmentin Extra 1000/62.5mg Film-coated tablet Oral use

Augmentin IV 500/100 mg Powder for injection


Augmentin IV 1000/200 mg Powder for injection


Augmentin 500/125mg tablet Oral use Augmentin 875/125 mg tablet Oral use Augmentin 250/62.5mg/ 5ml Powder for oral


Iceland

GlaxoSmithKline ehf. Þverholti 14 105 Reykjavík.



Augmentin Intravenous 500mg/100mg Powder for Solution for Injection or Infusion

500/100 mg Powder for solution for injection or infusion


Augmentin Intravenous 1000mg/200mg Powder for Solution for Injection or Infusion

1000/200 mg Powder for solution for injection or infusion


Augmentin Tablets 250mg/125mg

250/125mg

Film-coated tablet Oral use

Augmentin Dispersible Tablets 250mg/125mg

250/125mg Dispersible Tablet Oral use

Augmentin Duo Tablets 500/125mg

500/125mg Film-coated tablet Oral use

Augmentin 500/125mg Film-Coated Tablets


Augmentin 875mg/125mg Film Coated Tablets


Ireland

GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham, Dublin 16

Augmentin Paediatric Suspension

125/31.25mg / 5 ml



10

Member State EU/EEA





Augmentin Junior Suspension



Augmentin Duo Suspension 400mg/57mg

400/57mg/ 5ml Powder for oral suspension


Clavamel 250mg/125mg Tablets

250/125mg


Clavamel 125mg/31.25mg Paediatric Powder for Oral Suspension

125/31.25mg / 5 ml



Clonmel Healthcare Limited Waterford Road Clonmel Tipperary Ireland Clavamel 125mg/62.5mg

Junior Powder for Oral Suspension





Augmentin 2000/200 mg Powder for infusion Intravenous use 2000mg : 200mg Augmentin 875/125 mg Film-coated tablet Oral use Augmentin



Augmentin

400/57mg Powder for oral suspension

Oral use

GlaxoSmithKline S.p.A. - Via A. Fleming, 2 – 37135 Verona

Augmentin 875/125 mg Powder for oral suspension

Oral use

Neoduplamox 875/125 mg Film-coated tablet Oral use Neoduplamox 400/57mg/ 5ml Powder for oral

suspension Oral use 400mg : 57mg/ 5ml

Neoduplamox 400/57mg Powder for oral

suspension Oral use

Valeas S.p.A. via Vallisneri 10 20133 Milano

Neoduplamox 875/125 mg Powder for oral suspension

Oral use

Clavulin 875/125 mg Film-coated tablet Oral use

Italy

Solvay Pharma S.p.A. Via della Libertà, 30 10095 Grugliasco (TO)

Clavulin 400/57mg/ 5ml Powder for oral suspension


11

Member State EU/EEA





Clavulin 400/57mg Powder for oral suspension

Oral use

Clavulin 875/125 mg Powder for oral suspension

Oral use

Augmentin 1000/200 mg Powder for solution for injection


Augmentin 500/125mg Film-coated tablet Oral use Augmentin 875/125 mg Film-coated tablet Oral use Augmentin 400/57mg/ 5ml Powder for oral

suspension Oral use

400mg : 57mg/ 5ml

Augmentin ES 600/42.9mg / 5ml Powder for oral suspension

Oral use

600mg : 42.9mg/ 5ml

Latvia

GlaxoSmithKline Latvia SIA Bruninieku 5, Riga, LV-1001, Latvia

Augmentin SR 1000/62.5mg Film-coated tablet Oral use Augmentin 500/125mg Film-coated tablet Oral use Augmentin 875/125 mg Film-coated tablet Oral use Augmentin 200/28.5mg/ 5ml Powder for oral

suspension Oral use 200mg / 28.5 mg/

5ml

Beecham Group plc. 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom Augmentin 400/57mg/ 5ml Powder for oral

suspension Oral use 400mg / 57mg/ 5ml

Lithuania

UAB „GlaxoSmithKline Lietuva“ A. Goštauto g. 40A LT-01112 Vilnius, Lithuania

Augmentin ES 600/42.9mg / 5ml Powder for oral suspension

Oral use

600mg / 42.9mg/ 5ml

Augmentin P

500/50 mg


Intravenous use

500mg / 50mg/ 10.5ml or 25ml

Augmentin P

1000/100 mg

Powder for infusion Intravenous use

1000mg /100mg/ 50ml

Luxembourg

GlaxoSmithKline s.a. / n.v. Rue du Tilleul 13 1332 Genval

Augmentin 1000/200 mg


Intravenous use

1000mg / 200mg/ 20ml

12

Member State EU/EEA





Augmentin 2000/200 mg Powder for infusion Intravenous use 2000mg / 200mg/ 100ml



5ml Augmentin 250/62.5mg/5ml Powder for oral


Augmentin 500/125mg Powder for oral

suspension Oral use

Augmentin Retard, 1000/62.5 mg Modified release tablet

Oral use

Augmentin Intravenous 600mg 500/100 mg Powder for solution for injection or infusion


Beecham Group plc 980 Great West Road, Brentford, Middlesex TW8 9GS United Kingdom

Augmentin Intravenous 1.2g 1000/200 mg Powder for solution for injection or infusion


Augmentin 250/125mg 250/125mg Film-coated tablet Oral use Augmentin Duo 500/125 tablets

500/125mg Film-coated tablet Oral use GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham Dublin 16 Ireland

Augmentin 875/125mg tablets 875/125 mg Film-coated tablet Oral use

SmithKline Beecham plc 980 Great West Road Brentford Middlesex TW8 9GS

Augmentin Duo 400/57 400/57mg/ 5ml Powder for oral suspension


Noprilam 500/125 mg Coated tablet Oral use

Malta

Laboratórios BIAL Portela & Ca, S.A. Noprilam DT 875/125 mg Coated tablet Oral use

13

Member State EU/EEA





À Av. da Siderurgia Nacional – 4745-457 S. Mamede do Coronado Portugal

Noprilam DT 400/57mg/ 5ml Powder for oral suspension

Oral use 400/57mg/ 5ml

Augmentin 250/25mg Powder for injection







Intravenous use 1000mg :100mg/ 20.9ml




Augmentin 500/125mg Film-coated tablet Oral use Augmentin 875/125 mg Film-coated tablet Oral use Augmentin 100/12.5mg /ml Powder for oral

suspension Oral use 100mg : 12.5mg/ ml



Glaxo Smith Kline B.V. Huis ter Heideweg 62 3705 LZ ZEIST THE NETHERLANDS



Netherlands

Glaxo Smith Kline B.V. Huis ter Heideweg 62 3705 LZ ZEIST THE NETHERLANDS

amoxicilline/clavulaanzuur 250/62.5 mg Powder for oral suspension

Oral use



Poland

GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8



14

Member State EU/EEA






Augmentin 250/125mg Film-coated tablet Oral use Augmentin 500/125mg Film-coated tablet Oral use Augmentin 875/125 mg Film-coated tablet Oral use Augmentin 125/31.25mg/ 5ml Powder for oral

suspension Oral use 125mg:31.25mg/ 5ml


Oral use 250mg:62.5mg/ 5ml





9GS UK

Augmentin SR 1000/62.5mg Prolonged release tablet

Oral use

Augmentin 500/125mg Film-coated tablet Oral use Augmentin Duo 875/125 mg Film-coated tablet Oral use Augmentin 125/31.25 mg/

5ml Powder for oral suspension


Augmentin Forte 250/62.5 mg/ 5ml Powder for oral suspension

Oral use 250mg:62.5mg/ 5ml

Augmentin Duo 400/57 mg/ 5ml Powder for oral suspension


GlaxoSmithKline – Produtos Farmacêuticos Lda Rua Dr. António Loureiro Borges, 3 Aquiparque – Miraflores 1495 – 131 Algés



Clavamox 125 125/31.25 mg/ 5ml


Oral use 125 mg: 31.25 mg/ 5ml

Clavamox 250 250/62.5 mg/ 5 ml Powder for oral suspension

Oral use 250 mg : 62.5 mg/ 5ml

Clavamox 500 500/125 mg Film-coated tablet Oral use

Portugal

Bial - Portela & Cª, S.A À Av. da Siderurgia Nacional – 4745-457 S. Mamede do Coronado Portugal Clavamox DT 875/125 mg Film-coated tablet Oral use

15

Member State EU/EEA





Clavamox DT 400 400/ 57 mg/ 5 ml Powder for oral suspension

Oral use 400 mg : 57 mg/ 5 ml

Clavamox ES 600/42.9 mg/ 5 ml Powder for oral suspension


Noprilam 500/125 mg Film-coated tablet Oral use Noprilam 125/31.25 mg/5



Noprilam 250/62.5 mg/ 5 ml Powder for oral suspension


Noprilam DT 875/125 mg Film-coated tablet Oral use Penilan 500/125 mg Film-coated tablet Oral use Penilan 125/31.25 mg/ 5



Penilan DT 875/125 mg Film-coated tablet Oral use

Laboratórios Vitória, S.A. Rua Elias Garcia, 28 – Venda Nova 2700-327 Amadora (Sob licença GlaxoSmithKline – Produtos Farmacêuticos, Lda.)

Penilan Forte 250/62.5 mg/ 5 ml Powder for oral suspension


Augmentin intravenos 1,2g

1000/200 mg Powder for injection/infusion

Intravenous use

1000mg : 200mg/ 20.9ml

Augmentin Intravenos 2,2g

2000/200 mg Powder for infusion Intravenous use 2000mg : 200mg/ 120ml

Augmentin 625mg 500/125mg Film-coated tablet Oral use

Augmentin 1g 875/125 mg Film-coated tablet Oral use

Augmentin BIS 400/57mg/ 5ml Powder for oral suspension




Romania

Beecham Group PLC 980 Great West Road, Brentford, Middlesex TW8 9GS United Kingdom

Augmentin SR 1000/62.5mg Prolonged release film-coated tablet

Oral use

16

Member State EU/EEA





Augmentin 375mg 250/125mg Film-coated tablet Oral use Augmentin 625mg 500/125mg Film-coated tablet Oral use Augmentin 1g 875/125 mg Film-coated tablet Oral use Augmentin DUO 400/57mg/ 5ml Powder for oral

suspension Oral use 400mg : 57mg/ 5ml



Slovak Republic

GlaxoSmithKline Slovakia sro., Galvaniho7/A, 82104 Bratislava, Slovakia.

Augmentin SR 1000/62.5mg Prolonged-release tablet

Oral use

Augmentin Augmentin 0,6 g prašek za raztopino za injiciranje ali infundiranje

500/100 mg



Augmentin 1,2 g prašek za raztopino za injiciranje ali infundiranje

1000/200 mg Powder for injection


Augmentin 625 mg filmsko obložene tablete


Augmentin 1000 mg filmsko obložene tablete


Augmentin457 mg/5 ml prašek za peroralno suspenzijo



Slovenia

GSK d.o.o., Ljubljana Knezov štradon 90 SI-1000 Ljubljana Slovenija

Augmentin SR 1000 mg/62,5 mg filmsko obložene tablete s podaljšanim sproščanjem

1000/62.5mg Film-coated tablet Oral use

Augmentine Intravenoso 500/50 mg Powder for injection


Augmentine Intravenoso 1000/200 mg Powder for injection


Augmentine Intravenoso 2000/200 mg Powder for infusion Intravenous use 2000mg : 200mg/ 120ml

Spain GlaxoSmithKline, S.A. P.T.M.- C/Severo Ochoa, 228760 Tres Cantos (Madrid).

Augmentine 500/125mg Film-coated tablet Oral use

17

Member State EU/EEA





Augmentine 875/125 mg Film-coated tablet Oral use Augmentine 100/12.5mg/ ml Powder for oral

suspension Oral use 100mg :12.5mg/ ml

Augmentine 500/125mg Powder for oral suspension

Oral use

Augmentine 875/125 mg Powder for oral suspension

Oral use

Augmentine Plus 1000/62.5mg Film-coated tablet Oral use Pangamox 250/62.5mg Powder for oral

suspension Oral use

Pangamox 500/125mg Powder for oral suspension

Oral use

Laboratorios Beecham, S.A. P.T.M.- C/Severo Ochoa, 228760 Tres Cantos (Madrid). Pangamox 875/125 mg Powder for oral

suspension Oral use

Clavepen 500/125mg Film-coated tablet Oral use Clavumox 500/125mg Film-coated tablet Oral use Clavumox 875/125 mg Film-coated tablet Oral use Clavumox 125/31.25mg/ 5ml Oral suspension Oral use 125mg : 31.25mg/

5ml Clavumox 250/62.5mg Powder for oral

suspension Oral use

Clavepen 500/125mg Powder for oral suspension

Oral use

Clavumox 500/125mg Powder for oral suspension

Oral use

Clavumox 875/125 mg Powder for oral suspension

Oral use

Allen Farmacéutica, S.A.P.T.M.- C/Severo Ochoa, 2 28760 Tres Cantos (Madrid).

Amoxicilina/Ác. Clavulanico ALLEN

875/125 mg Powder for oral suspension

Oral use

Sweden

Meda AB Box 906 170 09 Sverige (SWE)

Spektramox

250/125 mg (Amoxicillin: 250 mg)


18

Member State EU/EEA





Spektramox 500/125mg (Amoxicillin : 500 mg)


Spektramox 875/125 mg (Amoxicillin 875 mg)


Spektramox 125/31.25mg/ 5ml(Amoxicillin 25 mg/ml)



Spektramox 125/31.25mg (Amoxicillin: 125 mg)


Oral use

Spektramox 250/62.5mg/ 5ml (Amoxicillin: 50 mg/ml)


Oral use 250mg : 62.5 mg/ 5m

Sweden

Spektramox 400/57mg/ 5ml (Amoxicillin: 80 mg/ml)



Augmentin Intravenous 600mg & 1.2gm



Augmentin Intravenous 600mg & 1.2gm



Augmentin 375 mg Tablets 250/125mg Film-coated tablet

Oral use

Augmentin 375 mg dispersible tablets

250/125mg Dispersible tablets

Oral use

Augmentin 1 g Tablets 875/125 mg Film-coated tablet Oral use Augmentin 625 mg Tablets 500/125mg Film-coated tablet Oral use Augmentin 250/62 SF Suspension



United Kingdom

Beecham Group PLC SB House Great West Road Brentford Middlesex TW8 9GS United Kingdom

Augmentin 125/31 SF Sachet 125/31.25mg Powder for oral suspension

Oral use

19

Member State EU/EEA





Augmentin 125/31 SF Suspension



Augmentin Duo 200/28.5mg/ 5ml Powder for oral suspension


20

ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

PRESENTED BY THE EMEA

21

SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF AUGMENTIN AND ASSOCIATED NAMES (SEE ANNEX I) Augmentin is a well-established and widely-used antibacterial combination product consisting of the semi-synthetic antibiotic amoxicillin (as amoxicillin trihydrate) and the β-lactamase inhibitor clavulanic acid (as the potassium salt). Amoxicillin/clavulanic acid was originally developed in response to the need for an oral broad-spectrum antibiotic that covered β-lactamase-producing pathogens. Oral formulations of Augmentin have been available worldwide since 1981 and intravenous formulation since 1984. Over the years, the ratio of amoxicillin to clavulanic acid has been varied to reflect prescribing needs, to improve dosing convenience, and as a response to recommendations for the treatment of more severe infections or those caused by resistant organisms. Amoxicillin works by inhibiting the transpeptidase enzyme responsible for cross-linking peptidoglycan in the bacterial cell wall, weakening, the cell wall and making the cell swell and rupture. Because amoxicillin is readily hydrolysed by β-lactamase, Augmentin also contains the β-lactamase inhibitor, clavulanic acid, which protects amoxicillin from degradation and extends its antibacterial spectrum to many bacteria normally resistant to penicillins and cephalosporins. A wide range of different presentations of Augmentin with an increasing ratio of amoxicillin to clavulanic acid are approved for oral (2:1, 4:1, 7:1, 8:1, 14:1 and 16:1) and parenteral (5:1 and 10:1) use in adults and children. All EU approvals have been obtained via National registration; leading to a number of differences in the PI, particularly in the Indication and Posology sections and a referral was therefore triggered in order to resolve the divergences amongst the nationally authorised SPCs and thus to harmonise the SPCs across the EU. The MAH discussed and assessed a number of indications in light of the MAH Global Data Sheets (GDS), published data, literature, relevant studies and current clinical practice. The benefit/risk assessment for the series of formulations approved in different Member States was conducted with reference to the existing resistance patterns in those Member States where the product is marketed. The benefit/risk assessment conducted by the CHMP has not addressed the use of these products in other markets, where different resistance patterns may apply. The MAH provided rationales for the various formulations grouped according to amoxicillin/clavulanic acid ratios, irrespective of strengths and pharmaceutical forms within each of those ratios grouping. For sections 4.1 and 4.2 of the SPC, the proposed text for formulations with the same amoxicillin/clavulanic acid ratio is discussed in sequence, starting with the lowest ratio 2:1, via the highest oral ratio 16:1 to the intravenous (IV) ratio 10:1. For other sections of the SPC and the PL, the proposed text is applicable to all formulations, irrespective of the ratio, except when clearly stated. During the evaluation, outstanding issues were identified, to be addressed by the MAH. 2.1 Critical Evaluation Section 4.1 –Therapeutic indications Prior to harmonisation, at start of procedure, the indications for the various ratios were grouped as follows:

• Lower-ratio oral presentations (2:1, 4:1, and 7:1), authorised broadly for the same set of indications.

• Two intravenous ratios (5:1 and 10:1), authorised for the same set of indications. • Augmentin ES (Extra Strength) and Sustained Release (SR), developed to meet specific

clinical needs related to the occurrence of resistant pathogens. This set of indications differs from that for the lower ratio formulations.

• The 8:1 ratio formulations, for general use in the renally-normal population, approved in France only, and associated with their own set of indications.

22

THERAPEUTIC INDICATIONS COMMON TO SEVERAL AUGMENTIN RATIOS: Tonsilitis The MAH acknowledged that Augmentin is not the first drug of choice for the treatment of acute streptococcal tonsillitis, however it is recommended as a possible alternative for the treatment of patients who have multiple recurrent episodes of streptococcal tonsillitis because Augmentin has been shown to yield high rates of eradication of streptococci from the nasopharynx. The MAH therefore considered that Augmentin is an effective treatment for recurrent tonsillitis, as it is effective and widely used for upper respiratory tract infections in general, plus it is active against Gram-positive and Gram-negative cocci and anaearobes. In addition, clavulanic acid protects amoxicillin from inactivation in cases where infections may be polymicrobial or when β-lactamase-producing non-pathogens may be present. The CHMP noted that tonsillitis/pharyngitis and uncomplicated sinusitis are often viral in origin, and when due to bacteria, the most common pathogen is S. pyogenes, which is always susceptible to penicillin, to be treated with amoxicillin alone or with penicillin. Treatment of recurrent tonsillitis with Augmentin is based on the assumption that betalactamases of other bacteria of the oral cavity excrete their betalactamse in the environment and so inactivate unprotected penicillins. The CHMP agreed that the available evidence for this indication is not sufficient unless supported by clinical data and deleted this indication for all formulations. Septicaemia The CHMP requested the withdrawal of the septicaemia indication in general, since the focus of septicaemia has to be treated sufficiently and therefore this indication is not acceptable. The MAH agreed to the withdrawal of the septicaemia indication from of all the oral and parental formulations SPCs. THERAPEUTIC INDICATIONS COMMON TO AUGMENTIN 2:1, 4:1, 7:1 AND 8:1 RATIO (ORAL) The MAH proposed the same indications for the 2:1, 4:1, 7:1 and 8:1 ratios and these are discussed in common. Equivalence of the different dosing regimens has been confirmed by randomised clinical trials in adults in several community acquired infections and paediatrics. Genito-Urinary tract infections The CHMP concluded that this general indication is not acceptable as neither amoxicillin/clavulanic acid nor amoxicillin are currently indicated for the treatment of diseases caused by N. gonorrhoeae. After assessment of the MAH responses, the CHMP agreed that Augmentin is a suitable drug for the claimed indications cystitis and pyelonephritis. Although many pathogens important for urinary tract infections exhibit resistance rates of > 10% towards Augmentin, it is considered a suitable alternative, as all antimicrobial agents with this indication share the problem and the choice of the agent depends on the patient and epidemiological situation. The CHMP adopted the indications “Cystitis” and “Pyelopnephritis”. Intra-abdominal sepsis Amoxicillin/clavulanic acid is not recommended for intra-abdominal sepsis. Empirical antibacterial therapy must provide broad-spectrum coverage of both aerobic and anaerobic pathogens. Augmentin has the appropriate PK/PD that would predict clinical efficacy against Gram-positive and many Gram-negative pathogens including anaerobic pathogens, and penetrates well into the peritoneum. These features make it an appropriate antibiotic for intra-abdominal infections. The CHMP endorsed the MAH data and rationale, especially the polymicrobial nature of intra-abdominal infections and the recent use of Augmentin in controlled trials support the use of Augmentin for both initial empirical IV treatment and continued oral treatment after switch from IV treatment. This is further supported by several Guidance documents and the CHMP adopted the indication: “Intra-abdominal infections” for the IV Augmentin formulations. Upper Respiratory Tract Infections The CHMP noted the clinical trials comparing the efficacy of the different dosing regimens of amoxicillin/clavulanic acid in recurrent tonsillitis and that a number of national guidelines

23

recommend Augmentin or penicillin + betalactams inhibitor as first line therapy for acute otitis media (AOM), usually a bacterial super-infection, with purulent or micropurulent middle ear fluid. In adults, AOM is rare but the bacteria involved are the same as in children and the therapeutic choices do not differ. A recommended therapy is amoxicillin/clavulanic acid, especially if no bacteriological markers are available. For infections other than acute media otitis, initial antibiotic therapy is not usually recommended. Overall, the indication is well-established and the CHMP concluded that the indication should be limited to “acute otitis media”. Lower Respiratory Tract Infections and Acute Bronchitis According to guidelines, antibiotic treatment should be considered in patients with LRTI in the following situations: suspected or definite pneumonia, selected exacerbations of chronic obstructive pulmonary disease, patients aged > 75 years and fever, cardiac failure, diabetes mellitus and serious neurological disorder. These indications are approved in all EU countries and Augmentin is accepted as an effective treatment in several national guidelines. For acute bronchitis in children, guidelines state that in the average patient with an uncomplicated LRTI in primary care, not suspected of pneumonia, antibiotic treatment has shown no benefit over placebo. A Cochrane review concluded that antibiotic treatment in patients with acute bronchitis had a modest beneficial effect not outweighing the side-effects of treatment. The CHMP considered that most acute bronchitis are of viral aetiology and the systematic need for antibiotic treatment is questionable. The MAH agreed to withdraw the indication acute bronchitis, as the wording “Acute exacerbations of chronic bronchitis (adequately diagnosed)” reflects the indication more adequately. Skin and Soft Tissue Infections The CHMP noted that amoxicillin/clavulanic acid has been evaluated in uncomplicated skin and soft tissue infections, including conditions such as wound infection, abscess, cellulitis, furunculosis and impetigo. Various comparative and non-comparative studies have been conducted in SSTIs including adults and children. Regarding cellulitis, the CHMP considered that therapy for the typical case of erysipelas or cellulitis should include an antibiotic active against streptococci and therefore considered that amoxicillin/clavulanic acid can be an alternative for the treatment of uncomplicated SSTI. For animal bites, the administration of oral or parenteral antibiotics depends on the depth and severity of the wound and on the time since the bite occurred. The CHMP agrees that amoxicillin/clavulanic acid is widely used as first-line therapy for the treatment of animal bites and therefore adopted the following wording: “Skin and soft tissue infections in particular cellulitis, animal bites and severe dental abscess with spreading cellulitis” Bone and joint infections Bone infections represent a diagnostic or therapeutic challenge as numerous exogenous and endogenous factors contribute to the onset of bone/joint infection. The MAH did not submit any data supporting this indication but proposed to re-classify this indication as osteomyelitis, providing an extensive justification, along with a discussion on PK/PD. Data on a few hundreds of patients and a summary of the clinical data in support of the treatment of osteomyelitis were provided. Safety data indicates that prolonged administration does not increase the incidence and severity of side effects compared to shorter therapeutic courses. There is no consensus on the appropriate treatment duration, as other factors such as the extent of infection, type of pathogen, clinical response, and presence of underlying risk factors are important considerations but the current SPCs only stipulate that patients on extended therapy beyond 14 days should be closely monitored. The MAH concluded that Augmentin therapy for osteomyelitis should be initially parenteral, followed by a switch to oral. Augmentin is considered suitable for the treatment of osteomyelitis as it has appropriate PK/PD properties, provides efficacy against MSSA, Gram-negative (susceptible isolates) and also anaerobic cover for polymicrobial infections. The IV and oral formulations facilitate switch or sequential therapy from initial intravenous therapy to subsequent oral treatment. The CHMP acknowledged the arguments and agreed that Augmentin is suitable for this indication. The CHMP adopted the following indication: “Bone and joint infections, in particular osteomyelitis.”

24

The discussion also focused on treatment duration and the CHMP agreed to amend Section 4.2 of the SPC. The CHMP adopted the following wording: “The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review. See also section 4.4 regarding prolonged therapy.” THERAPEUTIC INDICATIONS FOR AUGMENTIN 2:1 RATIO (ORAL) The 2:1 ratio has become a well-established dosing regimen in many countries, and has been the subject of numerous clinical studies, many of them by independent research groups and individuals. The data is largely from the extensive published literature and includes comparative data with other antibacterial agents in a range of infections for which Augmentin is indicated. The MAH provided a review of the currently authorised indications, and discussed each group of indications, referring to clinical development, studies and guidelines. The major indications discussed for the 2:1 Augmentin ratio included genito-urinary tract infections, RTIs, and SSTIs. The MAH also discussed the PK/PD of the 2:1 ratio, stating that time above minimum inhibitory concentration (T>MIC) is a determinant of efficacy for β-lactam antibacterials. The CHMP considered the indications for the 2:1 ratio in light of the increasing resistance spectrum of the causative agents and the risk of underdosing in the treatment of bacteria with higher MIC values and resistance development. The pattern of evolution of penicillin non-susceptible strains and the current rates of resistance differ widely across Europe and resistance rates have also changed through time. In addition, the number of intermediate penicillin susceptibility strains should also be considered, creating a need for high concentrations of amoxicillin. In contrast, in some countries, the level of PRSPs has not changed through time, where the non-susceptibility trends of S. pneumoniae from community-acquired respiratory tract infections and from bacteraemias demonstrated no evidence of an increase in non-susceptibility over time. This suggests that the lower doses of amoxicillin as used in some currently-approved regimens are appropriate. The MAH concluded that the PK/PD data supports the continued use of 2:1 oral formulation and that it continues to be active for many pathogens. In proposing a series of harmonised indications treatable using the 2:1 and 4:1 ratios, the MAH has taken into consideration clinical data, T>MIC values, local and national guidelines, and publications in peer-reviewed journals. The various ratios provide the prescriber with a degree of choice for treating infections, depending on the nature of the infection, relevant patient factors and also the local or regional susceptibility of the probable pathogens. The time above minimum inhibitory concentration (T>MIC) is one of the major determinants of efficacy for β-lactam antibacterials. This has been shown in in-vitro studies, in-vivo in numerous animal models, and has been confirmed by clinical trial data. Resistance to amoxicillin in S. pneumoniae is currently low in a number of Member States, with the majority of MICs ≤ 1 µg/mL. PK/PD analyses predict that the 2:1 Augmentin oral formulation (250/125mg) TID would achieve maximum eradication against S. pneumoniae strains with amoxicillin or amoxicillin/clavulanic acid MICs of ≤1 µg/mL whereas the 4:1 ratio (500/125mg) TID would be effective against strains with MICs of ≤ 2µg/mL. The published amoxicillin PK/PD data therefore support the continuing effectiveness against many pathogens of the 250/125mg (2:1) TID and 500/125mg (4:1) TID Augmentin oral formulations. In addition, only a very small concentration of clavulanic acid (0.12mg/l) is needed to restore susceptibility of these isolates to amoxicillin. The unit dose of clavulanic acid (125mg) for the 2:1 and 4:1 formulations is the same as the other oral Augmentin formulations, this concentration being sufficient to inhibit the target β-lactamases. Hence, the daily dose of clavulanic acid will depend upon the frequency of administration and not the formulation. The MAH concluded that all available scientific evidence, clinical data, T>MIC values, guidelines and publications demonstrate that the Augmentin 2:1 and 4:1 ratios are efficacious in a wide range of indications, and provide the appropriate clinical cover against the key pathogens implicated in these infections. The availability of the 2:1 ratio continues to provide clinicians with a valuable broad-spectrum antibiotic suitable for

25

treatment of a variety of bacterial infections in adults and paediatrics, particularly in areas with low resistance levels where the target organisms remain susceptible to this ratio. Similarly the 4:1 ratio is a well-established regimen, providing a valuable option for treatment of mild-to-moderate as well as more severe infections, in areas where bacterial resistance is not a significant concern. The CHMP considered that due to the known adverse effects of clavulanic acid and the PK/PD profile of this ß-lactamase inhibitor, a dose of 125 mg three times daily should not be exceeded. Thus, the maximum daily dose of amoxicillin delivered with the 2:1 ratio is 750 mg. According to the data, this daily dose is only suitable for pathogens with a MIC90 of < 1 µg/mL, i.e. pathogens where time over MIC is > 40%. Therefore, the 2:1 ratio is appropriate for areas that do not currently have major problems with penicillin-insusceptible pneumococci. The CHMP expressed concern regarding the potential for future DCP/MRP procedures in which Member States that do not have the 2:1 ratio and which have problems with penicillin-insusceptible pneumococci might be asked to approve them. In order to pre-empt this situation the CHMP stated that: “Not all the possible presentations of Augmentin suitable for use in all EU countries. The choice of presentations used in any one EU MS needs to be tailored to the prevalence of certain types of bacterial resistance, which is very variable between EU countries and will inevitably change over time. Therefore any future applications for marketing authorisation for Augmentin presentations should be supported by a discussion of the appropriateness of those specific presentations for the selected Concerned Member States. In particular, to discuss the prevalence of penicillin-insusceptible pneumococci across the CMS and the adequacy of the amoxicillin dose delivered by candidate presentations to treat these organisms. For example, the 250/125 mg tablets are not suitable for use in any EU Member State in which penicillin-insusceptible or penicillin-resistant Streptococcus pneumoniae occur commonly. This is because the daily dose of amoxicillin delivered by this presentation (750 mg) is insufficient to treat these bacteria. Also, achieving higher daily doses of amoxicillin by doubling the number of 250/125 mg tablets given daily is not recommended since this would result in administration of unnecessarily high doses of clavulanic acid. Therefore an alternative presentation of Augmentin should be selected.” The CHMP also considered the discussion on the indications commonly to the 2:1, 4:1, 7:1 and 8:1 ratios and the following harmonised wording for the harmonised SPCs was agreed and adopted by the CHMP: • Acute bacterial sinusitis (adequately diagnosed) • Cystitis • Pyelonephritis • Cellulitis • Animal bites • Severe dental abscess with spreading cellulitis. THERAPEUTIC INDICATIONS FOR AUGMENTIN 4:1 RATIO (ORAL) To date the 4:1 ratio has been approved widely in Europe and the approval in 1984 of the TID dosage was supported by clinical studies in paediatric and adult patients. The MAH stated the currently approved indications and discussed in particular the indications in genito-urinary tract, abdominal infections, respiratory tract infections and skin and soft tissue Infections (SSTIs), citing numerous clinical studies and guidelines recommending the use of the 4:1 ratio. The MAH concluded that treatment with Augmentin 4:1 is supported for the requested indications, providing patients and prescribers with a valuable option for treatment of mild-to-moderate as well as more severe infections, in areas where bacterial resistance is not considered to be a significant concern. The MAH discussed the arguments presented for the 2:1 ratio, considering the 4:1 ratio oral formulations to be active for many pathogens, and that its use is justified.

26

The CHMP agreed with the main conclusion drawn by the MAH, however new studies comparing the efficacy of the 4:1 and 8:1 ratio showed a clear inferiority of the 4:1 ratio, when bacteria with higher MIC values were the causative agents. For the indications already discussed for the 2:1 ratio, the only difference is an increased amoxicillin dose of 0.5 g TID (adults). This increase in amoxicillin dose clearly makes this ratio more suitable than the 2:1 ratio and this ratio might be appropriate for some indications in at least some areas. The biggest problem is huge regional even local differences across Europe and within countries. The MAH provided a common discussion on the rationale for use of Augmentin 2:1 and 4:1. The 4:1 ratio was further discussed by CHMP, noting that the maximum daily dose of amoxicillin delivered is 1500 mg. According to the data presented by the MAH, this daily dose is only suitable for pathogens with a MIC90 of < 2 µg/mL, i.e. only in these pathogens the required time over MIC is > 40%. Thus the 4:1 ratio is considered ineffective against penicillin-resistant S. pneumoniae. The CHMP also considered the discussion on the indications commonly to the 2:1, 4:1, 7:1 and 8:1 ratios and the following harmonised wording for the harmonised SPCs was agreed and adopted by the CHMP:

• Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis. • Bone and joint infections, in particular osteomyelitis.

THERAPEUTIC INDICATIONS FOR AUGMENTIN 7:1 RATIO (ORAL) The 7:1 ratio was developed for BID dosing to improve convenience and therefore compliance with the original lower-ratio TID regimens, because of the inconvenience associated with the mid-day dose and also because BID had become more of a standard regimen than TID. The ratio was approved in the 1990s. For both the adult and paediatric suspension, the unit dose of clavulanic acid remains unchanged, but is now given BID instead of TID; this remains sufficient to protect amoxicillin from the action of beta-lactamases. The MAH listed the currently approved indications, discussing in particular its use in SSTIs and recurrent tonsillitis, otitis media, sinusitis, LRTIs and UTIs, as well as URTIs and genito-urinary tract infections, and discussed the PK/PD, demonstrating the bacteriological equivalence of the BID and TID formulations. The MAH considered the 7:1 ratio as well established in clinical practice, and listed guidelines recommending Augmentin, concluding that the availability of the 7:1 ratio provides clinicians with a valuable broad-spectrum antibiotic suitable for the treatment of a variety of bacterial infections in adults and paediatrics. The indications are supported by clinical data, T>MIC values, and publications in peer-reviewed journals. The CHMP also considered the discussion on the indications commonly to the 2:1, 4:1, 7:1 and 8:1 ratios and the following harmonised wording for the harmonised SPCs was agreed and adopted by the CHMP: • Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis.

27

• Bone and joint infections, in particular osteomyelitis. THERAPEUTIC INDICATION FOR AUGMENTIN 8:1 RATIO (ORAL) The 8:1 Augmentin ratio was licensed in 1990, developed in response to concerns over the increasing prevalence of resistant S. pneumoniae strains in France, particularly amongst young children with acute otitis media. At the time, the Augmentin 4:1 ratio was widely used for treating infections in children. The lower dose of amoxicillin contained in the 4:1 ratio was considered insufficient to achieve the required MIC levels of amoxicillin to eradicate S. pneumoniae strains with reduced susceptibility to penicillin. The MAH listed the currently approved indications and discussed data from clinical trials in paediatric patients and adults in the treatment of otitis media and UTIs, demonstrating the bioequivalence of the 8:1 adult regimen to the 8:1 paediatric regimen and the efficacy of the 8:1 ratio BID in adults; consequently this regimen has now become well established in France for the treatment of respiratory tract infections in adults, including CAP, AECB, acute bronchitis, AOM and sinusitis. The MAH also listed a number of published studies and discussed other indications, such as skin and soft tissue infections (SSTI), bone and joint infections, abdominal infection, pelvic inflammatory disease, UTI and dental infections. Finally, the MAH discussed the PK/PD of the 8:1 ratio, stating that the steady-state mean T>MIC values predict that this formulation given TID achieves maximum eradication against S. pneumoniae strains with amoxicillin or amoxicillin/clavulanic acid MICs of ≤2µg/mL and is to have some efficacy against strains with MICs of 4µg/mL. For severe infections, and for pathogens with higher MICs, the 8:1 ratio is active for many of the intended pathogens. The MAH concluded that the 8:1 ratio would be more appropriate than the 4:1 ratio for the treatment of certain infections and in vivo results support the PK/PD prediction that Augmentin 8:1 will be efficacious against infections caused by S. pneumoniae with high amoxicillin MICs (2-4µg/mL). The CHMP concluded that the 8:1 ratio is comparable to the 7:1 ratio in terms of efficacy and safety data. The CHMP also considered the discussion on the indications commonly to the 2:1, 4:1, 7:1 and 8:1 ratios and the following harmonised wording for the harmonised SPCs was agreed and adopted by the CHMP:

• Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis. • Bone and joint infections, in particular osteomyelitis.

THERAPEUTIC INDICATIONS FOR AUGMENTIN 14:1 RATIO (ORAL - ES) Augmentin ES (extra strength), paediatric suspension, was developed using clinical studies in AOM (Acute Otitis Media) and PK/PD data from animal models, to provide improved eradication of Penicillin resistant S. pneumoniae (PRSPs) with penicillin MICs up to and including 4µg/mL. This ratio met a medical need established in treatment guidelines, which recommended increased dosages of amoxicillin for the treatment of respiratory tract infections, particularly in areas with high prevalence of resistant S. pneumoniae, particularly PRSPs. The MAH listed the currently approved indications and discussed respiratory tract infections (RTIs), AOM, community acquired pneumonia (CAP), tonsillo-pharyngitis and sinusitis, skin and soft tissue infections (SSTI) and urinary tract infections (UTI). The MAH agreed to withdraw the indication SSTI and tonsillopharyngitis, as well as the initially proposed indication UTI.

28

The development of Augmentin ES (14:1) was based on PK/PD data as well as clinical efficacy and safety studies, providing an increased dose of amoxicillin twice daily, while retaining the same dose of clavulanic acid as in existing Augmentin 7:1 ratio. The MAH considered the indications supported by clinical, PK/PD data and publications, and thus adequate for this ratio. The CHMP noted that Augmentin ES was studied for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. Due to such drug-resistant pathogens, this high-dose formulation could be acceptable for treatment of CAP. However, because no supporting documentation was provided in support of indications other than AOM and CAP, the remaining indications should be deleted. The MAH acknowledged that the Phase III programme studied only AOM and that the other indications including CAP, ABS and SSTI were extrapolated based on PK/PD principles, as results from AOM studies have shown that the PK/PD concept is predictive for clinical outcome. The MAH provided extensive justifications to retain the indication acute bacterial sinusitis (ABS). The CHMP concluded that due to the lack of efficacy data, bridging from efficacy in AOM to ABS it not supported. Regarding CAP, the 14:1 ratio is considered to appropriately cover PRSP. While there are no clinical data on the efficacy in CAP in children, it is considered possible to extrapolate from experience in adults. It was also considered that use of Augmentin should be restricted to indications where both components are needed. As Augmentin ES was studied in the treatment of penicillin-resistant S. pneumoniae, a statement was retained to advise prescribers that this ratio is appropriate for use in treating infections that are caused, or suspected to be caused, by penicillin-resistant S. pneumoniae. In summary, the following harmonised wording for inclusion in the harmonised SPCs was agreed and adopted by the CHMP: “Augmentin is indicated for the treatment of the following infections in children aged at least 3 months and less than 40 kg body weight, caused or thought likely to be caused by penicillin-resistant Streptococcus pneumoniae (see sections 4.2, 4.4 and 5.1): • Acute otitis media • Community acquired pneumonia. THERAPEUTIC INDICATIONS FOR AUGMENTIN 16:1 RATIO (ORAL - SR) Following the launch of Augmentin TID and BID regimens, resistance to penicillins in respiratory tract pathogens has generally increased significantly. Many guidelines for indications such as CAP and ABRS therefore recommended higher doses of amoxicillin to ensure that the eradication of infections caused by resistant pathogens continues and the potential for spread is reduced. Augmentin SR (Sustained-Release) was therefore developed to meet this new medical need. Augmentin SR is a pharmacokinetically-enhanced formulation, developed to maximise PK/PD and to provide more effective therapy against pathogens with reduced susceptibility to amoxicillin and penicillin, particularly S. pneumoniae. The tablet has one immediate-release amoxicillin trihydrate (562.5mg) and clavulanic acid (62.5mg) layer, and one sustained-release sodium amoxicillin (437.5mg) layer. The PK of the clavulanic acid components are the same as the conventional Augmentin formulations. The MAH listed the currently approved indications for Augmentin SR and discussed a number of indications in detail, as well as the PK/PD, stating that in vivo data supports the efficacy of Augmentin SR against infections caused by S. pneumoniae with high amoxicillin MICs (4-8µg/mL). The MAH considered that the Phase III results confirm the predicted efficacy of Augmentin SR in the clinical setting and cited a number of guidelines establishing Augmentin SR in clinical practice. The CHMP noted that PK/PD principles were applied to the development of this ratio but that no true PK/PD analysis has been performed in the clinical database. The MAH responded that Augmentin SR was developed to address an unmet medical need (eradication of penicillin resistant S. pneumoniae with penicillin MICs ≥2 µg/ml in RTI) and that the clinical development programme included PK studies to assess the enhanced PD properties. The data reviewed demonstrates the clinical benefits of the SR formulation, forming the scientific basis for authorisation of the current national licences for Augmentin SR. The MAH provided a comprehensive summary of the key studies evaluated and

29

further justifications and data to support the indication in CAP, ABS and acute exacerbations of chronic bronchitis (AECB). The MAH concluded that Augmentin SR demonstrates bacteriological and clinical efficacy against susceptible and resistant key respiratory pathogens when used empirically. The drug has been shown to be extremely useful in areas with high incidence of amoxicillin- or multi-drug resistant S. pneumoniae and in selected patients (i.e. with S. pneumoniae isolates having amoxicillin+/- clavulanic acid MICs up to and including 4µg/mL). The CHMP acknowledged the scientific rationale and the theoretical PK/PD consideration behind the development of this formulation and that it is exclusively intended to treat infections caused by PRSP. The indication in community acquired pneumonia (CAP) is supported but the indications for ABS and AECB required further discussion. It was noted that the recommended posology for the 16:1 ratio is a daily dose of 4g amoxicillin and 250 mg clavulanic acid, resulting in serum concentrations effective even against PRSP. Thus the 16:1 ratio should be effective in all indications where efficacy of the other formulations has been shown. However, as the clinical trial data is mainly restricted to data in patients with CAP in the presence of co-morbidities, the CHMP restricted the indication to CAP. In addition, the use of Augmentin should be restricted to indications where both components are needed. As Augmentin SR was developed, clinically tested and approved for treatment of PRSP, a statement was retained to advise prescribers that these formulations are appropriate for use in treating infections that are caused, or suspected to be caused, by penicillin-resistant S. pneumoniae. In summary, the following harmonised wording for inclusion in the harmonised SPCs was agreed and adopted by the CHMP: “Augmentin is indicated for the treatment of community-acquired pneumonia in adults and adolescents aged at least 16 years, caused or thought likely to be caused by penicillin-resistant Streptococcus pneumoniae (see section 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.” THERAPEUTIC INDICATIONS FOR INTRAVENOUS AUGMENTIN 5:1 AND 10:1 RATIOS Intravenous Augmentin is indicated for treatment of infections that are considered to require parenteral therapy because of the seriousness of the infection, or where the patient is unable to tolerate oral therapy. Two intravenous ratios have been developed: a 5:1 and a 10:1 formulation. These two ratios allow flexibility of the amoxicillin dosage, whilst delivering an appropriate clavulanic acid unit dose. The MAH provided comparative and non-comparative clinical studies establishing safety and efficacy and listed the studied indications. The studies suggested that a dose of 1.2g (1000/200 mg; 5:1 ratio) TID was generally adequate for treatment and that in many cases, IV treatment was followed by oral therapy. The MAH provided a large body of data supporting the use of IV Augmentin, including studies and review articles confirming the efficacy of both IV and sequential IV/oral Augmentin therapy in the treatment of LRTIs. The CHMP generally agreed with the MAH conclusion, but further discussed the indications in LRTIs, URTIs, UTIs, gynaecological infections, SSTIs, bone and joint infections and the prophylaxis of surgical infections and agreed and adopted the following harmonised wording for inclusion in the harmonised SPCs: • Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections,

epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms) • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis • Bone and joint infections, in particular osteomyelitis

30

• Intra-abdominal infections • Female genital infections. Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the: • Gastrointestinal tract • Pelvic cavity • Head and neck • Biliary tract surgery. Section 4.2 - Posology and method of administration The several Augmentin formulations differing in terms of ratio of amoxicillin to clavulanic acid allow the prescriber to vary the dose of each component independently and the convenience of a combined tablet or injection. The rationale has been to maintain a fixed dose of clavulanic acid for each Augmentin dose, whilst varying the quantity of amoxicillin according to the severity of infection, the site of infection (and hence likely range of pathogens) and the local pattern of amoxicillin/clavulanic acid susceptibility of the likely pathogens. In order to provide harmonised dosing recommendations for all countries, a standard dosage and higher dosage are proposed for each formulation, for both adults and children. A higher regimen may be appropriate in some indications, and in regions with higher prevalence of resistant organisms, even if the infection is not categorised as ‘severe’. Hence, when considering the appropriate total daily dose of amoxicillin for the varying severity of infection, there is some overlap in the recommendations, allowing the prescriber to choose the most suited dosing regimen to the individual patient’s needs (including age, weight and renal function). The paediatric recommendations have been harmonised according to weight ranges rather than age, with the sole exception of a lower age limit for very young patients. The recommendations for dosing patients with reduced renal and hepatic function have also been simplified and harmonised. Statements were also added for formulations containing 125 mg clavulanic acid per dose, stating that if a higher daily dose of amoxicillin is required, it is recommended to use another ratio of Augmentin to avoid administration of unnecessarily high daily doses of clavulanic acid. All discussions specific to a particular Augmentin ratio are reflected below. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 2:1 RATIO (ORAL) This ratio is not recommended for use in children less than six years of age. In adults, the higher dosage is recommended for severe infections, including chronic and recurrent UTIs and LRTIs. In children, the higher dosage is recommended for infections such as otitis media, sinusitis, LRTIs and UTIs. The CHMP agreed on dosing recommendations based on weight ranges in the paediatric population, as well as the proposal for the different dosing regimens taking into account the argument that “the choice of dosage regimen is determined by the prevailing background level of resistance, and also by factors such as the severity of infection”. However, in view of the results of the most recent studies, the CHMP included a statement that the lower dosage regimens (2:1 and 4:1) are not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. The section on daily dose was revised and the readability was improved. The posology text was revised, providing dosing guidance for the use of Augmentin suspension in children over 6 years and less than 40 kg. The CHMP also differentiated between the 2:1 tablets (and dispersible tablets) and the powder for oral suspension. The lower limit for the tablets is 40 kg bodyweight based on the minimum dose (250/125 mg TID) whereas the lower limit for the age is restricted to 6 years, based on currently approved 2:1 formulations. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 4:1 RATIO (ORAL)

31

No clinical data are available on doses higher than 40/10 mg/kg/day in children under 2 years. In adults, the higher dosage is recommended for severe infections, including chronic and recurrent urinary tract infections and lower respiratory tract infections. In children, the higher dosage is recommended for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections. Overall, the CHMP agreed to dosing recommendations according to weight ranges in the paediatric population, as well as the proposal for the different dosing regimens taking into account the argument that “the choice of dosage regimen is determined by the prevailing background level of resistance, and also (in some Member States) by factors such as the severity of infection”. However, in view of the results of the most recent studies, the CHMP included a statement that the lower dosage regimens (2:1 and 4:1) are not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. The section on daily dose was revised and the readability was improved. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 7:1 RATIO (ORAL) No clinical data are available on doses higher than 45/6.4 mg/kg/day in children under 2 years and dosing recommendations in this population can therefore not be made. In adults, the higher dose is recommended for severe infections, including chronic and recurrent urinary tract infections and lower respiratory tract infections. In children, the higher dosage is recommended for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections. Overall, the CHMP agreed and added a statement reflecting the regimen proposed in terms of PK/PD reasoning and prevalence of resistance across Europe. The text on daily dose was revised and the redability was improved. The available data supporting the BID and TID regimens was reflected and the BID regimen was stated as the standard dose while the TID regimen was mentioned as the higher dose particularly for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections, allowing the prescriber the flexibility to choose the most appropriate dosing regimen based on clinical and local/regional factors. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 8:1 RATIO (ORAL) There is no clinical data for children under 1 month of age. Dosing recommendations in this population can therefore not be made. In adults, the higher dosage is recommended for severe infections, including chronic and recurrent urinary tract infections and lower respiratory tract infections. In children aged one month and older, the higher dosage is recommended for more severe infections. The CHMP recommended the withdrawal of the recommendation to double the 2:1 and 4:1 ratio regimens in preference for using the higher ratio of amoxicillin to clavulanic acid formulations such as the 7:1 and 8:1 ratios. Data are lacking to support a specific mention of an acceptable maximal daily dose of clavulanic acid. As a daily dose of 375 mg is considered to sufficiently inhibit the sensitive beta-lactamases, the proposed statement was considered to better reflect the situation than mentioning of a maximum daily dose. The CHMP agreed, as it should result in a standard daily dose of clavulanic acid for all formulations with 125 mg clavulanic acid per dose. This standard daily dose should not be exceeded, and is in fact a maximum daily dose contributing to the safe use of Augmentin. The standard dose is TID and the CHMP restricted the lower dose to SSTI and non-severe sinusitis. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 14:1 RATIO (ORAL - ES) The Augmentin 14:1 ratio was specifically developed for use in children (weighing less than 40kg) where higher concentrations of amoxicillin are required, but with the same unit dose of clavulanic acid. Dosing recommendations for Augmentin ES are supported by clinical safety and efficacy data in AOM. Augmentin ES suspension is recommended for dosing at 90/6.4 mg/kg/day in two divided doses at 12-hourly intervals for 10 days. There are no clinical data on amoxicillin/clavulanic acid in children under 3 months of age.

32

POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 16:1 RATIO (ORAL - SR) The Augmentin 16:1 ratio was developed for, and studied in, specific indications in adults and adolescents aged 16 years and above, where higher concentrations of amoxicillin to clavulanic acid are required. Dosing recommendations for Augmentin SR are supported by extensive clinical safety and efficacy data. Augmentin SR plays an important role in the management of infections, particularly in countries and local areas of high levels of S. pneumoniae resistance. The MAH discussed the dosing regimen and stated that the mechanism of inhibition of bacterial β-lactamases by clavulanic acid is different from that of amoxicillin: whereas amoxicillin is a highly bactericidal agent that acts by binding to one or more of the penicillin-binding proteins (PBPs) involved in cell-wall synthesis, clavulanic acid is a competitive irreversible inhibitor of certain intracellular bacterial β-lactamases, and prevents these enzymes from inactivating amoxicillin. Thus, efficient eradication of β-lactamase-producing organisms by amoxicillin/clavulanic acid relies on effective initial inhibition of the β-lactamase by clavulanic acid. Furthermore, a post-β-lactamase inhibitor effect (PLIE) provides further support for the conclusion that the inhibitory effects of clavulanic acid against β-lactamases persists significantly once the clavulanic acid itself has effectively disappeared from the serum. The clinical studies in CAP and AECB further confirm the efficacy of Augmentin SR in treating infections due to beta-lactamase-producing H. influenzae and M. catarrhalis. The MAH considered that the available data confirms that the Augmentin SR regimen contains sufficient clavulanic acid to provide full protection from H. influenzae and M. catarrhalis beta-lactamase. The CHMP agreed that the dose of 125 mg clavulanic acid twice daily is considered appropriate to inhibit the beta-lactamases of H. influenzae and M. catarrhalis. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 5:1 RATIO (INTRAVENOUS) Surgical prophylaxis with Augmentin IV should aim to protect the patient for the period of risk of infection. Clear clinical signs of infection at operation will require a normal course of intravenous or oral therapy post-operatively. The CHMP agreed to remove the mention of addition of amoxicillin alone for the 5:1 ratio, as the 10:1 presentations provide a suitable alternative. The MAH proposed that a frequency of administration superior to three times a day (every 8 hours) is appropriate in some Member States depending on the type of infection or surgical procedure. The CHMP disagreed as the restriction to three times a day is based on the maximum dose for clavulanic acid which should not be exceeded without clear scientific evidence. The 12-hour dosing for the 5:1 ratio was revised for the treatment of infections, the majority of clinical studies evaluated a TID regimen. Additionally, a BID regimen of the 5:1 ratio in adults (≥40kg) would not provide the appropriate PK/PD and the pharmacokinetic parameters for a 1.2 g intravenous dose have not been determined. However, for 1.1 g amoxicillin/clavulanic acid given intravenously three times daily, T>MIC was present for 40% of the dosing interval for pathogens with an MIC of up to 4 µg/mL. A BID regimen would therefore probably not attain the required PK/PD target required to eradicate pathogens with higher MICs. Pathogens with higher MIC tend to be more prevalent in patients with more serious infections, and a BID IV regimen could potentially lead to poorer outcomes. Finally, the paediatric posology for the 5:1 ratio was revised as IV doses of clavulanic acid greater than 5 mg/kg are not recommended and Section 4.2 already contains texts advocating the use of different strengths where higher amoxicillin doses are needed. POSOLOGY AND METHOD OF ADMINISTRATION FOR AUGMENTIN 10:1 RATIO (INTRAVENOUS) Surgical prophylaxis with Augmentin IV should aim to protect the patient for the period of risk of infection. Clear clinical signs of infection at operation will require a normal course of intravenous or oral therapy post-operatively. Based on the argumentation to remove addition of amoxicillin alone for the 5:1 ratio, information was added on increasing the dose of clavulanic acid. The frequency of administration was revised, as it should not be greater than three times a day (every 8 hours), based on the maximum dose for clavulanic acid which should not be exceeded without clear scientific

33

evidence. In line with the previous discussion on 12-hour dosing, the CHMP changed the posology for the 10:1 IV ratio accordingly. ORAL SWITCH THERAPY The CHMP agreed with the MAH proposal to include wording in the SPC of several Augmentin formulations regarding the possibility to switch from IV to oral treatment for a number of indications but was of the opinion that switch from IV to oral therapy is not restricted to particular indications and should be an option for all indications. In addition, IV-to-oral switch therapy for Augmentin 14:1 (ES) and 16:1 (SR) was considered a valuable option for switch from IV treatment in infections where PRSP are, or are thought to be the causative agent and where oral continuation of Augmentin treatment is necessary. Therefore the following wording was adopted for all Augmentin IV formulations by the CHMP: “Treatment with Augmentin may be initiated by the use of an intravenous preparation and completed with an appropriate oral formulation as considered appropriate for the individual patient.” POSOLOGY IN SPECIAL PATIENT POPULATIONS For renal impairment, the published literature on the PK of amoxicillin and clavulanic acid, when administered to patients with renal impairment, indicates a decrease in the renal clearance of both drugs and that declining renal function has a greater influence on the clearance of amoxicillin than on that of clavulanic acid. The MAH considers that for treatment regimens using 7:1 and 8:1 ratios and 10:1 intravenous ratios, there are insufficient data on which to base a dosage recommendation for patients with severe renal impairment (<30 mL/min). Instead, prescribers are directed to use 4:1 ratio, where therapeutic levels of clavulanic acid in such cases have been detailed in the literature. The MAH also confirmed that the posology for the 4:1 ratio in patients with renal impairment is widely recommended across the EU. For hepatic impairment, there is insufficient data for dosage recommendations; prescribers are advised to dose with caution, and monitor hepatic function at regular intervals. A text was included in Section 4.4 for all formulations to reiterate that Augmentin should be used with caution in patients with hepatic impairement. Section 4.3 – Contraindications The contraindications section of the SPC defines those situations where the drug must not be administered to the patient for safety reasons. The contraindications discussed apply to all Augmentin ratios. In particular, the contraindications referring to mononucleosis, severe hepatic impairment or hepatic insufficiency, to the presence of aspartame in the oral suspension and hypersensitivity to amoxicillin, clavulanic acid or to any excipients were discussed. The CHMP considered a contraindication for all beta-lactams to be inappropriate and unnecessarily restrictive, potentially excluding the use of several beta-lactams in patients who could receive them safely. The following statements were agreed for the harmonised SPC to address this issue: “Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).” Section 4.4 - Special warnings and precautions for use This section contains detailed information of the conditions and special patient groups where Augmentin should be used with caution. For all formulations of Augmentin, the same warnings and precautions are applicable, apart from a number of formulation-specific statements, such as IV specific statements referring to the sodium and potassium content of Augmentin. In particular, data on

34

renal impairment, crystalluria and overgrowth of fungal infections and acute generalised exanthematous pustulosis (AGEP) was reviewed and proposals for a harmonised wording were made. The MAH also reviewed the additional statements present within the SPCs of some Member States. Most statements were either already covered by the proposed harmonised text, or lacked supportive evidence. Statements regarding the treatment of elderly patients (>60 years), the possible effect of amoxicillin on glucose tests, Glucose-Galactose Malapsorption and false-positive test results with the Platelia Aspergillus antigen test during treatment were discussed. In summary, a harmonised wording for inclusion in the harmonised SPCs was agreed and adopted by the CHMP. Section 4.5 - Interaction with other medicinal products, and other forms of interaction The interactions apply to all Augmentin ratios. Amoxicillin, like other beta-lactam antibiotics, is largely excreted renally and is not metabolised by CYP450 enzymes; clavulanic acid is partially metabolised by the liver and mostly excreted unchanged in the urine. Accordingly, metabolic drug interactions affecting the levels of either compound to a significant extent are unlikely to be of clinical significance. The CHMP noted the detailed literature search and analyses of available data carried out by the MAH, and agreed with the text on oral anticoagulants but requested the MAH to include a statement on the interaction with methotrexate. The CHMP agreed a text clearly stating that concomitant use of probenecid and Augmentin is not recommended. The scientific basis for inclusion of a statement on the interaction with oral contraceptives was assessed and there is a lack of evidence for an interaction between Augmentin and oral contraceptives. Section 4.6 - Pregnancy and lactation The information provided for this section applies to all Augmentin ratios. The CHMP noted the detailed analyses of the authorised texts and the wording proposed and in summary, the CHMP considered that the use of Augmentin should be avoided during pregnancy, unless considered essential by the physician and that amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. A harmonised wording was agreed by the CHMP for inclusion in the harmonised SPCs. Section 4.7 - Effects on ability to drive and use machines For all Augmentin ratios, the CHMP considered that undesirable effects may occur and included recommendations in the harmonised SPC.

Section 4.8 - Undesirable effects In recent years the MAH has developed a pro-active process for identifying safety signals, consisting of the ongoing review of important individual cases, the review of aggregate adverse event data through the use of disproportional analyses and the review of published medical literature. The CHMP requested that frequency data should be used in accordance with the SPC Guideline recommendations and recommended the use of an introduction describing the frequencies. The verbal statement of the frequencies should be in accordance to the updated QRD-Templates and the frequencies should be listed in a table. The CHMP adopted a harmonised text for this section. Section 4.9 - Overdose The CHMP recommended including the following in the harmonised SPC: “Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses.

35

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.” 5. PHARMACOLOGICAL PROPERTIES Section 5.1 - Pharmacodynamic properties This is a particularly important section for antibacterials. The MAH updated the Augmentin SPCs in line with the CHMP’s guidance on the development of antibacterial agents. Proposals were made for each sub-section (“Mode of Action” and “Mechanisms of resistance”, “PK/PD relationship” and “Breakpoints”). The EUCAST Breakpoints should be used exactly as written by EUCAST and the lists of pathogens for all formulations were also restricted to the pathogens important for the harmonised indications. The CHMP adopted the following sentence to state that Augmentin ES (14:1) and SR (16:1) ratios can be used to treat S. pneumoniae with decreased susceptibility to penicillin in the approved indications: “This presentation of amoxicillin/clavulanic acid is suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin in the approved indications only (see section 4.1).” Section 5.2 - Pharmacokinetic properties The MAH discussed the pharmacokinetic data for all the existing Augmentin formulations, grouped according to their respective ratios. The data forms the basis of the corresponding sections in the proposed harmonised SPCs. The ADME properties of amoxicillin and clavulanic acid, alone and in combination, were also summarised. The CHMP agreed to the MAH proposal. In summary, a harmonised wording for inclusion in the harmonised SPCs was agreed and adopted by the CHMP. Section 5.3 - Preclinical safety data The CHMP noted the MAH presentation and summary of the different available data of this section and agreed and adopted a harmonised text. 6. PHARMACEUTICAL PARTICULARS Sections 1, 2 and 3 are to be completed nationally. Similarly, Sections 6.1, 6.2, 6.3, 6.4 and 6.5 will also be completed nationally. For Section 6.6, there are “No special requirements” for disposal of surplus materials. PACKAGE LEAFLET AND USER TESTING The proposed changes mentioned for the SPCs were reflected adequately in the PLs, if relevant for the patients. A full PIQ review was also conducted and the PL was revised accordingly. The option of breaking Augmentin SR tablets for ease of swallowing was assessed and agreed upon. A full and comprehensive user testing of the PL was carried out, and the CHMP considered that the two legibility test reports provided, together with the bridging reports, are acceptable.

36

GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET Whereas - the scope of the referral was the harmonisation of the Summaries of Products Characteristics, labelling and package leaflet. - the Summaries of Products Characteristic, labelling and package leaflet proposed by the Marketing Authorisation Holders has been assessed based on the documentation submitted and the scientific discussion within the Committee, the CHMP has recommended the amendment of the Marketing Authorisations for which the Summary of Product Characteristics, labelling and package leaflet are set out in Annex III for Augmentin and associated names (see Annex I).

37

ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

Note: This SPC, labelling and package leaflet is the version valid at the time of Commission Decision.

After the Commission Decision the Member State Competent Authorities, in liaison with the

Reference Member State, will update the product information as required. Therefore, this SPC, labelling and package leaflet may not necessarily represent the current text

38

SUMMARY OF PRODUCT CHARACTERISTICS

39

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 250 mg/125 mg film-coated tablets} {Augmentin and associated names (see Annex I) 250 mg/125 mg dispersible tablets} {Augmentin and associated names (see Annex I) 125 mg/62.5 mg/5 ml powder for oral suspension} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM 250 mg/125 mg film-coated tablets Film-coated tablet. [To be completed nationally] 250 mg/125 mg dispersible tablets Dispersible tablet. [To be completed nationally] 125 mg/62.5 mg/5 ml powder for oral suspension Powder for oral suspension. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1). • Acute bacterial sinusitis (adequately diagnosed) • Cystitis • Pyelonephritis • Cellulitis • Animal bites • Severe dental abscess with spreading cellulitis. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below.

40

The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1). 250 mg/125 mg film-coated tablets, 250 mg/125 mg dispersible tablets For adults and children ≥ 40 kg, this formulation of Augmentin provides a total daily dose of 750 mg amoxicillin/375 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1). 125 mg/62.5 mg/5 ml powder for oral suspension For adults and children ≥ 40 kg, this formulation of Augmentin provides a total daily dose of 750 mg amoxicillin/375 mg clavulanic acid, when administered as recommended below. For children < 40 kg, this formulation of Augmentin provides a maximum daily dose of 720 mg amoxicillin/360 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1). Treatment should not be extended beyond 14 days without review. Adults and children ≥ 40 kg One 250 mg/125 mg tablet taken three times a day. Children < 40 kg 250 mg/125 mg film-coated tablets Augmentin 250 mg/125 mg film-coated tablets are not recommended in children < 40 kg. 250 mg/125 mg dispersible tablets Augmentin 250 mg/125 mg dispersible tablets are not recommended in children < 40 kg. 125 mg/62.5 mg/5 ml powder for oral suspension 9 mg/4.5 mg/kg/day to 18 mg/9 mg/kg/day given in three divided doses. Augmentin 125 mg/62.5 mg/5 ml powder for oral suspension is not recommended for use in patients aged less than 6 years. Elderly No dose adjustment is considered necessary. Renal impairment Dose adjustments are based on the maximum recommended level of amoxicillin. No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. Adults and children ≥ 40 kg CrCl: 10-30 ml/min 250 mg/125 mg twice daily CrCl < 10 ml /min 250 mg/125 mg once daily

41

Haemodialysis Two doses of 250 mg/125 mg every 24 hours, plus two doses of 250 mg/125 mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg In children < 40 kg with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 2:1 is not recommended, as no dose adjustments are available. In such patients, Augmentin formulations with an amoxicillin to clavulanic acid ratio of 4:1 are recommended. Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for oral use. Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. 250 mg/125 mg dispersible tablets Dispersible tablets should be stirred into a little water before taking. 125 mg/62.5 mg/5 ml powder for oral suspension Shake to loosen powder, add water as directed, invert and shake. Shake the bottle before each dose (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.

42

This presentation of Augmentin is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid (e.g. penicillin-insusceptible S. pneumoniae). Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

43

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods. 125 mg/62.5 mg/5 ml powder for oral suspension Augmentin 125 mg/62.5 mg/5 ml powder for oral suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. 125 mg/62.5 mg/5 ml powder for oral suspension This medicinal product contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see section 4.4 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.

44

Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility of sensitisation should be taken into account. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common

Overgrowth of non-susceptible organisms Not known Blood and lymphatic system disorders Reversible leucopenia (including neutropenia)

Rare

Thrombocytopenia Rare Reversible agranulocytosis Not known Haemolytic anaemia Not known Prolongation of bleeding time and prothrombin time1

Not known

Immune system disorders10

Angioneurotic oedema Not known Anaphylaxis Not known Serum sickness-like syndrome Not known Hypersensitivity vasculitis

Not known

Nervous system disorders Dizziness Uncommon Headache Uncommon Reversible hyperactivity Not known Convulsions2

Not known

45

Gastrointestinal disorders 250 mg/125 mg film-coated tablets 250 mg/125 mg dispersible tablets Diarrhoea Very common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known 125 mg/62.5 mg/5 ml powder for oral suspension Diarrhoea Common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known Tooth discolouration11

Not known

Hepatobiliary disorders Rises in AST and/or ALT5 Uncommon Hepatitis6 Not known Cholestatic jaundice6

Not known

Skin and subcutaneous tissue disorders 7 Skin rash Uncommon Pruritus Uncommon Urticaria Uncommon Erythema multiforme Rare Stevens-Johnson syndrome Not known Toxic epidermal necrolysis Not known Bullous exfoliative-dermatitis Not known Acute generalised exanthemous pustulosis (AGEP)9

Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4. 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 125 mg/62.5 mg/5 ml powder for oral suspension

11 Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.

46

4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4) Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02. Mode of action Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect. PK/PD relationship The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin. Mechanisms of resistance The two main mechanisms of resistance to amoxicillin/clavulanic acid are: • Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic

acid, including class B, C and D. • Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

47

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria. Breakpoints MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Organism Susceptibility Breakpoints (µg/ml) Susceptible Intermediate Resistant

Haemophilus influenzae1 ≤ 1 - > 1 Moraxella catarrhalis1 ≤ 1 - > 1 Staphylococcus aureus 2 ≤ 2 - > 2 Coagulase-negative staphylococci 2

≤ 0.25 > 0.25

Enterococcus1 ≤ 4 8 > 8 Streptococcus A, B, C, G5 ≤ 0.25 - > 0.25 Streptococcus pneumoniae3 ≤ 0.5 1-2 > 2 Enterobacteriaceae1,4 - - > 8 Gram-negative Anaerobes1 ≤ 4 8 > 8 Gram-positive Anaerobes1 ≤ 4 8 > 8 Non-species related breakpoints1

≤ 2 4-8 > 8

1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l. 2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

48

Commonly susceptible species Aerobic Gram-positive micro-organisms Enterococcus faecalis Staphylococcus aureus (methicillin-susceptible)£ Streptococcus agalactiae Streptococcus pneumoniae1

Streptococcus pyogenes and other beta-hemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organisms Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis

Pasteurella multocida Anaerobic micro-organisms Bacteroides fragilis Fusobacterium nucleatum Prevotella spp. Species for which acquired resistance may be a problem Aerobic Gram-positive micro-organisms Enterococcus faecium $ Aerobic Gram-negative micro-organisms Escherichia coli

Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris Inherently resistant organisms Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia $ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1Streptococcus pneumoniae that is fully susceptible to penicillin may be treated with this presentation of amoxicillin/clavulanic acid. Organisms that show any degree of reduced susceptibility to penicillin should not be treated with this presentation (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.

49

5.2 Pharmacokinetic properties Absorption Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (250 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below. Mean (± SD) pharmacokinetic parameters

Dose Cmax Tmax * AUC (0-24h) T 1/2 Active substance(s) administered (mg) (µg/ml) (h) ((µg.h/ml) (h)

Amoxicillin AMX/CA 250 mg/125 mg

250 3.3 ± 1.12

1.5 (1.0-2.0)

26.7±4.56

1.36 ± 0.56

Clavulanic acid AMX/CA 250 mg/125 mg

125 1.5 ± 0.70

1.2 (1.0-2.0)

12.6 ± 3.25

1.01 ± 0.11

AMX – amoxicillin, CA – clavulanic acid * Median (range)

Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone. Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6). Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air.

50

Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Gender Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.

51

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements 125 mg/62.5 mg/5 ml powder for oral suspension Check cap seal is intact before using. Shake bottle to loosen powder. Add 91 ml water, invert and shake well.

Strength Volume of water to be added at reconstitution (ml)

Final volume of reconstituted oral suspension (ml)

125 mg/62.5 mg/5 ml 91 100 Shake the bottle well before each dose. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{Tel}> <{Fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD month YYYY}

52

[To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

53

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 500 mg/125 mg film-coated tablets} {Augmentin and associated names (see Annex I) 500 mg/125 mg dispersible tablets} {Augmentin and associated names (see Annex I) 125 mg/31.25 mg powder for oral suspension in sachet} {Augmentin and associated names (see Annex I) 250 mg/62.5 mg powder for oral suspension in sachet} {Augmentin and associated names (see Annex I) 500 mg/125 mg powder for oral suspension in sachet} {Augmentin and associated names (see Annex I) 50 mg/12.5 mg/ml powder for oral suspension} {Augmentin and associated names (see Annex I) 125 mg/31.25 mg/5 ml powder for oral suspension} {Augmentin and associated names (see Annex I) 250 mg/62.5 mg/5 ml powder for oral suspension} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM 500 mg/125 mg film-coated tablets Film-coated tablet. [To be completed nationally] 500 mg/125 mg dispersible tablets Dispersible tablet. [To be completed nationally] 125 mg/31.25 mg, 250 mg/62.5 mg, 500 mg/125 mg powder for oral suspension in sachets; 50 mg/12.5 mg/ml, 125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml powder for oral suspensions Powder for oral suspension. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): • Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis.

54

• Bone and joint infections, in particular osteomyelitis. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below. The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1). For adults and children ≥ 40 kg, this formulation of Augmentin provides a total daily dose of 1500 mg amoxicillin/375 mg clavulanic acid, when administered as recommended below. For children < 40 kg, this formulation of Augmentin provides a maximum daily dose of 2400 mg amoxicillin/600 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1). The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Adults and children ≥ 40 kg One 500 mg/125 mg dose taken three times a day. Children < 40 kg 20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses. Children may be treated with Augmentin tablets, suspensions or paediatric sachets. Children aged 6 years and below should preferably be treated with Augmentin suspension or paediatric sachets. No clinical data are available on doses of Augmentin 4:1 formulations higher than 40 mg/10 mg/kg per day in children under 2 years.

Elderly No dose adjustment is considered necessary. Renal impairment Dose adjustments are based on the maximum recommended level of amoxicillin. No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

55

Adults and children ≥ 40 kg CrCl: 10-30 ml/min 500 mg/125 mg twice daily CrCl < 10 ml /min 500 mg/125 mg once daily

Haemodialysis 500 mg/125 mg every 24 hours, plus 500 mg/125 mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg CrCl: 10-30 ml/min 15 mg/3.75 mg/kg twice daily (maximum 500 mg/125 mg twice daily). CrCl < 10 ml /min 15 mg/3.75 mg/kg as a single daily dose (maximum 500 mg/125 mg).

Haemodialysis 15 mg/3.75 mg/kg per day once daily. Prior to haemodialysis 15 mg/3.75 mg/kg. In order to restore circulating drug levels, 15 mg/3.75 mg per kg should be administered after haemodialysis.

Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for oral use. Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. Therapy can be started parenterally according the SPC of the IV-formulation and continued with an oral preparation. 500 mg/125 mg dispersible tablets: Dispersible tablets should be stirred into a little water before taking. 500 mg/125 mg powder for oral suspension in sachets: The contents of the single-dose sachet are to be dispersed in half a glass of water before ingestion. 50 mg/12.5 mg/ml, 125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml powder for oral suspension Shake to loosen powder, add water as directed, invert and shake. Shake the bottle before each dose (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).

56

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. This presentation of Augmentin is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see section 4.2). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed

57

concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of Clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods. Augmentin 125 mg/31.25 mg powder for oral suspension in sachets contains 3.75 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 250 mg/62.5 mg powder for oral suspension in sachets contains 7.5 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 500 mg/125 mg powder for oral suspension in sachets contains 15 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 50 mg/12.5 mg/ml powder for oral suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 125 mg/31.25 mg/5 ml powder for oral suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 250 mg/62.5 mg/5 ml powder for oral suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. 125 mg/31.25 mg, 250 mg/62.5 mg, 500 mg/125 mg powder for oral suspension in sachets, 50 mg/12.5 mg/ml, 125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml powder for oral suspension This medicinal product contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine

58

4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician. Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10)

59

Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common


Rare


Not known



Not known


Not known

Gastrointestinal disorders 500 mg/125 mg film-coated tablets 500 mg/125 mg dispersible tablets 500 mg/125 mg powder for oral suspension in sachets Diarrhoea Very common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known 125 mg/31.25 mg, 250 mg/62.5 mg powder for oral suspension in sachets 50 mg/12.5 mg/ml, 125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml powder for oral suspension Diarrhoea Common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known Tooth discolouration11

Not known

Hepatobiliary disorders Rises in AST and/or ALT5 Uncommon Hepatitis6 Not known

60

Cholestatic jaundice6

Not known


Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 125 mg/31.25 mg and 250 mg/62.5 mg powder for oral suspension in sachets 50 mg/12.5 mg/ml, 125 mg/31.25 mg/5 ml 250 mg/62.5 mg/5 ml powder for oral suspension

11 Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

61

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02. Mode of action Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect. PK/PD relationship The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin. Mechanisms of resistance The two main mechanisms of resistance to amoxicillin/clavulanic acid are: • Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic

acid, including class B, C and D. • Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target. Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

62

Breakpoints MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Organism Susceptibility Breakpoints (µg/ml) Susceptible Intermediate Resistant


≤ 0.25 > 0.25


≤ 2 4-8 > 8



63

Commonly susceptible species Aerobic Gram-positive micro-organisms Enterococcus faecalis Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible)£ Coagulase-negative staphylococci (methicillin-susceptible) Streptococcus agalactiae Streptococcus pneumoniae1

Streptococcus pyogenes and other beta-haemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organisms Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis


Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris Inherently resistant organisms Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1Streptococcus pneumoniae that are resistant to penicillin should not be treated with this

64

presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%. 5.2 Pharmacokinetic properties Absorption Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (500 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below. Mean (± SD) pharmacokinetic parameters


Amoxicillin AMX/CA 500/125 mg

500 7.19 ± 2.26

1.5 (1.0-2.5)

53.5 ± 8.87

1.15 ± 0.20


125 2.40 ± 0.83

1.5 (1.0-2.0)

15.72 ± 3.86

0.98 ± 0.12


Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone. Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).

65

Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Gender Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

66

5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements 50 mg/12.5 mg/ml powder for oral suspension Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well.



50 mg/12.5 mg/ml 18 20 Shake the bottle well before each dose. 125 mg/31.25 mg/5 ml powder for oral suspension Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.

Strength Volume of water to be added Final volume of reconstituted oral

67

at reconstitution (ml) suspension (ml) 125 mg/31.25 mg/5 ml Make up to mark 60 74 80 92 100

Shake the bottle well before each dose. 250 mg/62.5 mg/5 ml powder for oral suspension Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.



250 mg/62.5 mg/5 ml Make up to mark 60 72 80 90 100

Shake the bottle well before each dose. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{Tel}> <{Fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD month YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

68

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 875 mg/125 mg film-coated tablets} {Augmentin and associated names (see Annex I) 875 mg/125 mg powder for oral suspension in sachets.} {Augmentin and associated names (see Annex I) 400 mg/57 mg powder for oral suspension in sachets} {Augmentin and associated names (see Annex I) 200 mg/28.5 mg/5 ml powder for oral suspension} {Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour)} {Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour)} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM 875 mg/125 mg film-coated tablets Film-coated tablet. [To be completed nationally] 400 mg/57 mg, 875 mg/125 mg powder for oral suspension in sachets 200 mg/28.5 mg/5 ml, 400 mg/57 mg/5 ml powder for oral suspension (strawberry and mixed fruit flavour) Powder for oral suspension. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): • Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis. • Bone and joint infections, in particular osteomyelitis. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

69

4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below.

The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1). For adults and children ≥ 40 kg, this formulation of Augmentin provides a total daily dose of 1750 mg amoxicillin/ 250 mg clavulanic acid with twice daily dosing and 2625 mg amoxicillin/375 mg clavulanic acid with three times daily dosing, when administered as recommended below. For children < 40 kg, this formulation of Augmentin provides a maximum daily dose of 1000-2800 mg amoxicillin/143-400 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1). The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Adults and children ≥ 40 kg Recommended doses: • standard dose: (for all indications) 875 mg/125 mg two times a day;

• higher dose - (particularly for infections such as otitis media, sinusitis, lower respiratory tract

infections and urinary tract infections): 875 mg/125 mg three times a day. Children < 40 kg Children may be treated with Augmentin tablets, suspensions or paediatric sachets. Recommended doses: • 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses;

• up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some infections

(such as otitis media, sinusitis and lower respiratory tract infections).

No clinical data are available for Augmentin 7:1 formulations regarding doses higher than 45 mg/6.4 mg per kg per day in children under 2 years There are no clinical data for Augmentin 7:1 formulations for patients under 2 months of age. Dosing recommendations in this population therefore cannot be made.

70

Elderly No dose adjustment is considered necessary. Renal impairment No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. In patients with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available. Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for oral use. Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. Therapy can be started parenterally according to the SmPC of the IV-formulation and continued with an oral preparation. 875 mg/125 mg, 400 mg/57 mg powder for oral suspension in sachets The contents of the single-dose sachet are to be dispersed in half a glass of water before ingestion. 200 mg/28.5 mg/ml, 400 mg/57 mg/5 ml powder for oral suspension Shake to loosen powder, add water as directed, invert and shake. Shake the bottle before each dose (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.

71

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. This presentation of Augmentin is not suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

72

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods. Augmentin 875 mg/125 mg powder for oral suspension in sachets contains 24.0 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 400 mg/57 mg powder for oral suspension in sachets contains 11.0 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 200 mg/28.5 mg/5 ml powder for oral suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour) Augmentin 400 mg/57 mg/5 ml powder for oral suspension contains 3.32 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour) Augmentin 400 mg/57 mg/5 ml powder for oral suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. 875 mg/125 mg and 400 mg/57 mg powder for oral suspension in sachets; 200 mg/28.5 mg/ml and 400 mg/57 mg/5 ml powder for oral suspension This medicinal product contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).

73

Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician. Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common

Overgrowth of non-susceptible organisms Not known

74

Blood and lymphatic system disorders Reversible leucopenia (including neutropenia)

Rare


Not known



Not known


Not known

Gastrointestinal disorders 875 mg/125 mg film-coated tablets 875 mg/125 mg powder for oral suspension in sachets Diarrhoea Very common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known 400 mg/57 mg powder for oral suspension in sachets 200 mg/28.5 mg/5 ml powder for oral suspension 400 mg/57 mg/5 ml powder for oral suspension Diarrhoea Common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known Tooth discolouration11

Not known


Not known

Skin and subcutaneous tissue disorders 7 Skin rash Uncommon Pruritus Uncommon Urticaria Uncommon Erythema multiforme Rare Stevens-Johnson syndrome Not known Toxic epidermal necrolysis Not known Bullous exfoliative-dermatitis Not known

75

Acute generalised exanthemous pustulosis (AGEP)9

Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.3 10 See section 4.4 400 mg/57 mg powder for oral suspension in sachets 200 mg/28.5 mg/5 ml powder for oral suspension 400 mg/57 mg/5 ml powder for oral suspension

11 Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4) Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

76

Mode of action Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect. PK/PD relationship The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin. Mechanisms of resistance The two main mechanisms of resistance to amoxicillin/clavulanic acid are: • Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic

acid, including class B, C and D. • Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target. Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria. Breakpoints MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Organism Susceptibility Breakpoints (µg/ml) Susceptible Intermediate Resistant


≤ 0.25 > 0.25


≤ 2 4-8 > 8

1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l.

77

2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive micro-organisms Enterococcus faecalis Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible) Streptococcus agalactiae Streptococcus pneumoniae1



Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris Inherently resistant organisms Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia

78

Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1 Streptococcus pneumoniae that are resistant to penicillin should not be treated with this presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.

5.2 Pharmacokinetic properties Absorption Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (875 mg/125 mg tablets given twice daily) was administered in the fasting state to groups of healthy volunteers are presented below. Mean (± SD) pharmacokinetic parameters



875 11.64 ± 2.78

1.50 (1.0-2.5)

53.52 ± 12.31

1.19 ± 0.21


125 2.18 ± 0.99

1.25 (1.0-2.0)

10.16 ± 3.04

0.96 ± 0.12


Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone. Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.

79

From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6). Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Gender Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

80

5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements 200 mg/28.5 mg/5 ml powder for oral suspension Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.



200 mg/28.5 mg/5 ml 64 70 Shake the bottle well before each dose. 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour) Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.

81

Strength Volume of water to be added

at reconstitution (ml) Final volume of reconstituted oral

suspension (ml) 400 mg/57 mg/5 ml 19 20 32 35 64 70 127 140

Shake the bottle well before each dose. 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour) Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.



400 mg/57 mg/5 ml 62 70 124 140


82

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 500 mg/62.5 mg film-coated tablets} {Augmentin and associated names (see Annex I) 1000 mg/125 mg powder for oral suspension in sachets} {Augmentin and associated names (see Annex I) 250 mg/31.25 mg powder for oral suspension in sachets} {Augmentin and associated names (see Annex I) 500 mg/62.5 mg powder for oral suspension in sachets} {Augmentin and associated names (see Annex I) 100 mg/12.5 mg/ml powder for oral suspension} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM 500 mg/62.5 mg film-coated tablets Film-coated tablet [To be completed nationally] 1000 mg/125 mg, 250 mg/31.25 mg, 500 mg/62.5 mg powder for oral suspension in sachets 100 mg/12.5 mg/ml powder for oral suspension Powder for oral suspension. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): • Acute bacterial sinusitis (adequately diagnosed) • Acute otitis media • Acute exacerbations of chronic bronchitis (adequately diagnosed) • Community acquired pneumonia • Cystitis • Pyelonephritis • Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with

spreading cellulitis. • Bone and joint infections, in particular osteomyelitis. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account:

83

• The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below. The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1). For adults and children ≥ 40 kg, this formulation of Augmentin provides a total daily dose of 2000 mg amoxicillin /250 mg clavulanic acid with twice daily dosing and 3000 mg amoxicillin/375 mg clavulanic acid with three times daily dosing, when administered as recommended below. For children < 40 kg, this formulation of Augmentin provides a maximum daily dose of 1600-3000 mg amoxicillin/200-400 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1). The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Adults and children ≥ 40 kg Recommended doses: • standard dose (for all indications): 1000 mg/125 mg three times a day; • lower dose - (particularly for infections such as skin and soft tissue infections and non-severe

sinusitis): 1000 mg/125 mg two times a day. Children < 40 kg Children may be treated with Augmentin tablets, suspensions or paediatric sachets. Recommended dose: • 40 mg/5 mg/kg/day to 80 mg/10 mg/kg/day (not exceeding 3000 mg/375 mg per day) given in

three divided doses, depending on the severity of infection. Elderly No dose adjustment is considered necessary. Renal impairment No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. In patients with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 8:1 is not recommended, as no recommendations for dose adjustments are available. Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).

84

Method of administration Augmentin is for oral use. Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. Therapy can be started parenterally according to the SPC of the IV-formulation and continued with an oral preparation. 250 mg/31.25 mg, 500 mg/62.5 mg, 1000 mg/125 mg powder for oral suspension in sachets The contents of the single-dose sachet are to be dispersed in half a glass of water before ingestion. 100 mg/12.5 mg/ml powder for oral suspension Shake to loosen powder, add water as directed, invert and shake. Shake the bottle before each dose (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. This presentation of Augmentin may not be suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation may not be suitable for treatment of penicillin-resistant S. pneumoniae). Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

85

Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

86

Augmentin 1000 mg/125 mg powder for oral suspension in sachets contains 30 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 250 mg/31.25 mg powder for oral suspension in sachets contains 7.5 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 500 mg/62.5 mg powder for oral suspension in sachets contains 15 mg of aspartame (E951) per sachet, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Augmentin 100 mg/12.5 mg/ml suspension contains 3.2 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. 1000 mg/125 mg, 250 mg/31.25 mg, 500 mg/62.5 mg powder for oral suspension in sachets 100 mg/12.5 mg/ml powder for oral suspension This medicinal product contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.5 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.

87

Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common


Rare


Not known



Not known


Not known

Gastrointestinal disorders

88

500 mg/62.5 mg film-coated tablets 1000 mg/125 mg powder for oral suspension in sachets Diarrhoea Very common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known 250 mg/31.25 mg powder for oral suspension in sachets 500 mg/62.5 mg powder for oral suspension in sachets 100 mg/12.5 mg/ml powder for oral suspension Diarrhoea Common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known Tooth discolouration11

Not known


Not known


Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 250 mg/31.25 mg, 500 mg/62.5 mg sachets powder for oral suspension in sachets 100 mg/12.5 mg/ml powder for oral suspension 11 Superficial tooth discolouration has been reported very rarely in children. Good oral

89

hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02. Mode of action Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect. PK/PD relationship The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin. Mechanisms of resistance The two main mechanisms of resistance to amoxicillin/clavulanic acid are:

90

• Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.

• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target. Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria. Breakpoints MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Organism Susceptibility Breakpoints (µg/ml) Susceptible Intermediate Resistant


≤ 0.25 > 0.25


≤ 2 4-8 > 8



91

Commonly susceptible species Aerobic Gram-positive micro-organisms Enterococcus faecalis Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible)£ Streptococcus agalactiae Streptococcus pneumoniae1



Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris Inherently resistant organisms Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1 This presentation of amoxicillin/clavulanic acid may not be suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin (see sections 4.2 and 4.4).

92

2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%. 5.2 Pharmacokinetic properties Absorption Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (1000 mg/125 mg powder for oral suspension in sachets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below. Mean (± SD) pharmacokinetic parameters

Dose Cmax Tmax * AUC (0-∞) T 1/2 Active substance(s) administered (mg) (µg/ml) (h) ((µg.h/ml) (h)


1000 14.4 ± 3.1

1.5 (0.75-2.0)

38.2 ± 8.0

1.1 ± 0.2

Clavulanic acid AMX/CA 1000/125 mg

125 3.2 ± 0.85

1.0 (0.75-1.0)

6.3 ± 1.8

0.91 ± 0.09


Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone. Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).

93

Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Gender Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

94

5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements 100 mg/12.5 mg/ml powder for oral suspension Check cap seal is intact before using. Shake bottle to loosen powder. Fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.



100 mg/12.5 mg/ml Make up to mark 30 Make up to mark 60 Make up to mark 120

Shake the bottle well before each dose. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address}

95

<{Tel}> <{Fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD month YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

96

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 600 mg/42.9 mg/ 5 ml powder for oral suspension} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for oral suspension. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in children aged at least 3 months and less than 40 kg body weight, caused or thought likely to be caused by penicillin-resistant Streptococcus pneumoniae (see sections 4.2, 4.4 and 5.1): • Acute otitis media • Community acquired pneumonia. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Adults and children ≥ 40 kg: There is no experience with Augmentin suspension in adults and children ≥ 40 kg, and therefore no dose recommendation can be given. Children < 40 kg (aged ≥ 3 months) The recommended dose of Augmentin suspension is 90/6.4 mg/kg/day in two divided doses. There are no clinical data on Augmentin in children under 3 months of age.

97

Renal impairment No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. In patients with creatinine clearance less than 30 ml/min, the use of Augmentin is not recommended, as no recommendations for dose adjustments are available. Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for oral use Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. Shake to loosen powder, add water as directed, invert and shake. Shake the bottle before each dose (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or beta-lactam agents (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

98

Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods. Augmentin powder for oral suspension contains 2.72 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria.

99

Augmentin powder for oral suspension contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician. Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

100

4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common


Rare


Not known



Not known


Not known

Gastrointestinal disorders Diarrhoea Common Nausea3 Common Vomiting Common Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue Not known Tooth discolouration5

Not known


Not known

101


Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria9 Not known 1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. 6 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 7 These events have been noted with other penicillins and cephalosporins (see section 4.4). 8 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 9 See section 4.9 10 See section 4.4 11 See section 4.3 and 4.4 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

102



Haemophilus influenzae1 ≤ 1 - > 1 Moraxella catarrhalis1 ≤ 1 - > 1 Staphylococcus aureus 2 ≤ 2 - > 2 Streptococcus A, B, C, G4 ≤ 0.25 - > 0.25 Streptococcus pneumoniae3 ≤ 0.5 1-2 > 2 1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l. 2 The reported values are Oxacillin concentrations.

103

3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive micro-organisms Staphylococcus aureus (methicillin-susceptible)$ Streptococcus pneumoniae1

Streptococcus pyogenes and other beta-haemolytic streptococci Aerobic Gram-negative micro-organisms Haemophilus influenzae2 Moraxella catarrhalis

Species for which acquired resistance may be a problem Aerobic Gram-negative micro-organisms Klebsiella pneumoniae Inherently resistant organisms Aerobic Gram-negative micro-organisms Legionella pneumophila Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 This presentation of amoxicillin/clavulanic acid is suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin in the approved indications only (see section 4.1). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%. 5.2 Pharmacokinetic properties Absorption Amoxicillin and clavulanic acid are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. Mean (±SD) Pharmacokinetic parameters are given below for Augmentin administered at 45 mg/3.2 mg/kg every 12 h to paediatric patients.

104

Formulation Cmax (µg/ml)

Tmax * (h)

AUC (0-t) (µg.h/ml)

T 1/2 (h)

Amoxicillin 15.7 ± 7.7

2.0 (1.0-4.0)

59.8 ± 20.0

1.4 ± 0.35

Clavulanic acid

Augmentin dosed at 45 mg/kg AMX and 3.2 mg/kg CA 12-hourly

1.7 ± 0.9

1.1 (1.0-4.0)

4.0 ± 1.9

1.1 ± 0.29


Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone. Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6). Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).

105

Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Gender Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally]

106

6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, Then top up with water exactly to the mark, invert and again shake well.



600 mg/42.9 mg/ml 50 50 70 75 90 100 135 150


107

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 1000 mg/62.5 mg prolonged release tablets} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Prolonged release tablet. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of community-acquired pneumonia in adults and adolescents aged at least 16 years, caused or thought likely to be caused by penicillin-resistant Streptococcus pneumoniae (see section 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Adults and adolescents ≥ 16 years Recommended doses: Two tablets twice daily for seven to ten days; Children < 16 years Augmentin is not indicated in children aged < 16 years. Elderly No dose adjustment is considered necessary.

108

Renal impairment No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. In patients with creatinine clearance less than 30 ml/min, the use of Augmentin is not recommended, as no recommendations for dose adjustments are available. Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for oral use. Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of Augmentin. Augmentin tablets have a scored breakline to allow the tablet to be broken into two halves for ease of swallowing. This is not intended to reduce the dose of medication: both halves must be taken at the same time. The recommended dose of Augmentin is two tablets twice a day. 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or beta-lactam agents (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

109

Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). No adjustment in Augmentin dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. Augmentin is not recommended in patients with creatinine clearance less than 30 ml/min. In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

110

This medicinal product contains 29.3 mg (1.3 mmol) of sodium per tablet. To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician. Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

111

4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common


Rare


Not known



Not known


Not known

Gastrointestinal disorders Diarrhoea Very common Nausea3 Common Abdominal pain Common Vomiting Uncommon Indigestion Uncommon Antibiotic-associated colitis4 Not known Black hairy tongue

Not known


Not known

112


Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See section 4.3 and 4.4 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

113



Haemophilus influenzae1 ≤ 1 - > 1 Moraxella catarrhalis1 ≤ 1 - > 1 Staphylococcus aureus 2 ≤ 2 - > 2 Streptococcus pneumoniae3 ≤ 0.5 1-2 > 2 1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l. 2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints.


114

Commonly susceptible species Aerobic Gram-positive micro-organisms Staphylococcus aureus (methicillin-susceptible)$ Streptococcus pneumoniae1

Aerobic Gram-negative micro-organisms Haemophilus influenzae2 Moraxella catarrhalis Species for which acquired resistance may be a problem Aerobic Gram-negative micro-organisms Klebsiella pneumoniae Inherently resistant organisms Aerobic Gram-negative micro-organisms Legionella pneumophila Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 This presentation of amoxicillin/clavulanic acid is suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin in the approved indications only (see section 4.1). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%. 5.2 Pharmacokinetic properties Absorption Amoxicillin and clavulanic acid are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. The pharmacokinetic results that have been obtained for amoxicillin and clavulanic acid following the administration of Augmentin (2 x 1000 mg/62.5 mg single dose) to healthy adults at the start of a meal are presented below:

Mean (±SD) pharmacokinetic parameters Medicinal product

administered Dose (mg)

T>MIC^ h (%)

Cmax (mg/l)

Tmax * (h)

AUC (0-∞) (ug.h/ml)

T1/2 (h)

Amoxicillin Augmentin

1000/62.5 mg x 2 2000 5.9 ± 1.2

(49 ± 10) 17.0 ± 4

1.50 (1.0-6.0)

71.6 ± 16.5

1.27 ± 0.2

Clavulanic acid Augmentin

1000/62.5 mg x 2 125 ND 2.05

± 0.8 1.03

(0.75-3.0)5.29

± 1.55 1.03

± 0.17

115

ND − Not determined * Median (range) ^ for an MIC of 4 mg/l

Augmentin sustained release formulation has a unique PK/PD profile. The T>MIC obtained with Augmentin can not be achieved with the same dose formulated as an immediate release tablet. Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man, and eliminated in urine and faeces, and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single amoxicillin/clavulanic acid 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal

116

impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{Tel}> <{Fax}> <{e-mail}>

117

8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD month YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

118

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 500 mg/100 mg powder for solution for injection or infusion.} {Augmentin and associated names (see Annex I) 1000 mg/200 mg powder for solution for injection or infusion.} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM 500 mg/100 mg powder for solution for injection or infusion Powder for solution for injection or infusion. [To be completed nationally] 1000 mg/200 mg powder for solution for injection or infusion Powder for solution for injection or infusion. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): • Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections,


spreading cellulitis • Bone and joint infections, in particular osteomyelitis • Intra-abdominal infections • Female genital infections. Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the: • Gastrointestinal tract • Pelvic cavity • Head and neck • Biliary tract surgery. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

119

4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below. The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1). This Augmentin powder for solution for injection or infusion provides a total daily dose of 3000 mg amoxicillin and 600 mg clavulanic acid when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required it is recommended that an alternative intravenous formulation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid. The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Consideration should be given to local guidelines on appropriate dosing frequencies for amoxicillin/clavulanic acid. Adults and children ≥ 40 kg For treatment of infections as indicated in section 4.1: 1000 mg/ 200 mg every 8 hours For surgical prophylaxis

For procedures less than 1 hour in duration, the recommended dose of Augmentin is 1000 mg/200 mg to 2000 mg/200 mg given at induction of anaesthesia (Doses of 2000 mg/200 mg can be achieved by using an alternative intravenous formulation of Augmentin). For procedures greater than 1 hour in duration, the recommended dose of Augmentin is 1000 mg/200 mg to 2000 mg/200 mg given at induction of anaesthesia, with up to 3 doses of 1000 mg/200 mg in 24 hours. Clear clinical signs of infection at operation will require a normal course of intravenous or oral therapy post-operatively.

120

Children < 40 kg Recommended doses: • Children aged 3 months and over: 25 mg/5 mg per kg every 8 hours • Children aged less than 3 months or weighing less than 4 kg: 25 mg/5 mg per kg every 12

hours. Elderly No dose adjustment is considered necessary. Renal impairment Dose adjustments are based on the maximum recommended level of amoxicillin. No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. Adults and children ≥ 40 kg CrCl: 10-30 ml/min Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given twice daily CrCl < 10 ml /min Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given every 24 hours

Haemodialysis Initial dose of 1000 mg/200 mg and then followed by 500 mg/100 mg every 24 hours, plus a dose of 500 mg/100 mg at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg CrCl: 10 to 30 ml/min 25 mg/5 mg per kg given every 12 hours CrCl < 10 ml /min 25 mg/5 mg per kg given every 24 hours

Haemodialysis 25 mg/5 mg per kg given every 24 hours, plus a dose of 12.5 mg/2.5 mg per kg at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased).

Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for intravenous use. Augmentin may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Augmentin is not suitable for intramuscular administration. Children aged less than 3 months should be administered Augmentin by infusion only. Treatment with Augmentin may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient.

121

4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see section 4.3 and 4.8). Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy should be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. This presentation of Augmentin may not be suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. As no specific data for T>MIC are available and the data for comparable oral presentations are borderline, this presentation (without additional amoxicillin) may not be suitable for the treatment of penicillin-resistant S. pneumoniae. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).

Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These

122

have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2). In patients with reduced urine output crystalluria has been observed very rarely, predominantly with parenteral therapy. During administration of high doses of amoxicillin it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods. 500 mg/100 mg powder for solution for injection or infusion This medicinal product contains 31.4 mg (1.4 mmol) of sodium per vial. To be taken into consideration by patients on a controlled sodium diet. 500 mg/100 mg powder for solution for injection or infusion This medicinal product contains 19.6 mg (0.5 mmol) of potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. 1000 mg/200 mg powder for solution for injection or infusion This medicinal product contains 62.9 mg (2.7 mmol) of sodium per vial. To be taken into consideration by patients on a controlled sodium diet. 1000 mg/200 mg powder for solution for injection or infusion This medicinal product contains 39.3 mg (1.0 mmol) of potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

123

4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician. Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects.

124

Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common


Rare


Not known



Not known

Nervous system disorders Dizziness Uncommon Headache Uncommon Convulsions2

Not known

Vascular disorders Thrombophlebitis3

Rare

Gastrointestinal disorders Diarrhoea Common Nausea Uncommon Vomiting Uncommon Indigestion Uncommon Antibiotic-associated colitis4

Not known


Not known

Skin and subcutaneous tissue disorders 7 Skin rash Uncommon Pruritus Uncommon Urticaria Uncommon Erythema multiforme Rare Stevens-Johnson syndrome Not known Toxic epidermal necrolysis Not known Bullous exfoliative-dermatitis Not known

125

Acute generalised exanthemous pustulosis (AGEP)9

Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4 3 At the site of injection 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

126




≤ 0.25 > 0.25


≤ 2 4-8 > 8

1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l.

127

2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive micro-organisms Enterococcus faecalis Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible)£ Streptococcus agalactiae Streptococcus pneumoniae1 Streptococcus pyogenes and other beta-haemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organisms Actinobacillus actinomycetemcomitans Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis

Neisseria gonorrhoeae§ Pasteurella multocida Anaerobic micro-organisms Bacteroides fragilis Fusobacterium nucleatum Prevotella spp. Species for which acquired resistance may be a problem Aerobic Gram-positive micro-organisms Enterococcus faecium $ Aerobic Gram-negative micro-organisms Escherichia coli

Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris Inherently resistant organisms Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas sp.

128

Serratia sp. Stenotrophomonas maltophilia Other micro-organisms Chlamydia trachomatis Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. § All strains with resistance to amoxicillin that is not mediated by beta-lactamases are resistant to amoxicillin/clavulanic acid. 1 This presentation of amoxicillin/clavulanic acid may not be suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%. 5.2 Pharmacokinetic properties Absorption The pharmacokinetic results for studies in which amoxicillin/clavulanic acid was administered to groups of healthy volunteers as either 500 mg/100 mg or 1000 mg/200 mg given as a bolus intravenous injection are presented below. Mean (±SD) pharmacokinetic parameters Bolus intravenous injection

Amoxicillin Dose administered Dose Mean peak

serum conc (µg/ml)

T 1/2 (h) AUC (h.mg/l)

Urinary recovery (%, 0 to 6 h )

AMX/CA 500 mg/100 mg

500 mg 32.2 1.07 25.5 66.5


1000 mg 105.4 0.9 76.3 77.4


100 mg 10.5 1.12 9.2 46.0


200 mg 28.5 0.9 27.9 63.8

AMX – amoxicillin, CA – clavulanic acid

Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.

129

From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man, and eliminated in urine and faeces and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of a single 500/100 mg or a single 1000/200 mg bolus intravenous injection. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

130

5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. Preparation of solutions for intravenous injection 500 mg/100 mg powder for solution for injection or infusion Water for Injection Ph.Eur. is the normal solvent. Augmentin 500/100 mg should be dissolved in 10 ml of solvent. This yields approximately 10.5 ml of solution for single-dose use. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour. Augmentin should be administered within 20 min of reconstitution. 1000 mg/200 mg powder for solution for injection or infusion Water for Injection Ph.Eur. is the normal solvent. Augmentin 1000 mg/200 mg should be dissolved in 20 ml of solvent. This yields approximately 20.9 ml of solution for single-dose use. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour. Augmentin should be administered within 20 min of reconstitution.

131

Preparation of solutions for intravenous infusion Augmentin vials are not suitable for multi-dose use. 500 mg/100 mg powder for solution for injection or infusion Augmentin should be reconstituted as described above for injection. Without delay the reconstituted solution should be added to 50 ml of infusion fluid using a minibag or in-line burette. 1000 mg/200 mg powder for solution for injection or infusion Augmentin should be reconstituted as described above for injection. Without delay the reconstituted solution should be added to 100 ml of infusion fluid using a minibag or in-line burette. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{Tel}> <{Fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD month YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

132

1. NAME OF THE MEDICINAL PRODUCT {Augmentin and associated names (see Annex I) 250 mg/25 mg powder for solution for injection or infusion} {Augmentin and associated names (see Annex I) 500 mg/50 mg powder for solution for injection or infusion} {Augmentin and associated names (see Annex I) 1000 mg/100 mg powder for solution for injection or infusion} {Augmentin and associated names (see Annex I) 2000 mg/200 mg powder for solution for infusion} [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM 250 mg/25 mg powder for solution for injection or infusion Powder for solution for injection or infusion. [To be completed nationally] 500 mg/50 mg, 1000 mg/100 mg powder for solution for injection or infusion Powder for solution for injection or infusion. [To be completed nationally] 2000 mg/200 mg powder for solution for infusion Powder for solution for infusion. [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): • Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections,


spreading cellulitis • Bone and joint infections, in particular osteomyelitis • Intra-abdominal infections • Female genital infections. Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the:

133

• Gastrointestinal tract • Pelvic cavity • Head and neck • Biliary tract surgery. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component. The dose of Augmentin that is selected to treat an individual infection should take into account: • The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4) • The severity and the site of the infection • The age, weight and renal function of the patient as shown below.

The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see section 5.1). This Augmentin powder for solution for injection or infusion provides a total daily dose of up to 6000 mg amoxicillin and 600 mg clavulanic acid when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, this must not be achieved by increasing the Augmentin dose. This is in order to avoid administration of unnecessarily high daily doses of clavulanic acid. The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy). Consideration should be given to local guidelines on appropriate dosing frequencies for amoxicillin/clavulanic acid. Adults and children ≥ 40 kg: Recommended doses for treatment of infections as indicated in section 4.1: • 1000 mg/100 mg every 8-12 hours or • 2000 mg/200 mg every 12 hours. For very severe infections the dose may be increased to a maximum of 2000 mg/200 mg every 8 hours. For surgical prophylaxis For procedures less than 1 hour in duration, the

recommended dose is 1000 mg/100 mg to 2000 mg/200 mg given at induction of anaesthesia For procedures greater than 1 hour in duration, the recommended dose is 1000 mg/100 mg to 2000 mg/200 mg given at induction of anaesthesia, with up to 3 doses of 1000 mg/100 mg in 24 hours.

134

Clear clinical signs of infection at operation will require a normal course of intravenous or oral therapy post-operatively.

Children < 40 kg Recommended doses: • Children aged 3 months and over: 50 mg/5 mg per kg every 8 hours • Children aged less than 3 months or weighing less than 4 kg: 50 mg/5 mg per kg every 12 hours. Elderly No dose adjustment is considered necessary. Renal impairment Dose adjustments are based on the maximum recommended level of amoxicillin. No dose adjustment is necessary for patients with creatinine clearance (CrCl) greater than 30 ml/min. 250 mg/25 mg; 500 mg/50 mg, 1000 mg/100 mg powder for solution for injection or infusion In patients with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 10:1 is not recommended, as no dose adjustments are available. In such patients, Augmentin formulations with an amoxicillin to clavulanic acid ratio of 5:1 are recommended. 2000 mg/200 mg powder for solution for infusion Augmentin 2000 mg/200 mg should only be used in patients with creatinine clearance less than 30 ml/min for surgical prophylaxis when it should be used in one infusion. Hepatic impairment Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). Method of administration Augmentin is for intravenous use. 250 mg/25 mg; 500 mg/50 mg, 1000 mg/100 mg powder for solution for injection or infusion Augmentin may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Augmentin is not suitable for intramuscular administration. Children aged less than 3 months should be administered Augmentin by infusion only. Treatment with Augmentin may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient. 2000 mg/200 mg powder for solution for infusion Augmentin 2000 mg/200 mg should be administered by intravenous infusion over 30 to 40 min. Augmentin is not suitable for intramuscular administration. 4.3 Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.

135

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8). 4.4 Special warnings and precautions for use Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy should be discontinued and appropriate alternative therapy instituted. In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance. This presentation of Augmentin may not be suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. At recommended doses of up to 1000 mg/100 mg every 8 hours, this presentation may not be suitable for treatment of penicillin-resistant S. pneumoniae. For coverage of this pathogen, a dose of at least 2000 mg/200 mg every 12 hours is required. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may occasionally result in overgrowth of non-susceptible organisms. The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin. Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8).

136

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2). In patients with reduced urine output crystalluria has been observed very rarely, predominantly with parenteral therapy. During administration of high doses of amoxicillin it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods. The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods 250 mg/25 mg powder for solution for injection or infusion This medicinal product contains 15.7 mg (0.7 mmol) of sodium per vial. To be taken into consideration by patients on a controlled sodium diet. 250 mg/25 mg powder for solution for injection or infusion This medicinal product contains 4.9 mg (0.1 mmol) of potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. 500 mg/50 mg powder for solution for injection or infusion This medicinal product contains 31.5 mg (1.4 mmol) of sodium per vial or bottle. To be taken into consideration by patients on a controlled sodium diet. 500 mg/50 mg powder for solution for injection or infusion This medicinal product contains 9.8 mg (0.3 mmol) of potassium per per vial or bottle. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. 1000 mg/100 mg powder for solution for injection or infusion This medicinal product contains 62.9 mg (2.7 mmol) of sodium per per vial or bottle. To be taken into consideration by patients on a controlled sodium diet.

137

1000 mg/100 mg powder for solution for injection or infusion This medicinal product contains 19.6 mg (0.5 mmol) of potassium per per vial or bottle. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. 2000 mg/200 mg powder for solution for infusion This medicinal product contains 125.9 mg (5.5 mmol) of sodium per per vial or bottle. To be taken into consideration by patients on a controlled sodium diet. 2000 mg/200 mg powder for solution for infusion This medicinal product contains 39.3 mg (1.0 mmol) of potassium per per vial or bottle. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. 4.5 Interaction with other medicinal products and other forms of interaction Oral anticoagulants Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8). Methotrexate Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity. Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 4.6 Pregnancy and lactation Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin / clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician. Lactation Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

138

4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting. The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects. Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Infections and infestations Mucocutaneous candidosis

Common


Rare


Not known



Not known

Nervous system disorders Dizziness Uncommon Headache Uncommon Convulsions2

Not known

Vascular disorders Thrombophlebitis3

Rare

Gastrointestinal disorders Diarrhoea Common Nausea Uncommon Vomiting Uncommon Indigestion Uncommon Antibiotic-associated colitis4

Not known

139


Not known


Not known

Renal and urinary disorders Interstitial nephritis Not known Crystalluria8 Not known 1 See section 4.4 2 See section 4.4 3 At the site of injection 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 4.9 Overdose Symptoms and signs of overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4). Treatment of intoxication Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

140




≤ 0.25 > 0.25

Enterococcus1 ≤ 4 8 > 8 Streptococcus A, B, C, G5 ≤ 0.25 - > 0.25 Streptococcus pneumoniae3 ≤ 0.5 1-2 > 2

141

Enterobacteriaceae1,4 - - > 8 Gram-negative Anaerobes1 ≤ 4 8 > 8 Gram-positive Anaerobes1 ≤ 4 8 > 8 Non-species related breakpoints1

≤ 2 4-8 > 8


The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive micro-organisms Enterococcus faecalis Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible)£ Streptococcus agalactiae Streptococcus pneumoniae1

Streptococcus pyogenes and other beta-haemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organisms Actinobacillus actinomycetemcomitans Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis

Neisseria gonorrhoeae§ Pasteurella multocida Anaerobic micro-organisms Bacteroides fragilis Fusobacterium nucleatum Prevotella spp. Species for which acquired resistance may be a problem Aerobic Gram-positive micro-organisms Enterococcus faecium $ Aerobic Gram-negative micro-organisms Escherichia coli

Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris Inherently resistant organisms Aerobic Gram-negative micro-organisms

142

Acinetobacter sp. Citrobacter freundii Enterobacter sp. Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia Other micro-organisms Chlamydia trachomatis Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae $ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. § All strains with resistance to amoxicillin that is not mediated by beta-lactamases are resistant to amoxicillin/clavulanic acid. 1 This presentation of Augmentin may not be suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%. 5.2 Pharmacokinetic properties Absorption The pharmacokinetic results for studies in which amoxicillin/clavulanic acid was administered to groups of healthy volunteers as 2000 mg/200 mg given as an intravenous infusion over 30 min are presented below. Mean (±SD) pharmacokinetic parameters Intravenous infusion over 30 min

Amoxicillin Dose administered Dose Mean peak

serum conc (µg/ml)

T 1/2 (h) AUC (h.mg/l)

Urinary recovery (%, 0 to 6 h )


2000 mg 108 ± 21

- 119

± 10.6

74.7


200 mg 13.9 ± 2.8

- 18.2

± 3.0

51.4

AMX – amoxicillin, CA – clavulanic acid

143

Distribution About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6) Biotransformation Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man, and eliminated in urine and faeces and as carbon dioxide in expired air. Elimination The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of a single 500/100 mg or a single 1000/200 mg bolus intravenous injection. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5). Age The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Renal impairment The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

144

5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Augmentin or its components. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. Preparation of solutions for intravenous injection 250 mg/25 mg powder for solution for injection or infusion Water for Injection Ph.Eur. is the normal solvent. Augmentin 250 mg/25 mg should be dissolved in 5 ml of solvent. This yields approximately 5.2 ml of solution for single-dose use. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour. Augmentin should be administered within 20 min of reconstitution. 500 mg/50 mg powder for solution for injection or infusion Water for Injection Ph.Eur. is the normal solvent. Augmentin 500 mg/50 mg should be dissolved in 10 ml of solvent. This yields approximately 10.5 ml of solution for single-dose use. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour.

145

Augmentin should be administered within 20 min of reconstitution. 1000 mg/100 mg powder for solution for injection or infusion Water for Injection Ph.Eur. is the normal solvent. Augmentin 1000 mg/100 mg should be dissolved in 20 ml of solvent. This yields approximately 20.9 ml of solution for single-dose use. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour. Augmentin should be administered within 20 min of reconstitution. 2000 mg/200 mg powder for solution for infusion Augmentin 2000 mg/200 mg is not suitable for bolus injection. Administration should be by intravenous infusion. Preparation of solutions for intravenous infusion 250 mg/25 mg, 500 mg/50 mg, 1000 mg/100 mg powder for solution for injection or infusion Augmentin should be reconstituted as described above for injection. Without delay the reconstituted solution should be added to 50 ml of infusion fluid using a minibag or in-line burette. 2000 mg/200 mg powder for solution for infusion Augmentin 2000 mg/200 mg should be reconstituted in 20 ml of Water for Injection Ph.Eur. (this is a minimum volume). A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour. Without delay the reconstituted solution should be added to 100 ml of infusion fluid using a minibag or in-line burette. Augmentin vials are not suitable for multi-dose use. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{Tel}> <{Fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION {DD month YYYY} [To be completed nationally] 10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

146

LABELLING

147

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/125 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM YYYY} 9. SPECIAL STORAGE CONDITIONS [To be completed nationally]

148

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE [To be completed nationally] 16. INFORMATION IN BRAILLE [To be completed nationally]

149

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER AND DESICCATED POUCH 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/125 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]

3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. OTHER

150

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/125 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


151


152

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/125 mg dispersible tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


153


154

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/125 mg dispersible tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


155



156


157

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS AND DESICCATED POUCH 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 500 mg/125 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


158



159


160

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 500 mg/125 mg dispersible tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


161


162

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 500 mg/125 mg dispersible tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


163

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 500 mg/62.5 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


164


165

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 500 mg/62.5 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


166



167


168

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS AND DESICCATED POUCH 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 875 mg/125 mg film-coated tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


169



170


171

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 1000/62.5 mg prolonged-release tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


172


173

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 1000/62.5 mg prolonged-release tablets [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


174

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 125 mg/31.25 mg powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


175


176

MINIMUM PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING SACHETS 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 125 mg/31.25 mg powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


177



178


179



180

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 400 mg/57 mg powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM YYYY} 9. SPECIAL STORAGE CONDITIONS Do not store above 25 °C Store in the original package in order to protect from moisture

181


182

MINIMUM PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING SACHETS 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 400 mg/57 mg powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]


183



184


185



186



187


188



189



190


191



192



193


194



195



196


197



198

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 50 mg/12.5 mg/ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add 18 ml of water Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM YYYY} 9. SPECIAL STORAGE CONDITIONS

199

[To be completed nationally] 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE [To be completed nationally] 16. INFORMATION IN BRAILLE [To be completed nationally]

200

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 50 mg/12.5 mg/ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


201


202

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 100 mg/12.5 mg/ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add water in 2 portions up to the mark on the bottle label Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


203


204



205


206

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 125 mg/62.5 mg/5 ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add 91 ml of water Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


207


208



209


210

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 125 mg/31.25 mg/5 ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add water in 2 portions up to the mark on the bottle label (60 ml) Add 74 ml of water (or add water in 2 portions up to the mark) (80 ml) Add 92 ml of water (or add water in 2 portions up to the mark) (100 ml) Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM YYYY}

211

9. SPECIAL STORAGE CONDITIONS [To be completed nationally] 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE [To be completed nationally] 16. INFORMATION IN BRAILLE [To be completed nationally]

212



213


214

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 200 mg/28.5 mg/5 ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add 64 ml of water (or add water in 2 portions up to the mark) Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


215


216



217


218

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/62.5 mg/5 ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add water in 2 portions up to the mark on the bottle label (60 ml) Add 72 ml of water (or add water in 2 portions up to the mark) (80 ml) Add 90 ml of water (or add water in 2 portions up to the mark) (100 ml) Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


219


220



221


222

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour) [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add 19 ml of water (or add water in 2 portions up to the mark) (20 ml) Add 32 ml of water (or add water in 2 portions up to the mark) (35 ml) Add 64 ml of water (or add water in 2 portions up to the mark) (70 ml) Add 127 ml of water (or add water in 2 portions up to the mark) (140 ml) Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


223


224

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour) [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


225

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE [To be completed nationally]

226

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour) [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add 62 ml of water (or add water in 2 portions up to the mark) (70 ml) Add 124 ml of water (or add water in 2 portions up to the mark) (140 ml) Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


227


228

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour) [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


229


230

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 600 mg/42.9 mg/5 ml powder for oral suspension [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use Check cap seal is intact before use Add 50 ml of water (or add water in 2 portions up to the mark) (50 ml) Add 70 ml of water (or add water in 2 portions up to the mark) (75 ml) Add 90 ml of water (or add water in 2 portions up to the mark) (100 ml) Add 135 ml of water (or add water in 2 portions up to the mark) (150 ml) Invert and shake well 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


231


232

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 600 mg/42.9 mg/5 ml powder for oral suspension (strawberry flavour) [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use Shake well before use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


233


234

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 250 mg/25 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


235


236

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Augmentin and associated names (see Annex I) 250 mg/25 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use 3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

237



238


239

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL OR BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Augmentin and associated names (see Annex I) 500 mg/50 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use 3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

240



241


242

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Augmentin and associated names (see Annex I) 500 mg/100 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use 3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

243

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 1000 mg/100 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally]. 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


244


245

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Augmentin and associated names (see Annex I) 1000 mg/100 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use 3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

246



247


248

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL OR BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Augmentin and associated names (see Annex I) 1000 mg/200 mg powder for solution for injection or infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use 3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

249

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Augmentin and associated names (see Annex I) 2000 mg/200 mg powder for solution for infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid 2. STATEMENT OF ACTIVE SUBSTANCE(S) [To be completed nationally] 3. LIST OF EXCIPIENTS [To be completed nationally] 4. PHARMACEUTICAL FORM AND CONTENTS [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT


250


251

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL OR BOTTLE LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Augmentin and associated names (see Annex I) 2000 mg/200 mg powder for solution for infusion [See Annex I - To be completed nationally] Amoxicillin/clavulanic acid IV 2. METHOD OF ADMINISTRATION Read the package leaflet before use 3. EXPIRY DATE EXP {MM YYYY} 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 6. OTHER

252

PACKAGE LEAFLET

253

PACKAGE LEAFLET: INFORMATION FOR THE USER

{Augmentin and associated names (see Annex I) 250 mg/125 mg film-coated tablets} {Augmentin and associated names (see Annex I) 500 mg/125 mg film-coated tablets} {Augmentin and associated names (see Annex I) 875 mg/125 mg film-coated tablets} {Augmentin and associated names (see Annex I) 500 mg/62.5 mg film-coated tablets}

[See Annex I - To be completed nationally]

Amoxicillin/clavulanic acid

Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you (or for your child). Do not pass it on to others. It

may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you take Augmentin 3. How to take Augmentin 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in adults and children to treat the following infections: 250 mg/125 mg film-coated tablets • sinus infections • urinary tract infections • skin infections • dental infections. 500 mg/125 mg, 875/125 mg, 500 mg/62.5 mg film-coated tablets • middle ear and sinus infections • respiratory tract infections • urinary tract infections • skin and soft tissue infections including dental infections • bone and joint infections.

254

2. BEFORE YOU TAKE AUGMENTIN Do not take Augmentin: • if you are allergic (hypersensitive) to amoxicillin, clavulanic acid, penicillin or any of the other

ingredients of Augmentin (listed in section 6) • if you have ever had a severe allergic (hypersensitive) reaction to any other antibiotic. This can

include a skin rash or swelling of the face or neck • if you have ever had liver problems or jaundice (yellowing of the skin) when taking an

antibiotic. Do not take Augmentin if any of the above apply to you. If you are not sure, talk to your

doctor or pharmacist before taking Augmentin. Take special care with Augmentin Talk to your doctor or pharmacist before taking this medicine if you: • have glandular fever • are being treated for liver or kidney problems • are not passing water regularly. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4.

Blood and urine tests If you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor or pharmacist if you are using or have recently used any other medicines. This includes medicines that can be bought without a prescription and herbal medicines. If you are taking allopurinol (used for gout) with Augmentin, it may be more likely that you’ll have an allergic skin reaction. If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding If you are pregnant, you think you might be pregnant or if you are breast-feeding, please tell your doctor or pharmacist.

255

Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Augmentin can have side effects and the symptoms may make you unfit to drive. Don’t drive or operate machinery unless you are feeling well. 3. HOW TO TAKE AUGMENTIN Always take Augmentin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Adults and children weighing 40 kg and over 250 mg/125 mg film-coated tablets The usual dose is: • 1 tablet three times a day 500 mg/125 mg film-coated tablets The usual dose is: • 1 tablet three times a day 875 mg/125 mg film-coated tablets • Usual dose – 1 tablet two times a day • Higher dose – 1 tablet three times a day 500 mg/62.5 mg film-coated tablets • Usual dose – 2 tablets three times a day • Lower dose – 2 tablets two times a day Children weighing less than 40 kg Children aged 6 years or less should preferably be treated with Augmentin oral suspension or sachets. 250 mg/125 mg film-coated tablets Augmentin tablets are not recommended. 500 mg/125 mg film-coated tablets Ask your doctor or pharmacist for advice when giving Augmentin tablets to children weighing less than 40 kg. 875 mg/125 mg film-coated tablets Ask your doctor or pharmacist for advice when giving Augmentin tablets to children weighing less than 40 kg. 500 mg/62.5 mg film-coated tablets Ask your doctor or pharmacist for advice when giving Augmentin tablets to children weighing less than 40 kg. Patients with kidney and liver problems • If you have kidney problems the dose might be changed. A different strength or a different

medicine may be chosen by your doctor. • If you have liver problems you may have more frequent blood tests to check how your liver is

working. How to take Augmentin • Swallow the tablets whole with a glass of water at the start of a meal or slightly before

256

• Space the doses evenly during the day, at least 4 hours apart. Do not take 2 doses in 1 hour. • Do not take Augmentin for more than 2 weeks. If you still feel unwell you should go back to

see the doctor. If you take more Augmentin than you should If you take too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to your doctor as soon as possible. Take the medicine carton or bottle to show the doctor. If you forget to take Augmentin If you forget to take a dose, take it as soon as you remember. You should not take the next dose too soon, but wait about 4 hours before taking the next dose. If you stop taking Augmentin Keep taking Augmentin until the treatment is finished, even if you feel better. You need every dose to help fight the infection. If some bacteria survive they can cause the infection to come back. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. Conditions you need to look out for

Allergic reactions: • skin rash • inflammation of blood vessels (vasculitis) which may be visible as red or purple raised spots on

the skin, but can affect other parts of the body • fever, joint pain, swollen glands in the neck, armpit or groin • swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing • collapse.

Contact a doctor immediately if you get any of these symptoms. Stop taking Augmentin. Inflammation of large intestine Inflammation of the large intestine, causing watery diarrhoea usually with blood and mucus, stomach pain and/or fever.

Contact your doctor as soon as possible for advice if you get these symptoms. Very common side effects These may affect more than 1 in 10 people • diarrhoea (in adults). Common side effects These may affect up to 1 in 10 people • thrush (candida - a yeast infection of the vagina, mouth or skin folds) • feeling sick (nausea), especially when taking high doses → if affected take Augmentin before food • vomiting • diarrhoea (in children). Uncommon side effects These may affect up to 1 in 100 people

257

• skin rash, itching • raised itchy rash (hives) • indigestion • dizziness • headache.

Uncommon side effects that may show up in your blood tests: • increase in some substances (enzymes) produced by the liver. Rare side effects These may affect up to 1 in 1000 people • skin rash, which may blister, and looks like small targets (central dark spots surrounded by a

paler area, with a dark ring around the edge – erythema multiforme) if you notice any of these symptoms contact a doctor urgently.

Rare side effects that may show up in your blood tests: • low number of cells involved in blood clotting • low number of white blood cells. Other side effects

Other side effects have occurred in a very small number of people but their exact frequency is unknown.

• Allergic reactions (see above) • Inflammation of the large intestine (see above) • Serious skin reactions:

- a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome), and a more severe form, causing extensive peeling of the skin (more than 30% of the body surface – toxic epidermal necrolysis) - widespread red skin rash with small pus-containing blisters (bullous exfoliative dermatitis) - a red, scaly rash with bumps under the skin and blisters (exanthemous pustulosis).

Contact a doctor immediately if you get any of these symptoms.

• inflammation of the liver (hepatitis) • jaundice, caused by increases in the blood of bilirubin (a substance produced in the liver) which

may make your skin and whites of the eyes appear yellow • inflammation of tubes in the kidney • blood takes longer to clot • hyperactivity • convulsions (in people taking high doses of Augmentin or who have kidney problems) • black tongue which looks hairy • stained teeth (in children), usually removed by brushing.

Side effects that may show up in your blood or urine tests: • severe reduction in the number of white blood cells • low number of red blood cells (haemolytic anaemia) • crystals in urine.

If you get side effects Tell your doctor or pharmacist if any of the side effects become severe or troublesome, or if

you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN

258

[To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Augmentin contains [To be completed nationally] What Augmentin looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: 250 mg/125 mg film-coated tablets Bulgaria – Augmentin Czech Republic – Augmentin Denmark – Spektramox Hungary – Augmentin Ireland – Augmentin, Clavamel Malta – Augmentin Poland – Augmentin Slovak Republic – Augmentin Sweden – Spektramox United Kingdom – Augmentin 500 mg/125 mg film-coated tablets Austria – Augmentin, Clavamox Belgium – Augmentin Bulgaria – Augmentin Cyprus – Augmentin, Noprilam Czech Republic –Augmentin Denmark –Spektramox Estonia – Augmentin Greece – Augmentin Hungary – Augmentin, Augmentin Duo Iceland – Augmentin Ireland – Augmentin Duo, Augmentin Latvia – Augmentin Lithuania – Augmentin Luxembourg – Augmentin Malta – Augmentin, Noprilam

259

Netherlands – Augmentin, Amoxicilline/clavulaanzuur Poland – Augmentin Portugal – Augmentin, Clavamox, Noprilam, Penilan Romania – Augmentin Slovak Republic – Augmentin Slovenia –Augmentin Spain – Augmentine, Clavumox Sweden – Spektramox United Kingdom – Augmentin 875 mg/125 mg film-coated tablets Austria – Augmentin, Clavamox Belgium - Augmentin Bulgaria - Augmentin Cyprus – Augmentin, Noprilam DT Czech Republic – Augmentin Denmark - Spektraforte Estonia - Augmentin Finland – Augmentin, Clavurion Germany – Augmentan Greece - Augmentin Hungary – Augmentin Duo Iceland - Augmentin Ireland – Augmentin Italy – Augmentin, Neoduplamox, Clavulin Latvia - Augmentin Lithuania – Augmentin Luxembourg - Augmentin Malta – Augmentin, Noprilam DT Netherlands - Augmentin Poland - Augmentin Portugal – Augmentin Duo, Clavamox DT, Noprilam DT, Penilan DT Romania – Augmentin Slovak Republic – Augmentin Slovenia - Augmentin Spain – Augmentine, Clavumox Sweden - Spektramox United Kingdom – Augmentin 500 mg/62.5 mg film-coated tablets France – Augmentin This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

260

--------------------------------------------------------------------------------------------------------------------------- Instructions for reconstitution [To be completed nationally]

Advice/medical education Antibiotics are used to treat infections caused by bacteria. They have no effect against infections caused by viruses. Sometimes an infection caused by bacteria does not respond to a course of an antibiotic. One of the commonest reasons for this to occur is because the bacteria causing the infection are resistant to the antibiotic that is being taken. This means that they can survive and even multiply despite the antibiotic. Bacteria can become resistant to antibiotics for many reasons. Using antibiotics carefully can help to reduce the chance of bacteria becoming resistant to them. When your doctor prescribes a course of an antibiotic it is intended to treat only your current illness. Paying attention to the following advice will help prevent the emergence of resistant bacteria that could stop the antibiotic working.

1. It is very important that you take the antibiotic at the right dose, at the right times and for the right number of days. Read the instructions on the label and if you do not understand anything ask your doctor or pharmacist to explain.

2. You should not take an antibiotic unless it has been prescribed specifically for you and you should use it only to treat the infection for which it was prescribed.

3. You should not take antibiotics that have been prescribed for other people even if they had an infection that was similar to yours.

4. You should not give antibiotics that were prescribed for you to other people. 5. If you have any antibiotic left over when you have taken the course as directed by your

doctor you should take the remainder to a pharmacy for appropriate disposal.

261


{Augmentin and associated names (see Annex I) 1000 mg/62.5 mg prolonged release tablets}



Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even

if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you take Augmentin 3. How to take Augmentin 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections. It is used to treat infections of the lungs caused by bacteria. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in adults and children over 16 years to treat the following infections: • lung infections. 2. BEFORE YOU TAKE AUGMENTIN Do not take Augmentin: • if you are allergic (hypersensitive) to amoxicillin, clavulanic acid, penicillin or any of the other




doctor or pharmacist before taking Augmentin. Take special care with Augmentin Talk to your doctor or pharmacist before taking this medicine if you: • have glandular fever • are being treated for liver or kidney problems

262

• are not passing water regularly. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4. Blood and urine tests If you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor or pharmacist if you are using or have recently used any other medicines. This includes medicines that can be bought without a prescription and herbal medicines. If you are taking allopurinol (used for gout) with Augmentin, it may be more likely that you’ll have an allergic skin reaction. If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding If you are pregnant, you think you might be pregnant or if you are breast-feeding, please tell your doctor or pharmacist. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Augmentin can have side effects and the symptoms may make you unfit to drive. Don’t drive or operate machinery unless you are feeling well. Important information about some of the ingredients of Augmentin Augmentin contains approximately 2.5 mmol or 58.6 mg of sodium per unit dose (two tablets). This should be considered if you are on a controlled sodium diet. 3. HOW TO TAKE AUGMENTIN Always take Augmentin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Adults and children over 16 years

263

The usual dose is: • 2 tablets two times a day, for 7 to 10 days. Children under 16 years Augmentin tablets are not recommended. Patients with kidney and liver problems • If you have kidney problems the dose might be changed. A different strength or a different


working. How to take Augmentin • Augmentin tablets have a breakline to aid breaking the tablets into two halves. This is so they

can be swallowed more easily. Both halves of each tablet must be taken at the same time. • Swallow the tablets with a glass of water at the start of a meal or slightly before • Space the doses evenly during the day, at least 4 hours apart. Do not take 2 doses in 1 hour. • Do not take Augmentin for more than 10 days. If you still feel unwell you should go back to see

the doctor. If you take more Augmentin than you should If you take too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to your doctor as soon as possible. Take the medicine carton to show the doctor. If you forget to take Augmentin If you forget to take a dose, take it as soon as you remember. You should not take the next dose too soon, but wait about 4 hours before taking the next dose. If you stop taking Augmentin Keep taking Augmentin until the treatment is finished, even if you feel better. You need every dose to help fight the infection. If some bacteria survive they can cause the infection to come back. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. The side effects below may happen with this medicine. Conditions you need to look out for




264

Contact your doctor as soon as possible for advice if you get these symptoms. Very common side effects These may affect more than 1 in 10 people • diarrhoea (in adults). Common side effects These may affect up to 1 in 10 people • thrush (candida - a yeast infection of the vagina, mouth or skin folds) • feeling sick (nausea), especially when taking high doses → if affected take Augmentin before food • vomiting • diarrhoea (in children). Uncommon side effects These may affect up to 1 in 100 people • skin rash, itching • raised itchy rash (hives) • indigestion • dizziness • headache.



Rare side effects that may show up in your blood tests: • low number of cells involved in blood clotting • low number of white blood cells. Other side effects






may make your skin and whites of the eyes appear yellow • inflammation of tubes in the kidney • blood takes longer to clot

265

• hyperactivity • convulsions (in people taking high doses of Augmentin or who have kidney problems) • black tongue which looks hairy • stained teeth (in children), usually removed by brushing.



you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN [To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Augmentin contains

[To be completed nationally] What Augmentin looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: Belgium – Augmentin Retard Bulgaria – Augmentin SR Czech Republic – Augmentin SR France – Duamentin Greece – Augmentin SR Hungary – Augmentin Extra Latvia – Augmentin SR Luxembourg – Augmentin Retard Poland – Augmentin SR Romania – Augmentin SR Slovak Republic – Augmentin SR

266

Slovenia – Augmentin SR Spain – Augmentine Plus This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

267








268


{Augmentin and associated names (see Annex I) 250 mg/125 mg dispersible tablets} {Augmentin and associated names (see Annex I) 500 mg/125 mg dispersible tablets}





please tell your doctor or pharmacist. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you take Augmentin 3. How to take Augmentin 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in adults and children to treat the following infections: 250 mg/125 mg dispersible tablets • sinus infections • urinary tract infections • skin infections • dental infections 500 mg/125 dispersible tablets • middle ear and sinus infections • respiratory tract infections • urinary tract infections • skin and soft tissue infections including dental infections • bone and joint infections. 2. BEFORE YOU TAKE AUGMENTIN

269

Do not take Augmentin: • if you are allergic (hypersensitive) to amoxicillin, clavulanic acid, penicillin or any of the other



antibiotic. Do not take Augmentin if any of the above apply. If you are not sure, talk to your doctor or

pharmacist before taking Augmentin. Take special care with Augmentin Talk to your doctor or pharmacist before taking this medicine if you: • have glandular fever • are being treated for liver or kidney problems • are not passing water regularly. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4. Blood and urine tests If you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor or pharmacist if you are using or have recently used any other medicines. This includes medicines that can be bought without a prescription and herbal medicines. If you are taking allopurinol (used for gout) with Augmentin, it may be more likely that you’ll have an allergic skin reaction. If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding If you are pregnant, you think you might be pregnant or if you are breast-feeding, please tell your doctor or pharmacist. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines

270

Augmentin can have side effects and the symptoms may make you unfit to drive. Don’t drive or operate machinery unless you are feeling well. 3. HOW TO TAKE AUGMENTIN Always take Augmentin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Adults and children weighing 40 kg and over The usual dose is: 250 mg/125 mg dispersible tablets • 1 tablet three times a day 500 mg/125 mg dispersible tablets • 1 tablet three times a day Children weighing less than 40 kg Augmentin dispersible tablets are not recommended for children weighing less than 40 kg. Ask your doctor or pharmacist for advice. Patients with kidney and liver problems • If you have kidney problems the dose might be changed. A different strength or a different


working. How to take Augmentin • Just before you need to take the tablet, stir it in a glass of water so that it disperses, • Swallow the mixture at the start of a meal or slightly before. • Space the doses evenly during the day, at least 4 hours apart. Do not take 2 doses in 1 hour. • Do not take Augmentin for more than 2 weeks. If you still feel unwell you should go back to

see the doctor. If you take more Augmentin than you should If you have too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to your doctor as soon as possible. Take the medicine carton to show the doctor. If you forget to take Augmentin If you forget to take a dose, take it as soon as you remember. You should not take the next dose too soon, but wait about 4 hours before taking the next dose. If you stop taking Augmentin Keep taking Augmentin until the treatment is finished, even if you feel better. You need every dose to help fight the infection. If some bacteria survive they can cause the infection to come back. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. The side effects below may happen with this medicine.

271

Conditions you need to look out for







Rare side effects that may show up in your blood tests: • low number of cells involved in blood clotting • low number of white blood cells.

272

Other side effects









you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN [To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Augmentin contains [To be completed nationally]

273

What Augmentin looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: 250 mg/125 mg dispersible tablets Ireland – Augmentin United Kingdom – Augmentin 500 mg/125 mg dispersible tablets Austria - Augmentin, Clavamox Germany - Augmentan Greece – Augmentin This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

274








275


{Augmentin and associated names (see Annex I) 500 mg/125 mg powder for oral suspension in sachets}







please tell your doctor or pharmacist. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you take Augmentin 3. How to take Augmentin 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in adults and children to treat the following infections: • middle ear and sinus infections • respiratory tract infections • urinary tract infections • skin and soft tissue infections including dental infections • bone and joint infections. 2. BEFORE YOU TAKE AUGMENTIN Do not take Augmentin: • if you are allergic (hypersensitive) to amoxicillin, clavulanic acid, penicillin or any of the other



antibiotic.

276

Do not take Augmentin if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Augmentin.

Take special care with Augmentin Talk to your doctor or pharmacist before taking this medicine if you: • have glandular fever • are being treated for liver or kidney problems • are not passing water regularly. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4.

Blood and urine tests If you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor or pharmacist if you are using or have recently used any other medicines. This includes medicines that can be bought without a prescription and herbal medicines. If you are taking allopurinol (used for gout) with Augmentin, it may be more likely that you’ll have an allergic skin reaction. If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding If you are pregnant, you think you might be pregnant or if you are breast-feeding, please tell your doctor or pharmacist. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Augmentin can have side effects and the symptoms may make you unfit to drive. Don’t drive or operate machinery unless you are feeling well. Important information about some of the ingredients of Augmentin • Augmentin contains aspartame (E951) which is a source of phenylalanine. This may be harmful

for patients with a condition called ’phenylketonuria’.

277

• Augmentin contains maltodextrin (glucose). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE AUGMENTIN Always take Augmentin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Adults and children weighing 40 kg and over 500 mg/125 mg powder for oral suspension in sachets The usual dose is: • 1 sachet three times a day 875 mg/125 mg powder for oral suspension in sachets • Usual dose – 1 sachet two times a day • Higher dose – 1 sachet three times a day 1000 mg/125 mg powder for oral suspension in sachets • Usual dose – 1 sachet three times a day • Lower dose – 1 sachets two times a day Children weighing less than 40 kg Augmentin 500 mg/125 mg sachets are not recommended. Augmentin 875 mg/125 mg sachets are not recommended. Augmentin 1000 mg/125 mg sachets are not recommended. Patients with kidney and liver problems • If you have kidney problems the dose might be changed. A different strength or a different


working. How to take Augmentin • Just before you need to take Augmentin, open the sachet and mix the contents in half a glass of

water. • Swallow the mixture at the start of a meal or slightly before. • Space the doses evenly during the day, at least 4 hours apart. Do not take 2 doses in 1 hour. • Do not take Augmentin for more than 2 weeks. If you still feel unwell you should go back to

see the doctor. If you take more Augmentin than you should If you take too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to your doctor as soon as possible. Take the medicine carton to show the doctor. If you forget to take Augmentin If you forget to take a dose, take it as soon as you remember. You should not take the next dose too soon, but wait about 4 hours before taking the next dose. If you stop taking Augmentin Keep taking Augmentin until the treatment is finished, even if you feel better. You need every dose to help fight the infection. If some bacteria survive they can cause the infection to come back. If you have any further questions on the use of this product, ask your doctor or pharmacist.

278

4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. The side effects below may happen with this medicine. Conditions you need to look out for








279

Other side effects









you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN [To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Augmentin contains [To be completed nationally]

280

What Augmentin looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: 500 mg/125 mg powder for oral suspension in sachets Belgium – Augmentin Luxembourg – Augmentin Spain – Augmentine, Clavumox 875 mg/125 mg powder for oral suspension in sachets Italy – Augmentin, Neoduplamox, Clavulin Spain – Augmentine, Clavumox 1000 mg/125 mg powder for oral suspension in sachets France – Augmentin This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

281








282


{Augmentin and associated names (see Annex I) 125 mg/31.25 mg powder for oral suspension in sachets}







Read all of this leaflet carefully before you start giving your child this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine is usually prescribed for a baby or child. Do not pass it on to others. It may harm

them, even if their symptoms are the same as your child’s. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you give Augmentin 3. How to give Augmentin 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in children to treat the following infections: • middle ear and sinus infections • respiratory tract infections • urinary tract infections • skin and soft tissue infections including dental infections • bone and joint infections. 2. BEFORE YOU GIVE AUGMENTIN Do not give your child Augmentin: • if they are allergic (hypersensitive) to amoxicillin, clavulanic acid or any of the other

ingredients of Augmentin (listed in section 6)

283

• if they have ever had a severe allergic (hypersensitive) reaction to any other antibiotic. This can include a skin rash or swelling of the face or neck

• if they have ever had liver problems or jaundice (yellowing of the skin) when taking an antibiotic.

Do not give Augmentin to your child if any of the above apply to your child. If you are not

sure, talk to their doctor or pharmacist before giving Augmentin. Take special care with Augmentin Check with their doctor or pharmacist before giving your child this medicine if they: • have glandular fever • are being treated for liver or kidney problems • are not passing water regularly. If you are not sure if any of the above apply to your child, talk to their doctor or pharmacist before giving Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your child’s infection. Depending on the results, your child may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while your child is taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4.

Blood and urine tests If your child is having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that they are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor or pharmacist if your child is taking or has recently taken any other medicines. This includes medicines that can be bought without a prescription and herbal medicines. If your child is taking allopurinol (used for gout) with Augmentin, it may be more likely that they will have an allergic skin reaction. If your child is taking probenecid (used for gout), your doctor may decide to adjust the dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding If your child who is about to take this medicine is pregnant or breast-feeding, please tell your doctor or pharmacist. Ask your doctor or pharmacist for advice before taking any medicine. Important information about some of the ingredients of Augmentin Important information about some of the ingredients of Augmentin

284

• Augmentin contains aspartame (E951) which is a source of phenylalanine. This may be harmful for children born with a condition called ’phenylketonuria’.

• Augmentin contains maltodextrin (glucose). If you have been told by your doctor that your child has an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO GIVE AUGMENTIN Always give Augmentin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Adults and children weighing 40 kg or over • These sachets are not usually recommended for adults and children weighing 40 kg and over.

Ask your doctor or pharmacist for advice. Children weighing less than 40 kg All doses are worked out depending on the child’s bodyweight in kilograms. • Your doctor will advise you how much Augmentin you should give to your baby or child. 125 mg/31.25 mg and 250 mg/62.5 mg powder for oral suspension in sachets • Usual dose – 20 mg/5 mg to 60 mg/15 mg for each kilogram of body weight a day, given in

three divided doses. 400 mg/57 mg powder for oral suspension in sachets • Usual dose – 25 mg/3.6 mg up to 45 mg/6.4 mg for each kilogram of body weight a day, given

in two divided doses. • Higher dose – up to 70 mg/10 mg for each kilogram of body weight a day, given in two divided

doses. 250 mg/31.25 mg and 500 mg/62.5 mg powder for oral suspension in sachets • Usual dose – 40 mg/5 mg to 80 mg/10 mg for each kilogram of body weight a day, given in

three divided doses. Patients with kidney and liver problems • If your child has kidney problems the dose might be lowered. A different strength or a different

medicine may be chosen by your doctor. • If your child has liver problems they may have more frequent blood tests to see how their liver

is working. How to give Augmentin • Just before you need to give Augmentin, open the sachet and mix the contents in a glass of

water • Give your child the mixture at the start of a meal or slightly before • Space the doses evenly during the day, at least 4 hours apart. Do not give 2 doses in 1 hour. • Do not give your child Augmentin for more than 2 weeks. If your child still feels unwell they

should go back to see the doctor If you give more Augmentin than you should If you give your child too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to their doctor as soon as possible. Take the medicine carton to show the doctor. If you forget to give Augmentin If you forget to give your child a dose, give it as soon as you remember. You should not give your child the next dose too soon, but wait about 4 hours before giving the next dose.

285

If your child stops taking Augmentin Keep giving your child Augmentin until the treatment is finished, even if they feel better. Your child needs every dose to help fight the infection. If some bacteria survive they can cause the infection to come back. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. The side effects below may happen with this medicine. Conditions you need to look out for



Contact a doctor immediately if your child gets any of these symptoms. Stop taking Augmentin.

Inflammation of large intestine Inflammation of the large intestine, causing watery diarrhoea usually with blood and mucus, stomach pain and/or fever.

Contact your doctor as soon as possible for advice if your child gets these symptoms. Very common side effects These may affect more than 1 in 10 people • diarrhoea (in adults). Common side effects These may affect up to 1 in 10 people • thrush (candida - a yeast infection of the vagina, mouth or skin folds) • feeling sick (nausea), especially when taking high doses → if affected take Augmentin before food • vomiting • diarrhoea (in children). Uncommon side effects These may affect up to 1 in 100 people • skin rash, itching • raised itchy rash (hives) • indigestion • dizziness • headache.

Uncommon side effects that may show up in blood tests: • increase in some substances (enzymes) produced by the liver. Rare side effects

286

These may affect up to 1 in 1000 people • skin rash, which may blister, and looks like small targets (central dark spots surrounded by a


Rare side effects that may show up in blood tests: • low number of cells involved in blood clotting • low number of white blood cells. Other side effects




Contact a doctor immediately if your child gets any of these symptoms.


may make your child’s skin and whites of the eyes appear yellow • inflammation of tubes in the kidney • blood takes longer to clot • hyperactivity • convulsions (in people taking high doses of Augmentin or who have kidney problems) • black tongue which looks hairy • stained teeth (in children), usually removed by brushing.

Side effects that may show up in blood or urine tests: • severe reduction in the number of white blood cells • low number of red blood cells (haemolytic anaemia) • crystals in urine.

If your child gets side effects Tell your doctor or pharmacist if any of the side effects become severe or troublesome, or if

you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN [To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

287

6. FURTHER INFORMATION What Augmentin contains [To be completed nationally] What Augmentin looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: 125 mg/31.25 mg powder for oral suspension in sachets Sweden – Spektramox United Kingdom – Augmentin 250 mg/62.5 mg powder for oral suspension in sachets Spain – Clavumox 400 mg/57 mg powder for oral suspension in sachets Italy - Augmentin, Neoduplamox, Clavulin 250 mg/31.25 mg powder for oral suspension in sachets France – Augmentin 500 mg/62.5 mg powder for oral suspension in sachets France – Augmentin This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

288








289


{Augmentin and associated names (see Annex I) 125 mg/62.5 mg/5 ml powder for oral suspension}

{Augmentin and associated names (see Annex I) 50 mg/12.5 mg/ml powder for oral suspension} {Augmentin and associated names (see Annex I) 125 mg/31.25 mg/5 ml powder for oral

suspension} {Augmentin and associated names (see Annex I) 250 mg/62.5 mg/5 ml powder for oral


suspension} {Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension

(strawberry flavour)} {Augmentin and associated names (see Annex I) 400 mg/57 mg/5 ml powder for oral suspension

(mixed fruit flavour)} {Augmentin and associated names (see Annex I) 100 mg/12.5 mg/ml powder for oral


suspension}



Read all of this leaflet carefully before you start giving your child this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine is usually prescribed for a baby or child. Do not pass it on to others. It may harm

them, even if their symptoms are the same as your child’s. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you give Augmentin 3. How to give Augmentin 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections.. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in babies and children to treat the following infections: 125 mg/62.5 mg/5 ml powder for oral suspension • sinus infections • urinary tract infections • skin and soft tissue infections • dental infections.

290

50 mg/12.5 mg/ml, 125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml, 200 mg/28.5 mg/5 ml, 400 mg/57 mg/5 ml (strawberry flavour), 400 mg/57 mg/5 ml (mixed fruit flavour), 100 mg/12.5 mg/ml powder for oral suspension • middle ear and sinus infections • respiratory tract infections • urinary tract infections • skin and soft tissue infections including dental infections • bone and joint infections. 600 mg/42.9 mg/5 ml powder for oral suspension • middle ear infections • lung infections. 2. BEFORE YOU GIVE AUGMENTIN Do not give your child Augmentin: • if they are allergic (hypersensitive) to amoxicillin, clavulanic acid or any of the other

ingredients of Augmentin (listed in section 6) • if they have ever had a severe allergic (hypersensitive) reaction to any other antibiotic. This can

include a skin rash or swelling of the face or neck • if they have ever had liver problems or jaundice (yellowing of the skin) when taking an

antibiotic. Do not give Augmentin to your child if any of the above apply to your child. If you are not

sure, talk to their doctor or pharmacist before giving Augmentin. Take special care with Augmentin Check with their doctor or pharmacist before giving your child this medicine if they: • have glandular fever • are being treated for liver or kidney problems • are not passing water regularly. If you are not sure if any of the above apply to your child, talk to their doctor or pharmacist before giving Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your child’s infection. Depending on the results, your child may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while your child is taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4.

Blood or urine tests If your child is having blood tests (such as red blood cell status tests or liver function tests) or urine tests, let the doctor or nurse know that they are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor or pharmacist if your child is taking or has recently taken any other medicines. This includes medicines that can be bought without a prescription and herbal medicines.

291

If your child is taking allopurinol (used for gout) with Augmentin, it may be more likely that they will have an allergic skin reaction. If your child is taking probenecid (used for gout), your doctor may decide to adjust the dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding If your child who is about to take this medicine is pregnant or breast-feeding, please tell your doctor or pharmacist. Ask your doctor or pharmacist for advice before taking any medicine. Important information about some of the ingredients of Augmentin • Augmentin contains aspartame (E951) which is a source of phenylalanine. This may be harmful

for children born with a condition called ’phenylketonuria’. • Augmentin contains maltodextrin (glucose). If you have been told by your doctor that your

child has an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO GIVE AUGMENTIN Always give Augmentin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Adults and children weighing 40 kg or over • This suspension is not usually recommended for adults and children weighing 40 kg and over.

Ask your doctor or pharmacist for advice. Children weighing less than 40 kg All doses are worked out depending on the child’s bodyweight in kilograms. • Your doctor will advise you how much Augmentin you should give to your baby or child. 125 mg/62.5 mg/5 ml powder for oral suspension • Usual dose – 9 mg/4.5 mg to 18 mg/9 mg for each kilogram of body weight a day, given in

three divided doses. Augmentin 125 mg/62.5 mg/5 ml suspension is not usually recommended for use in children aged less than 6 years. 50 mg/12.5 mg/ml powder for oral suspension • You may be provided with a plastic syringe doser. You should use this to give the correct dose

to your baby or child. • Usual dose –20 mg/5 mg to 60 mg/15 mg for each kilogram of body weight a day, given in

three divided doses. 125 mg/31.25 mg/5 ml and 250 mg/62.5 mg/5 ml powder for oral suspension • You may be provided with a plastic measuring spoon or measuring cup. You should use this to

give the correct dose to your baby or child.

292

• Usual dose – 20 mg/5 mg to 60 mg/15 mg for each kilogram of body weight a day, given in three divided doses.

200 mg/28.5 mg/5 ml; 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour) • You may be provided with a plastic measuring spoon or measuring cup. You should use this to

give the correct dose to your baby or child. • Usual dose – 25 mg/3.6 mg to 45 mg/6.4 mg for each kilogram of body weight a day, given in

two divided doses. • Higher dose – up to 70 mg/10 mg for each kilogram of body weight a day, given in two divided

doses. 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour) • You may be provided with a plastic syringe dose, measuring spoon or measuring cup. You

should use this to give the correct dose to your baby or child. • Usual dose – 25 mg/3.6 mg to 45 mg/6.4 mg for each kilogram of body weight a day, given in

two divided doses. • Higher dose – up to 70 mg/10 mg for each kilogram of body weight a day, given in two divided

doses. 100 mg/12.5 mg/ml powder for oral suspension • You may be provided with a plastic syringe doser. You should use this to give the correct dose

to your baby or child. • Usual dose – 40 mg/5 mg to 80 mg/10 mg for each kilogram of body weight a day, given in

three divided doses. 600 mg/42.9 mg/5 ml powder for oral suspension • You may be provided with a plastic measuring spoon or measuring cup. You should use this to

give the correct dose to your baby or child. • Usual dose – 90 mg/6.4 mg for each kilogram of body weight a day, given in two divided doses. Augmentin is not recommended for children aged less than 3 months. Patients with kidney and liver problems • If your child has kidney problems the dose might be lowered. A different strength or a different

medicine may be chosen by your doctor. • If your child has liver problems they may have more frequent blood tests to see how their liver

is working. How to give Augmentin • Always shake the bottle well before each dose • Give at the start of a meal or slightly before • Space the doses evenly during the day, at least 4 hours apart. Do not take 2 doses in 1 hour. • Do not give your child Augmentin for more than 2 weeks. If your child still feels unwell they

should go back to see the doctor. If you give more Augmentin than you should If you give your child too much Augmentin, signs might include an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. Talk to their doctor as soon as possible. Take the medicine bottle to show the doctor. If you forget to give Augmentin If you forget to give your child a dose, give it as soon as you remember. You should not give your child the next dose too soon, but wait about 4 hours before giving the next dose. If your child stops taking Augmentin

293

Keep giving your child Augmentin until the treatment is finished, even if they feel better. Your child needs every dose to help fight the infection. If some bacteria survive they can cause the infection to come back. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. The side effects below may happen with this medicine. Conditions you need to look out for



Contact a doctor immediately if your child gets any of these symptoms. Stop taking Augmentin.

Inflammation of large intestine Inflammation of the large intestine, causing watery diarrhoea usually with blood and mucus, stomach pain and/or fever.

Contact your doctor as soon as possible for advice if your child gets these symptoms. Very common side effects These may affect more than 1 in 10 people • diarrhoea (in adults). Common side effects These may affect up to 1 in 10 people • thrush (candida - a yeast infection of the vagina, mouth or skin folds) • feeling sick (nausea), especially when taking high doses → if affected take Augmentin before food • vomiting • diarrhoea (in children). Uncommon side effects These may affect up to 1 in 100 people • skin rash, itching • raised itchy rash (hives) • indigestion • dizziness • headache.

Uncommon side effects that may show up in blood tests: • increase in some substances (enzymes) produced by the liver. Rare side effects These may affect up to 1 in 1000 people

294

• skin rash, which may blister, and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge – erythema multiforme)

if you notice any of these symptoms contact a doctor urgently.

Rare side effects that may show up in blood tests: • low number of cells involved in blood clotting • low number of white blood cells. Other side effects




Contact a doctor immediately if your child gets any of these symptoms.


may make your child’s skin and whites of the eyes appear yellow • inflammation of tubes in the kidney • blood takes longer to clot • hyperactivity • convulsions (in people taking high doses of Augmentin or who have kidney problems) • black tongue which looks hairy • stained teeth (in children), usually removed by brushing.

Side effects that may show up in blood or urine tests: • severe reduction in the number of white blood cells • low number of red blood cells (haemolytic anaemia) • crystals in urine.

If your child gets side effects Tell your doctor or pharmacist if any of the side effects become severe or troublesome, or if

you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN [To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

295

6. FURTHER INFORMATION What Augmentin contains [To be completed nationally] What Augmentin looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: 125 mg/62.5 mg/5 ml powder for oral suspension Ireland – Augmentin, Clavamel 50 mg/12.5 mg/ml powder for oral suspension Germany - Augmentan 125 mg/31.25 mg/5 ml powder for oral suspension Austria – Clavamox Belgium- Augmentin Bulgaria- Augmentin Cyprus –Noprilam Czech Republic- Augmentin Denmark- Spektramox Germany – Augmentan Greece – Augmentin Hungary- Augmentin Ireland – Augmentin, Clavamel Luxembourg – Augmentin Netherlands – Augmentin, Amoxicilline/clavulaanzuur Poland – Augmentin Portugal – Augmentin, Clavamox, Noprilam, Penilan Spain – Clavumox Sweden – Spektramox United Kingdom – Augmentin 250 mg/62.5 mg/5 ml powder for oral suspension Austria – Clavamox Belgium- Augmentin Bulgaria- Augmentin Cyprus – Augmentin, Noprilam Czech Republic- Augmentin Denmark- Spektramox Germany – Augmentan Greece – Augmentin Hungary- Augmentin Iceland – Augmentin Luxembourg – Augmentin Netherlands – Augmentin, Amoxicilline/clavulaanzuur Poland – Augmentin

296

Portugal – Augmentin Forte, Clavamox, Noprilam, Penilan Forte Sweden – Spektramox United Kingdom - Augmentin 200 mg/28.5 mg/5 ml powder for oral suspension Finland – Clavurion Lithuania – Augmentin United Kingdom – Augmentin Duo 400 mg/57 mg/5 ml powder for oral suspension (mixed fruit flavour) Bulgaria – Augmentin Germany – Augmentan Lithuania - Augmentin 400 mg/57 mg/5 ml powder for oral suspension (strawberry flavour) Austria – Augmentin, Clavamox Duo Cyprus – Augmentin, Noprilam DT Czech Republic- Augmentin Duo Estonia – Augmentin Finland – Augmentin, Clavurion Greece – Augmentin Hungary- Augmentin Duo Iceland – Augmentin Ireland – Augmentin Duo Italy – Augmentin, Neoduplamox, Clavulin Latvia – Augmentin Malta – Augmentin, Noprilam DT Poland – Augmentin Portugal – Augmentin Duo, Clavamox DT Romania – Augmentin BIS Slovak Republic- Augmentin DUO Slovenia – Augmentin Sweden – Spektramox United Kingdom – Augmentin Duo 100 mg/12.5 mg/ml powder for oral suspension France – Augmentin Netherlands – Augmentin Spain - Augmentine 600 mg/42.9 mg/5 ml powder for oral suspension Bulgaria – Augmentin ES Cyprus – Augmentin ES Greece – Augmentin ES Hungary – Augmentin Extra Latvia – Augmentin ES Lithuania – Augmentin ES Poland – Augmentin ES Portugal – Augmentin ES, Clavamox ES Romania- Augmentin ES Slovak Republic- Augmentin ES This leaflet was last approved in {MM/YYYY}. [To be completed nationally]

297








298


{Augmentin and associated names (see Annex I) 250 mg/25 mg powder for solution for

injection/infusion} {Augmentin and associated names (see Annex I) 500 mg/50 mg powder for solution for





infusion}



Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, pharmacist or nurse. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor, pharmacist or nurse. In this leaflet: 1. What Augmentin is and what it is used for 2. Before you have Augmentin 3. How Augmentin is given 4. Possible side effects 5. How to store Augmentin 6. Further information 1. WHAT AUGMENTIN IS AND WHAT IT IS USED FOR Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening. Augmentin is used in adults and children to treat the following infections: • severe ear, nose and throat infections • respiratory tract infections • urinary tract infections • skin and soft tissue infections including dental infections • bone and joint infections • intra-abdominal infections • genital organ infections in women. Augmentin is used in adults and children to prevent infections associated with major surgical procedures.

299

2. BEFORE YOU HAVE AUGMENTIN You should not have Augmentin: • if you are allergic (hypersensitive) to amoxicillin, clavulanic acid, penicillin or any of the other




doctor, pharmacist or nurse before having Augmentin. Take special care with Augmentin Talk to your doctor, pharmacist or nurse before taking this medicine if you: • have glandular fever • are being treated for liver or kidney problems • are not passing water regularly. If you are not sure if any of the above apply to you, talk to your doctor, pharmacist or nurse before taking Augmentin. In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of Augmentin or a different medicine. Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4.

Blood and urine tests If you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking Augmentin. This is because Augmentin can affect the results of these types of tests. Using other medicines Please tell your doctor, pharmacist or nurse if you are using or have recently used any other medicines. This includes medicines that can be bought without a prescription and herbal medicines. If you are taking allopurinol (used for gout) with Augmentin, it may be more likely that you’ll have an allergic skin reaction. If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of Augmentin. If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed. Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works. Pregnancy and breast-feeding Ask your doctor, pharmacist or nurse for advice if you are pregnant or breast-feeding. Important information about some of the ingredients of Augmentin 250 mg/25 mg powder for injection or infusion

300

• Augmentin 250 mg/25 mg contains approximately 15.7 mg (0.7 mmol) of sodium. This should be considered if you are on a controlled sodium diet.

• Augmentin 250 mg/25 mg contains approximately 4.9 mg (0.1 mmol) of potassium. This should be considered by patients with kidney problems or patients on a controlled potassium diet.

500 mg/50 mg powder for injection or infusion • Augmentin 500 mg/50 mg contains approximately 31.5 mg (1.4 mmol) of sodium. This should

be considered if you are on a controlled sodium diet. • Augmentin 500 mg/50 mg contains approximately 9.8 mg (0.3 mmol) of potassium. This

should be considered by patients with kidney problems or patients on a controlled potassium diet.

500 mg/100 mg powder for injection or infusion • Augmentin 500 mg/100 mg contains approximately 31.4 mg (1.4 mmol) of sodium. This

should be considered if you are on a controlled sodium diet. • Augmentin 500 mg/100 mg contains approximately 19.6 mg (0.5 mmol)of potassium. This



should be considered if you are on a controlled sodium diet. • Augmentin 1000 mg/100 mg contains approximately 19.6 mg (0.5 mmol) of potassium. This





2000 mg/200 mg powder for infusion • Augmentin 2000 mg/200 mg contains approximately 125.9 mg (5.5 mmol) of sodium. This



3. HOW AUGMENTIN IS GIVEN You will never give yourself this medicine. A qualified person, like a doctor or a nurse, will give you this medicine. The usual doses are: 250 mg/25 mg, 500 mg/50 mg, 1000 mg/100 mg, 2000 mg/200 mg powder for injection or infusion Adults and children weighing 40 kg and over Standard dose

1000 mg/100 mg every 8 to 12 hours.

Higher dose 1000 mg/100 mg every 8 hours or 2000 mg/200 mg every 12 hours

301

For very severe infections, the dose may be increased up to 2000 mg/200 mg every 8 hours.

To stop infections during and after surgery 1000 mg/100 mg to 2000 mg/200 mg before the surgery when you are given your anaesthetic. The dose can differ depending on the type of operation you are having. Your doctor may repeat the dose if your surgery takes longer than 1 hour.

Children weighing less than 40 kg • All doses are worked out depending on the child’s bodyweight in kilograms. Children aged 3 months and over: 50 mg/5 mg for each kilogram of bodyweight

every 8 hours. Children aged less than 3 months or weighing less than 4 kg

50 mg/5 mg for each kilogram of bodyweight every 12 hours.

500 mg/100 mg, 1000 mg/200 mg powder for injection or infusion Adults, and children weighing 40 kg and over Standard dose

1000 mg/200 mg every 8 hours.

To stop infections during and after surgery 1000 mg/200 mg before the surgery when you are given your anaesthetic. The dose can differ depending on the type of operation you are having. Your doctor may repeat the dose if your surgery takes longer than 1 hour.

Children weighing less than 40 kg • All doses are worked out depending on the child’s bodyweight in kilograms. Children aged 3 months and over: 25 mg/5 mg for each kilogram of bodyweight

every 8 hours. Children aged less than 3 months or weighing less than 4 kg

25 mg/5 mg for each kilogram of bodyweight every 12 hours.

Patients with kidney and liver problems • If you have kidney problems you may be given a different dose. A different strength or a

different medicine may be chosen by your doctor. • If you have liver problems your doctor will keep a close check on you and you may have more

regular liver function tests. How Augmentin will be given to you • Augmentin will be given as an injection into a vein or by intravenous infusion. • Make sure you drink plenty of fluids while having Augmentin. • You will not normally be given Augmentin for longer than 2 weeks without the doctor

reviewing your treatment. If more Augmentin is given to you than recommended It is unlikely you will be given too much, but if you think you have been given too much Augmentin, tell your doctor, pharmacist or nurse immediately. Signs may be an upset stomach (feeling sick, being sick or diarrhoea) or convulsions.

302

If you have any further questions about how this product is given, ask your doctor, pharmacist or nurse. 4. POSSIBLE SIDE EFFECTS Like all medicines, Augmentin can cause side effects, although not everybody gets them. The side effects below may happen with this medicine. Conditions you need to look out for




Contact your doctor as soon as possible for advice if you get these symptoms. Common side effects These may affect up to 1 in 10 people • thrush (candida - a yeast infection of the vagina, mouth or skin folds) • diarrhoea Uncommon side effects These may affect up to 1 in 100 people • skin rash, itching • raised itchy rash (hives) • feeling sick (nausea), especially when taking high doses → if affected take Augmentin before food • vomiting • indigestion • dizziness • headache.



• swelling and redness along a vein which is extremely tender when touched


303

Other side effects






may make your skin and whites of the eyes appear yellow • inflammation of tubes in the kidney • blood takes longer to clot • convulsions (in people taking high doses of Augmentin or who have kidney problems). Side effects that may show up in your blood or urine tests: • severe reduction in the number of white blood cells • low number of red blood cells (haemolytic anaemia) • crystals in urine.


you notice any side effects not listed in this leaflet. 5. HOW TO STORE AUGMENTIN [To be completed nationally] Keep out of the reach and sight of children. Do not use Augmentin after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Augmentin contains [To be completed nationally] What Augmentin looks like and contents of the pack [To be completed nationally]

304

Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: 250 mg/25 mg powder for solution for injection or infusion Germany – Augmentan Netherlands - Augmentin 500 mg/50 mg powder for solution for injection or infusion Austria – Augmentin intravenös, Clavamox intravenös Belgium – Augmentin France – Augmentin IV Luxembourg – Augmentin Netherlands – Augmentin Spain – Augmentine Intravenoso 500 mg/100 mg powder for solution for injection or infusion Cyprus – Augmentin Czech Republic – Augmentin France – Augmentin IV Germany – Augmentan IV Greece – Augmentin Hungary – Augmentin Iceland – Augmentin IV Ireland – Augmentin Intravenous Malta – Augmentin Intravenous Netherlands – Augmentin Poland – Augmentin Slovenia – Augmentin United Kingdom- Augmentin Intravenous 1000 mg/100 mg powder for solution for injection or infusion Austria – Augmentin intravenös, Clavamox intravenös Belgium – Augmentin France – Augmentin IV Luxembourg – Augmentin Netherlands – Augmentin 1000 mg/200 mg powder for solution for injection or infusion Belgium – Augmentin Cyprus – Augmentin Czech Republic – Augmentin Estonia – Augmentin France – Augmentin IV Germany – Augmentan IV Greece – Augmentin Hungary- Augmentin Iceland- Augmentin IV Ireland- Augmentin Intravenous Italy - Augmentin Latvia – Augmentin Luxembourg – Augmentin

305

Malta – Augmentin Intravenous Netherlands – Augmentin Poland – Augmentin Romania – Augmentin Intravenos Slovenia – Augmentin Spain – Augmentine Intravenoso United Kingdom – Augmentin Intravenous 2000 mg/200 mg powder for solution for infusion Austria – Augmentin intravenös, Clavamox intravenös Belgium – Augmentin France – Augmentin IV Germany – Augmentan IV Italy - Augmentin Luxembourg – Augmentin Netherlands – Augmentin Poland – Augmentin Romania – Augmentin Intravenos Spain – Augmentine Intravenoso This leaflet was last approved in {MM/YYYY}. [To be completed nationally] --------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: Please refer to the Summary of Product Characteristics for further information Administration Augmentin may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Augmentin is not suitable for intramuscular administration. Reconstitution [To be completed nationally] Stability of prepared solutions [To be completed nationally]

annex i list of the names, pharmaceutical forms, … · products, routes of administration,...

Documents