vancomycin article 31-1440 - european...

1

ANNEX I

2

Member State

EU/EEA

Marketing authorisation holder

Invented name INN + Strength Pharmaceutical form

Route of administration

Austria Actavis Group Ptc Ehf.

Vancomycin Actavis VANCOMYCIN 1000MG VIAL

POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Austria Actavis Group Ptc Ehf.



INTRAVENOUS USE

Austria Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL

POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Austria Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Austria Riemser Pharma Gmbh

Vancomycin Enterocaps 250 Mg Kapseln

VANCOMYCIN HYDROCHLORIDE 250MG CAPSULE

CAPSULE, HARD ORAL USE

Austria Hikma Farmacêutica (Portugal), S.A.

Vancomycin Hikma VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE




INTRAVENOUS USE


Vancomycin Hikma VANCOMYCIN 50MG/ML

POWDER FOR CONCENTRATE FOR

INTRAVENOUS USE

3

Member State

EU/EEA




SOLUTION FOR INFUSION

Austria Mip Pharma Austria Gmbh

Vancomycin Mip VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Austria Mip Pharma Austria Gmbh

Vancomycin Mip VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Austria Arcana Arzneimittel Gmbh

Vancomycin Mylan VANCOMYCIN 50MG/ML


INTRAVENOUS USE, ORAL USE

Austria Noridem Enterprises Ltd

Vancomycin Noridem VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Austria Noridem Enterprises Ltd



INTRAVENOUS USE

Austria Pfizer Corporation Austria Gesellschaft M.B.H.

Vancomycin Pfizer VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Austria Pfizer Corporation Austria Gesellschaft M.B.H.

Vancomycin Pfizer VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Austria Xellia Vancomycin Xellia VANCOMYCIN POWDER FOR INTRAVENOUS USE

4

Member State

EU/EEA




Pharmaceuticals Aps HYDROCHLORIDE 513MG VIAL


Austria Xellia Pharmaceuticals Aps

Vancomycin Xellia VANCOMYCIN HYDROCHLORIDE 1026MG VIAL


INTRAVENOUS USE

Austria Hospira Deutschland Gmbh

Vanycin VANCOMYCIN 50MG/ML



Belgium Teva Pharma Belgium N.V.-S.A

Vamysin VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE




INTRAVENOUS USE

Belgium Cnp Pharma Gmbh Vancomycin Cnp Pharma

VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Belgium Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Belgium Hospira Benelux Bvba

Vancomycin Hospira VANCOMYCIN 50MG/ML



Belgium Hospira Benelux Vancomycin Hospira VANCOMYCIN POWDER FOR INTRAVENOUS USE,

5

Member State

EU/EEA




Bvba HYDROCHLORIDE 50MG/ML


ORAL USE

Belgium Hospira Benelux Bvba

Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 50MG/ML



Belgium Mylan Bvba-Sprl Vancomycin Mylan VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Belgium Mylan Bvba-Sprl Vancomycin Mylan VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Belgium Mylan Bvba-Sprl Vancomycin Mylan VANCOMYCIN 500MG/ML


INTRAVENOUS USE

Belgium Fresenius Kabi Nv-Sa Vancomycine Fresenius Kabi



INTRAVENOUS USE

Belgium Fresenius Kabi Nv-Sa Vancomycine Fresenius Kabi



INTRAVENOUS USE

Belgium Mylan Bvba-Sprl Vancomycine Mylan VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Belgium Sandoz N.V. Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE

POWDER FOR SOLUTION FOR

INTRAVENOUS USE

6

Member State

EU/EEA




1000MG VIAL INJECTION Belgium Sandoz N.V. Vancomycine Sandoz VANCOMYCIN

HYDROCHLORIDE 500MG VIAL

POWDER FOR SOLUTION FOR INJECTION

INTRAVENOUS USE


Vancomycine Teva VANCOMYCIN HYDROCHLORIDE 1G


INTRAVENOUS USE


Vancomycine Teva VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Belgium Mylan Bvba-Sprl Vancomylan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE



DIRECT INTRAVENOUS INJECTION



INTRAVENOUS USE

Bulgaria Lek Pharmaceuticals D.D. Ljubljana

Edicin VANCOMYCIN HYDROCHLORIDE 1G VIAL


INTRAVENOUS USE

Bulgaria Tchaikapharma High Quality Medicines, Inc.

Vancocin Cp VANCOMYCIN HYDROCHLORIDE 1G AMPOULE


INTRAVENOUS USE

7

Member State

EU/EEA




Bulgaria Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Bulgaria Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Bulgaria Sandoz Pharmaceuticals D.D.

Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INHALATION USE

Bulgaria Actavis Group Ptc Ehf.

аквисцин VANCOMYCIN HYDROCHLORIDE 1000000 I.U. VIAL


INTRAVENOUS USE

Bulgaria Actavis Group Ptc Ehf.

аквисцин VANCOMYCIN HYDROCHLORIDE 500000 I.U. VIAL


INTRAVENOUS USE

Bulgaria Mip Pharma Gmbh ванкомицин Mip VANCOMYCIN 1000MG VIAL



Bulgaria Mip Pharma Gmbh ванкомицин Mip VANCOMYCIN 500MG VIAL



Bulgaria Fresenius Kabi Bulgaria Eood

ванкомицин каби VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Bulgaria Fresenius Kabi ванкомицин каби VANCOMYCIN 500MG POWDER FOR INTRAVENOUS USE

8

Member State

EU/EEA




Bulgaria Eood CONCENTRATE FOR SOLUTION FOR INFUSION

Bulgaria Fresenius Kabi Bulgaria Eood

ванкомицин каби VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Bulgaria Hospira Uk Ltd ванкомицин хоспира VANCOMYCIN 50MG/ML



Bulgaria Hospira Uk Ltd ванкомицин хоспира VANCOMYCIN 50MG/ML



Croatia Pliva Hrvatska D.O.O.

Adimicin VANCOMYCIN HYDROCHLORIDE 1000MG/1000 MG

POWDER FOR INJECTION

INTRAVENOUS USE

Croatia Pliva Hrvatska D.O.O.

Adimicin VANCOMYCIN HYDROCHLORIDE 500MG/500 MG

POWDER FOR INJECTION

INTRAVENOUS USE

Croatia Sandoz D.O.O. Edicin VANCOMYCIN HYDROCHLORIDE 0.5G VIAL


INTRAVENOUS USE

Croatia Sandoz D.O.O. Edicin VANCOMYCIN HYDROCHLORIDE 1G VIAL


INTRAVENOUS USE

Croatia Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE



9

Member State

EU/EEA




50MG/ML SOLUTION FOR INFUSION

Croatia Fresenius Kabi D.O.O.

Vancomycin Kabi VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Croatia Fresenius Kabi D.O.O.



INTRAVENOUS USE

Croatia Cnp Pharma Gmbh Vankomicin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Croatia Cnp Pharma Gmbh Vankomicin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Croatia Pharmaswiss D.O.O. Vankomicin Pharmaswiss

VANCOMYCIN HYDROCHLORIDE 1025.14MG VIAL



Croatia Pharmaswiss D.O.O. Vankomicin Pharmaswiss




Cyprus Sapiens Pharmaceuticals Ltd

Vanco VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION


Cyprus Pharmaceutical Trading Co Ltd

Vancomycin Hydrochloride Pharmaceutical


POWDER FOR CONCENTRATE FOR SOLUTION FOR


10

Member State

EU/EEA




Trading INFUSION Cyprus Mylan S.A.S Vancomycin Mylan VANCOMYCIN 1G VIAL POWDER FOR


INTRAVENOUS USE

Cyprus Mylan S.A.S Vancomycin Mylan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Czech Republic Lek Pharmaceuticals D.D.

Edicin VANCOMYCIN 500MG VIAL



Czech Republic Lek Pharmaceuticals D.D.




Czech Republic Actavis Group Ptc Ehf.



INTRAVENOUS USE

Czech Republic Actavis Group Ptc Ehf.



INTRAVENOUS USE

Czech Republic Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Czech Republic Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Czech Republic Hikma Farmacêutica Vancomycin Hikma VANCOMYCIN POWDER FOR INTRAVENOUS USE

11

Member State

EU/EEA




(Portugal), S.A. 1000MG VIAL CONCENTRATE FOR SOLUTION FOR INFUSION

Czech Republic Hikma Farmacêutica (Portugal), S.A.



INTRAVENOUS USE

Czech Republic Fresenius Kabi S.R.O Vancomycin Kabi VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Czech Republic Fresenius Kabi S.R.O Vancomycin Kabi VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Czech Republic Mylan S.A.S Vancomycin Mylan VANCOMYCIN HYDROCHLORIDE 1000MG VIAL



Czech Republic Mylan S.A.S Vancomycin Mylan VANCOMYCIN HYDROCHLORIDE 500MG VIAL



Czech Republic Hospira Uk Ltd Vanmicira VANCOMYCIN 50MG/ML



Denmark Mip Pharma Gmbh Bactocin VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

12

Member State

EU/EEA




Denmark Mip Pharma Gmbh Bactocin VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Denmark Strides Arcolab International Limited

Vancocin VANCOMYCIN HYDROCHLORIDE 125MG CAPSULE


Denmark Strides Arcolab International Limited

Vancocin VANCOMYCIN HYDROCHLORIDE 250MG CAPSULE


Denmark Cnp Pharma Gmbh Vancomycin "cnp" VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Denmark Cnp Pharma Gmbh Vancomycin "cnp" VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Denmark Farmaplus A.S. Vancomycin "farmaplus"

VANCOMYCIN HYDROCHLORIDE 0.5G BOTTLE


INTRAVENOUS USE

Denmark Farmaplus A.S. Vancomycin "farmaplus"

VANCOMYCIN HYDROCHLORIDE 1G BOTTLE


INTRAVENOUS USE

Denmark Actavis Group Ptc Ehf.



INTRAVENOUS USE

Denmark Actavis Group Ptc Vancomycin Actavis VANCOMYCIN 500MG POWDER FOR INTRAVENOUS USE

13

Member State

EU/EEA




Ehf. VIAL CONCENTRATE FOR SOLUTION FOR INFUSION


Vancomycin Actavis VANCOMYCIN 125MG CAPSULE





Denmark Fresenius Kabi Ab Vancomycin Fresenius Kabi



INTRAVENOUS USE

Denmark Fresenius Kabi Ab Vancomycin Fresenius Kabi



INTRAVENOUS USE

Denmark Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Denmark Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 1G VIAL


INTRAVENOUS USE

Denmark Orion Corporation Vancomycin Orion VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Denmark Orion Corporation Vancomycin Orion VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

14

Member State

EU/EEA




INFUSION Denmark Sandoz A-S Vancomycin Sandoz VANCOMYCIN



INTRAVENOUS USE

Denmark Sandoz A-S Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Denmark Teva Denmark A-S Vancomycin Teva VANCOMYCIN HYDROCHLORIDE 1000MG/1000 G


CUTANEOUS USE

Denmark Teva Denmark A-S Vancomycin Teva VANCOMYCIN HYDROCHLORIDE 500MG/MG


CUTANEOUS USE

Denmark Xellia Pharmaceuticals Aps

Vancomycin Xellia VANCOMYCIN 125MG CAPSULE








INTRAVENOUS USE




INTRAVENOUS USE

Estonia Actavis Group Ptc Ehf.



INTRAVENOUS USE

15

Member State

EU/EEA




INFUSION Estonia Actavis Group Ptc

Ehf. Vancomycin Actavis VANCOMYCIN 500MG

VIAL POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Estonia Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Estonia Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Estonia Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 50MG/ML


ORAL USE

Estonia Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 50MG/ML



Estonia Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Estonia Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Estonia Sandoz Pharmaceuticals D.D.



INTRAVENOUS USE

16

Member State

EU/EEA




Estonia Sandoz Pharmaceuticals D.D.

Vancomycin Sandoz VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Estonia Mip Pharma Gmbh Vancosan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Estonia Mip Pharma Gmbh Vancosan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Finland Actavis Group Ptc Ehf.



INTRAVENOUS USE










INTRAVENOUS USE

Finland Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Finland Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Finland Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN POWDER FOR INTRAVENOUS USE

17

Member State

EU/EEA




HYDROCHLORIDE 1G VIAL

SOLUTION FOR INJECTION

Finland Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Finland Orion Corporation Vancomycin Orion VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Finland Orion Corporation Vancomycin Orion VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Finland Sandoz A-S Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INTRAVENOUS USE

Finland Sandoz A-S Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Finland Xellia Pharmaceuticals Aps

Vancomycin Xellia VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE










INTRAVENOUS USE

18

Member State

EU/EEA




INFUSION Finland Mip Pharma Gmbh Vancosan VANCOMYCIN

1000MG VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Finland Mip Pharma Gmbh Vancosan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

France Fresenius Kabi France S.A.S.

Vancomycine Kabi VANCOMYCIN HYDROCHLORIDE 1000MG


INTRAVENOUS USE

France Fresenius Kabi France S.A.S.

Vancomycine Kabi VANCOMYCIN HYDROCHLORIDE 500MG


INTRAVENOUS USE

France Mip Pharma Gmbh Vancomycine Mip VANCOMYCIN HYDROCHLORIDE 1020MG VIAL


INTRAVENOUS USE

France Mip Pharma Gmbh Vancomycine Mip VANCOMYCIN HYDROCHLORIDE 510MG VIAL


INTRAVENOUS USE

France Mylan S.A.S Vancomycine Mylan VANCOMYCIN HYDROCHLORIDE 1.025G VIAL


INTRAVENOUS USE

France Mylan S.A.S Vancomycine Mylan VANCOMYCIN HYDROCHLORIDE 128.25MG VIAL


INTRAVENOUS USE

France Mylan S.A.S Vancomycine Mylan VANCOMYCIN HYDROCHLORIDE 256.5MG VIAL


INTRAVENOUS USE

19

Member State

EU/EEA




France Mylan S.A.S Vancomycine Mylan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

France Sandoz Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 1G VIAL


INTRAVENOUS USE

France Sandoz Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 1G VIAL


INTRAVENOUS USE

France Sandoz Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 125.18MG VIAL


INTRAVENOUS USE

France Sandoz Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 256.3MG VIAL


INTRAVENOUS USE

France Sandoz Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Germany Ratiopharm Gmbh Vanco VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Germany Ratiopharm Gmbh Vanco VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Germany Cell Pharm Gmbh Vanco-Cell VANCOMYCIN HYDROCHLORIDE 1025MG/1025 MG

POWDER FOR SOLUTION FOR INFUSION / POWDER FOR ORAL SOLUTION


20

Member State

EU/EEA




Germany Cell Pharm Gmbh Vanco-Cell VANCOMYCIN HYDROCHLORIDE 512.5MG/512.5 MG

POWDER FOR SOLUTION FOR INFUSION / POWDER FOR ORAL SOLUTION


Germany Riemser Pharma Gmbh

Vancomycin "lederle" 1000

VANCOMYCIN HYDROCHLORIDE 1000MG


INTRAVENOUS USE


Vancomycin "lederle" 500

VANCOMYCIN HYDROCHLORIDE 500MG


INTRAVENOUS USE

Germany Actavis Group Ptc Ehf.

Vancomycin Actavis VANCOMYCIN HYDROCHLORIDE 512.6MG VIAL

POWDER FOR ORAL SOLUTION, POWDER FOR SOLUTION FOR INJECTION


Germany Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Germany Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Germany Hikma Farmacêutica (Portugal), S.A.

Vancomycin Cp VANCOMYCIN HYDROCHLORIDE 1025.2 - 1040.2MG VIAL

POWDER FOR ORAL SOLUTION, SOLUTION FOR INFUSION


Germany Hikma Farmacêutica (Portugal), S.A.

Vancomycin Cp VANCOMYCIN HYDROCHLORIDE 512.6 - 520.1MG VIAL

POWDER FOR ORAL SOLUTION, SOLUTION FOR INFUSION


Germany Dr. Friedrich Eberth Vancomycin Dr. VANCOMYCIN CAPSULE, HARD ORAL USE

21

Member State

EU/EEA




Arzneimittel Gmbh Eberth HYDROCHLORIDE 125MG CAPSULE

Germany Dr. Friedrich Eberth Arzneimittel Gmbh

Vancomycin Dr. Eberth

VANCOMYCIN 250MG CAPSULE



Vancomycin Enterocaps 250mg

VANCOMYCIN HYDROCHLORIDE 250MG CAPSULE


Germany Hexal Ag Vancomycin Hexal VANCOMYCIN HYDROCHLORIDE 0.5G VIAL



Germany Hexal Ag Vancomycin Hexal VANCOMYCIN HYDROCHLORIDE 1G VIAL



Germany Hospira Deutschland Gmbh

Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 952.38MG VIAL



Germany Hospira Deutschland Gmbh

Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 476.19MG VIAL



Germany Fresenius Kabi Deutschland Gmbh



INTRAVENOUS USE

Germany Fresenius Kabi Deutschland Gmbh



INTRAVENOUS USE

Germany Lyomark Pharma Vancomycin Lyomark VANCOMYCIN POWDER FOR INTRAVENOUS USE

22

Member State

EU/EEA




Gmbh HYDROCHLORIDE 1025MG VIAL

SOLUTION FOR INJECTION/INFUSION

Germany Lyomark Pharma Gmbh

Vancomycin Lyomark VANCOMYCIN HYDROCHLORIDE 512.5MG VIAL


INTRAVENOUS USE

Germany Mip Pharma Gmbh Vancomycin Mip Pharma



INTRAVENOUS USE

Germany Mip Pharma Gmbh Vancomycin Mip Pharma



INTRAVENOUS USE

Germany Mylan Dura Gmbh Vancomycin Mylan VANCOMYCIN 1000MG VIAL



Germany Mylan Dura Gmbh Vancomycin Mylan VANCOMYCIN 500MG VIAL



Germany Noridem Enterprises Ltd



INTRAVENOUS USE

Germany Noridem Enterprises Ltd



INTRAVENOUS USE

Germany Ratiopharm Gmbh Vancomycin VANCOMYCIN POWDER FOR ORAL INTRAVENOUS USE,

23

Member State

EU/EEA




Ratiopharm HYDROCHLORIDE 512.5MG VIAL

SOLUTION, POWDER FOR SOLUTION FOR INJECTION

ORAL USE

Germany Xellia Pharmaceuticals Aps

Vanco-Ratiopharm VANCOMYCIN HYDROCHLORIDE 1026MG VIAL


INTRAVENOUS USE

Germany Xellia Pharmaceuticals Aps

Vanco-Ratiopharm VANCOMYCIN HYDROCHLORIDE 513MG VIAL


INTRAVENOUS USE

Germany Mip Pharma Gmbh Vanco-Saar VANCOMYCIN HYDROCHLORIDE 1020MG VIAL

POWDER FOR ORAL SOLUTION, POWDER FOR SOLUTION FOR INFUSION


Germany Mip Pharma Gmbh Vanco-Saar VANCOMYCIN HYDROCHLORIDE 510MG VIAL



Germany Cnp Pharma Gmbh Vancosan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Germany Cnp Pharma Gmbh Vancosan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Germany Mip Pharma Gmbh Vancosan Oral VANCOMYCIN 500MG VIAL

POWDER FOR ORAL SOLUTION

ORAL USE

Greece Actavis Group Ptc Ehf.



INTRAVENOUS USE

24

Member State

EU/EEA




Greece Actavis Group Ptc Ehf.



INTRAVENOUS USE

Greece Farmaplus A.S. Vancomycin Farmaplus 1000 Mg

VANCOMYCIN HYDROCHLORIDE 1025.2MG UNITS


INTRAVENOUS USE

Greece Farmaplus A.S. Vancomycin Farmaplus 500 Mg

VANCOMYCIN HYDROCHLORIDE 512.571MG UNITS


INTRAVENOUS USE

Greece Generics Pharma Hellas Ltd

Vancomycin Generics VANCOMYCIN 1000MG VIAL



Greece Generics Pharma Hellas Ltd

Vancomycin Generics VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Greece Hospira Uk Ltd Vancomycin Hydrochloride Hospira




Greece Fresenius Kabi Hellas A.E.



INTRAVENOUS USE

Greece Fresenius Kabi Hellas A.E.



INTRAVENOUS USE

Greece Noridem Enterprises Ltd



INTRAVENOUS USE

25

Member State

EU/EEA





Greece Noridem Enterprises Ltd



INTRAVENOUS USE

Greece Norma Hellas S.A. Vancomycin Norma VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Greece Vocate φαρμακευτικη αε

Vancomycin Vocate VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Greece Vocate φαρμακευτικη αε

Vancomycin Vocate VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Greece Finixfarm Ltd Vancomycin φοινιξφαρμ



INTRAVENOUS USE

Greece Pharmaserve-Lilly Saci

Voncon VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Greece Demo Abee Vondem VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Greece Demo Abee Vondem VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Greece Vianex S.A. Voxin® 1g/Vial VANCOMYCIN 1G VIAL POWDER FOR INTRAVENOUS USE

26

Member State

EU/EEA





Greece Vianex S.A. Voxin® 500mg/Vial VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Hungary Actavis Group Ptc Ehf.

Selamat VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Hungary Actavis Group Ptc Ehf.

Selamat VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Hungary Pharmacologic Kft Vancocin VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Hungary Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Hungary Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Hungary Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 50MG/ML



Hungary Fresenius Kabi Hungary Kft.



INTRAVENOUS USE

27

Member State

EU/EEA





Hungary Fresenius Kabi Hungary Kft.



INTRAVENOUS USE

Hungary Pharmaswiss česká Republika S.R.O.

Vancomycin Pharmaswiss




Hungary Pharmaswiss česká Republika S.R.O.





Hungary Teva Gyógyszergyár Zrt

Vancomycin-Human Teva Gyógyszergyár



INTRAVENOUS USE

Hungary Teva Gyógyszergyár Zrt

Vancomycin-Human Teva Gyógyszergyár



INTRAVENOUS USE

Iceland Actavis Group Ptc Ehf.



INTRAVENOUS USE


Vancomycin Actavis VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INTRAVENOUS USE

28

Member State

EU/EEA












CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE


Vancomycin Actavis VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Iceland Fresenius Kabi Ab Vancomycin Fresenius Kabi



INTRAVENOUS USE

Iceland Fresenius Kabi Ab Vancomycin Fresenius Kabi



INTRAVENOUS USE

Iceland Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Iceland Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Iceland Xellia Pharmaceuticals Aps



Iceland Xellia Vancomycin Xellia VANCOMYCIN 250MG CAPSULE, HARD ORAL USE

29

Member State

EU/EEA




Pharmaceuticals Aps CAPSULE Iceland Xellia

Pharmaceuticals Aps Vancomycin Xellia VANCOMYCIN

1000MG VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Iceland Xellia Pharmaceuticals Aps



INTRAVENOUS USE

Ireland Flynn Pharma Ltd. Vancocin VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Ireland Flynn Pharma Limited Vancocin VANCOMYCIN 50MG/ML

POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION, POWDER FOR ORAL SOLUTION


Ireland Flynn Pharma Limited Vancocin Matrigel VANCOMYCIN 125MG CAPSULE


Ireland Flynn Pharma Ltd. Vancocin Matrigel VANCOMYCIN 125MG CAPSULE


Ireland Flynn Pharma Limited Vancocin Matrigel VANCOMYCIN 250MG CAPSULE


Ireland Flynn Pharma Ltd. Vancocin Matrigel VANCOMYCIN 250MG CAPSULE


Ireland Actavis Group Ptc Ehf.


CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE



CONCENTRATE FOR SOLUTION FOR

INTRAVENOUS USE

30

Member State

EU/EEA




INFUSION Ireland Actavis Group Ptc

Ehf. Vancomycin Actavis Group



INTRAVENOUS USE


Vancomycin Actavis Group



INTRAVENOUS USE

Ireland Fresenius Kabi Limited

Vancomycin Fresenius Kabi



INTRAVENOUS USE

Ireland Fresenius Kabi Limited




INTRAVENOUS USE

Ireland Hikma Farmacêutica (Portugal), S.A.

Vancomycin Hikma Farmacêutica (Portugal), S.A.

VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Ireland Hospira Uk Ltd Vancomycin Hydrochloride Hospira Uk

VANCOMYCIN HYDROCHLORIDE 1G VIAL



Ireland Hospira Uk Ltd Vancomycin Hydrochloride Hospira Uk

VANCOMYCIN HYDROCHLORIDE 500MG VIAL



31

Member State

EU/EEA




Ireland Generics [uk] Limited Vancomycin Mylan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Ireland Generics [uk] Limited Vancomycin Mylan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Ireland Mcdermott Laboratories Ltd

Vancomycin Mylan VANCOMYCIN 50MG/ML



Ireland Noridem Enterprises Ltd

Vancomycin Noridem Enterprises

VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Ireland Noridem Enterprises Ltd

Vancomycin Noridem Enterprises Ltd.



INTRAVENOUS USE

Ireland Pfizer Healthcare Ireland

Vancomycin Pfizer Healthcare Ireland



INTRAVENOUS USE

Ireland Pfizer Healthcare Ireland

Vancomycin Pfizer Healthcare Ireland



INTRAVENOUS USE

Italy Genetic Spa Levovanox VANCOMYCIN 1G VIAL ORAL SOLUTION, INTRAVENOUS USE,

32

Member State

EU/EEA




POWDER FOR INFUSION

ORAL USE

Italy Genetic Spa Levovanox VANCOMYCIN 250MG CAPSULE


Italy Genetic Spa Levovanox VANCOMYCIN 500MG VIAL

ORAL SOLUTION, POWDER FOR INFUSION


Italy Genetic Spa Maxivanil VANCOMYCIN HYDROCHLORIDE 1025.14MG VIAL



Italy Genetic Spa Maxivanil VANCOMYCIN HYDROCHLORIDE 256MG CAPSULE


Italy Genetic Spa Maxivanil VANCOMYCIN HYDROCHLORIDE 512.57MG VIAL



Italy Eli Lilly Italia S.P.A. Vancocina A.P. VANCOMYCIN HYDROCHLORIDE 512.57MG VIAL



Italy Hikma Italia S.P.A. Vancomicina VANCOMYCIN HYDROCHLORIDE 1025.14MG VIAL



Italy Hikma Italia S.P.A. Vancomicina Hikma VANCOMYCIN HYDROCHLORIDE

POWDER FOR ORAL SOLUTION, POWDER


33

Member State

EU/EEA




1025.14MG VIAL FOR SOLUTION FOR INFUSION

Italy Hikma Italia S.P.A. Vancomicina Hikma VANCOMYCIN HYDROCHLORIDE 512.57MG BOTTLE



Italy Hospira Spa Vancomicina Hospira VANCOMYCIN HYDROCHLORIDE 1.025G VIAL



Italy Hospira Spa Vancomicina Hospira VANCOMYCIN HYDROCHLORIDE 512.5MG VIAL



Italy Fresenius Kabi Italia S.R.L.

Vancomicina Kabi VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Italy Fresenius Kabi Italia S.R.L.



INTRAVENOUS USE

Italy Mylan S.P.A. Vancomicina Mylan VANCOMYCIN 50MG/ML



Italy Farmaplus As Vancomycin Farmaplus

VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Italy Pharmatex Italia Srl Vancotex VANCOMYCIN HYDROCHLORIDE 512.57MG VIAL



34

Member State

EU/EEA




Italy Pharmatex Italia Srl Vancotex VANCOMYCIN HYDROCHLORIDE 1025.14MG VIAL



Italy Fisiopharma Srl Zengac VANCOMYCIN HYDROCHLORIDE 1025.14MG VIAL



Italy Fisiopharma Srl Zengac VANCOMYCIN HYDROCHLORIDE 512.57MG VIAL



Latvia Lek Pharmaceuticals D.D. Ljubljana

Edicin VANCOMYCIN HYDROCHLORIDE 1000000 I.U. G


INTRAVENOUS USE

Latvia Actavis Group Ptc Ehf.



INTRAVENOUS USE

Latvia Actavis Group Ptc Ehf.



INTRAVENOUS USE

Latvia Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Latvia Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Latvia Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN 50MG/ML



35

Member State

EU/EEA





Latvia Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Latvia Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Latvia Pfizer Europe Ma Eeig Vancomycin Pfizer VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Latvia Pfizer Europe Ma Eeig Vancomycin Pfizer VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Latvia Sandoz Pharmaceuticals D.D.



INTRAVENOUS USE

Latvia Sandoz Pharmaceuticals D.D.



INTRAVENOUS USE

Latvia Mip Pharma Gmbh Vancosan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Latvia Mip Pharma Gmbh Vancosan VANCOMYCIN 500MG POWDER FOR INTRAVENOUS USE

36

Member State

EU/EEA




VIAL SOLUTION FOR INFUSION

Lithuania Actavis Group Ptc Ehf.



INTRAVENOUS USE

Lithuania Actavis Group Ptc Ehf.



INTRAVENOUS USE

Lithuania Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Lithuania Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Lithuania Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN 50MG/ML



Lithuania Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Lithuania Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

37

Member State

EU/EEA




Lithuania Teva Pharma B.V. Vancomycin Teva VANCOMYCIN 1000 I.U. / MG


INTRAVENOUS USE

Lithuania Mip Pharma Gmbh Vancosan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Lithuania Mip Pharma Gmbh Vancosan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Luxembourg Teva Pharma Belgium N.V.-S.A



INTRAVENOUS USE




INTRAVENOUS USE

Luxembourg Fresenius Kabi Deutschland Gmbh



INTRAVENOUS USE

Luxembourg Fresenius Kabi Deutschland Gmbh



INTRAVENOUS USE

Luxembourg Sandoz N.V. Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INTRAVENOUS USE

38

Member State

EU/EEA




Luxembourg Sandoz N.V. Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE


Vancomycine Teva VANCOMYCIN 1000MG/20 ML




Vancomycine Teva VANCOMYCIN 500MG/10 ML



Malta Hospira Uk Ltd Vancomycin Hydrochloride Hospira Uk




Malta Norma Hellas S.A. Vancomycin Norma VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Malta Wockhardt Uk Ltd Vancomycin Wockhardt Uk Ltd




Netherlands Eurocept B.V. Vancocin Cp VANCOMYCIN 500MG and 1000MG


INTRAVENOUS USE

Netherlands Eurocept B.V. Vancocin Cp VANCOMYCIN 250MG CAPSULE

CAPSULE ORAL USE

Netherlands Hospira Benelux Bvba

Vancomycin Hospira VANCOMYCIN 1000MG and 500 MG VIAL



Netherlands Cnp Pharma Gmbh Vancomycine Cnp VANCOMYCIN POWDER FOR INTRAVENOUS USE

39

Member State

EU/EEA




1000MG VIAL SOLUTION FOR INFUSION

Netherlands Cnp Pharma Gmbh Vancomycine Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Netherlands Fresenius Kabi Nederland B.V.

Vancomycine Fresenius Kabi



INTRAVENOUS USE

Netherlands Fresenius Kabi Nederland B.V.

Vancomycine Fresenius Kabi



INTRAVENOUS USE

Netherlands Hikma Farmacêutica (Portugal), S.A.

Vancomycine Hikma VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Netherlands Hikma Farmacêutica (Portugal), S.A.

Vancomycine Hikma VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Netherlands Mylan B.V. Vancomycine Mylan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Netherlands Mylan B.V. Vancomycine Mylan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Netherlands Pfizer B.V. Vancomycine Pfizer VANCOMYCIN POWDER FOR INTRAVENOUS USE

40

Member State

EU/EEA




1000MG VIAL CONCENTRATE FOR SOLUTION FOR INFUSION

Netherlands Pfizer B.V. Vancomycine Pfizer VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Netherlands Pharma Regulatory Solutions Ltd.

Vancomycine Pharma Regulatory

VANCOMYCIN 500 mg per vial


INTRAVENOUS USE

Netherlands Pharma Regulatory Solutions Ltd.

Vancomycine Pharma Regulatory

VANCOMYCIN 1000 mg per vial


INTRAVENOUS USE

Netherlands Sandoz B.V. Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INTRAVENOUS USE

Netherlands Sandoz B.V. Vancomycine Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Netherlands Teva Nederland B.V. Vancomycine Teva VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Netherlands Teva Nederland B.V. Vancomycine Teva VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

41

Member State

EU/EEA




INFUSION Netherlands Xellia

Pharmaceuticals Aps Vancomycine Xellia VANCOMYCIN



INTRAVENOUS USE

Netherlands Xellia Pharmaceuticals Aps

Vancomycine Xellia VANCOMYCIN HYDROCHLORIDE 513MG VIAL


INTRAVENOUS USE

Norway Actavis Group Ptc Ehf.

Vancomycin Actavis Group Ptc Ehf.



INTRAVENOUS USE

Norway Actavis Group Ptc Ehf.

Vancomycin Actavis Group Ptc Ehf.



INTRAVENOUS USE

Norway Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Norway Cnp Pharma Gmbh Vancomycin Cnp Pharma



INTRAVENOUS USE

Norway Fresenius Kabi Norge As




INTRAVENOUS USE

Norway Fresenius Kabi Norge As




INTRAVENOUS USE

Norway Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

42

Member State

EU/EEA




Norway Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Norway Mip Pharma Gmbh Vancomycin Mip VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Norway Mip Pharma Gmbh Vancomycin Mip VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Norway Farmaplus A.S. Vancomycin Mylan VANCOMYCIN HYDROCHLORIDE 1G BOTTLE


INTRAVENOUS USE

Norway Farmaplus A.S. Vancomycin Mylan VANCOMYCIN HYDROCHLORIDE 0.5G BOTTLE


INTRAVENOUS USE

Norway Pfizer As Vancomycin Pfizer VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Norway Pfizer As Vancomycin Pfizer VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Norway Xellia Pharmaceuticals Aps



Norway Xellia Vancomycin Xellia VANCOMYCIN POWDER FOR INTRAVENOUS USE

43

Member State

EU/EEA




Pharmaceuticals Aps HYDROCHLORIDE 500MG VIAL


Poland Sandoz Gmbh Edicin VANCOMYCIN HYDROCHLORIDE 1G VIAL


INTRAVENOUS USE

Poland Sandoz Gmbh Edicin VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Poland Actavis Group Ptc Ehf.



INTRAVENOUS USE

Poland Actavis Group Ptc Ehf.



INTRAVENOUS USE

Poland Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Poland Fresenius Kabi Polska Sp. Z O.O.



INTRAVENOUS USE

Poland Mip Pharma Polska Sp. Z O.O.

Vancomycin Mip VANCOMYCIN HYDROCHLORIDE 1020MG VIAL



44

Member State

EU/EEA




Poland Mip Pharma Polska Sp. Z O.O.

Vancomycin Mip VANCOMYCIN HYDROCHLORIDE 510MG VIAL



Poland Sandoz Gmbh Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INTRAVENOUS USE

Poland Sandoz Gmbh Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Portugal Axellia Pharmaceuticals ApS

Vancomicina Axelia Vancomycin hydrochloride 1000 vial

POWDER FOR SOLUTION FOR Injection

intravenous use

Portugal Axellia Pharmaceuticals ApS

Vancomicina Axelia Vancomycin hydrochloride 500 vial

POWDER FOR SOLUTION FOR INjection

intravenous use

Portugal Laboratórios Azevedos - Indústria Farmacêutica, S.A.

Vancomicina Azevedos

VANCOMYCIN Hydrochloride1000MG VIAL


INTRAVENOUS USE

Portugal Laboratórios Azevedos - Indústria Farmacêutica, S.A.

Vancomicina Azevedos

VANCOMYCIN Hydrochloride 500MG VIAL


INTRAVENOUS USE

Portugal Accord Healthcare Limited

Vancomicina Combino

VANCOMYCIN HYDROCHLORIDE 1000 mg bottle


INTRAVENOUS USE

Portugal Accord Healthcare Limited

Vancomicina Combino

VANCOMYCIN Hydrochloride 500MG bottle


INTRAVENOUS USE

45

Member State

EU/EEA




Portugal Generis Farmacêutica, S.A.

Vancomicina Generis VANCOMYCIN HYDROCHLORIDE 1000 mg


INTRAVENOUS USE

Portugal Generis Farmacêutica, S.A.

Vancomicina Generis VANCOMYCIN HYDROCHLORIDE 500 mg VIAL


INTRAVENOUS USE

Portugal Hikma Farmacêutica (Portugal), S.A.

Vancomicina Hikma VANCOMYCIN Hydrochloride 1000MG VIAL


INTRAVENOUS USE


Vancomicina Hikma VANCOMYCIN HYDROCHLORIDE 1000 mg VIAL


INTRAVENOUS USE


Vancomicina Hikma VANCOMYCIN Hydrochloride 500 mg vial


INTRAVENOUS USE


Vancomicina Hikma VANCOMYCIN HYDROCHLORIDE 500 mg vial


INTRAVENOUS USE

Portugal Fresenius Kabi Pharma Portugal Lda.

Vancomicina Kabi VANCOMYCIN Hydrochloride 1000MG VIAL


INTRAVENOUS USE

Portugal Fresenius Kabi Pharma Portugal Lda.

Vancomicina Kabi VANCOMYCIN Hydrochloride 500MG VIAL


INTRAVENOUS USE

46

Member State

EU/EEA




Portugal Labesfal Laboratorios Almiro, S.A.

Vancomicina Labesfal VANCOMYCIN Hydrochloride1000MG vial


INTRAVENOUS USE

Portugal Labesfal Laboratorios Almiro, S.A.

Vancomicina Labesfal VANCOMYCIN Hydrochloride 500MG vial


INTRAVENOUS USE

Portugal Laboratórios Normon, S.A.

Vancomicina Normon VANCOMYCIN HYDROCHLORIDE 1026MG Vial


INTRAVENOUS USE, oral use

Portugal Laboratórios Normon, S.A.

Vancomicina Normon VANCOMYCIN HYDROCHLORIDE 513MG Vial


INTRAVENOUS USE, oral use

Portugal Quimedical Produtos Farmacêuticos, Lda

Vancomicina Quimedical



INTRAVENOUS USE

Portugal Quimedical Produtos Farmacêuticos, Lda

Vancomicina Quimedical



INTRAVENOUS USE

Portugal Hospira Portugal Lda Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 1000MG vial


INTRAVENOUS USE

Portugal Hospira Portugal Lda Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 500MG Vial


INTRAVENOUS USE

portugal Anfarm Hellas, S.A Vangrotin Vancomycin hydrochloride 500 Vial

powder for solution for infusion

intravenous use

47

Member State

EU/EEA




Romania Lek Pharmaceuticals D.D. Ljubljana

Edicin VANCOMYCIN HYDROCHLORIDE 1MG VIAL


INTRAVENOUS USE

Romania Lek Pharmaceuticals D.D. Ljubljana



INTRAVENOUS USE

Romania Mylan S.A.S Vancomicina Farmaplus




Romania Mylan S.A.S Vancomicina Farmaplus




Romania Hospira Uk Ltd Vancomicină Hospira VANCOMYCIN 50MG/ML



Romania Fresenius Kabi Romania S.R.L.



INTRAVENOUS USE

Romania Fresenius Kabi Romania S.R.L.



INTRAVENOUS USE

Romania Pharmaswiss česká Republika S.R.O.

Vancomicină Pharmaswiss

VANCOMYCIN HYDROCHLORIDE



48

Member State

EU/EEA




1025.14MG/20 ML INFUSION Romania Pharmaswiss česká

Republika S.R.O. Vancomicină Pharmaswiss

VANCOMYCIN HYDROCHLORIDE 512.57MG/10 ML



Romania Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL



Romania Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL



Romania Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN HYDROCHLORIDE 50MG/ML



Slovakia Sandoz Pharmaceuticals D.D.



INTRAVENOUS USE

Slovakia Sandoz Pharmaceuticals D.D.



INTRAVENOUS USE

Slovakia Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Slovakia Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Slovakia Mylan S.A.S. Vancomycin FarmaPlus



INTRAVENOUS USE

49

Member State

EU/EEA




Slovakia Hospira Uk Ltd Vancomycin Hospira VANCOMYCIN 50MG/ML



Slovakia Fresenius Kabi S.R.O Vancomycin Kabi VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Slovakia Fresenius Kabi S.R.O Vancomycin Kabi VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Slovakia Mylan S.A.S Vancomycin Mylan VANCOMYCIN 50MG/ML



Slovakia Hikma Farmacêutica (Portugal), S.A.


VANCOMYCIN 50MG/ML



Slovenia Lek Pharmaceuticals D.D. Ljubljana



INTRAVENOUS USE




INTRAVENOUS USE

Slovenia Mylan S.A.S Vancomycin Mylan VANCOMYCIN 50MG/ML



Slovenia Actavis Group Ptc Vankomicin Actavis VANCOMYCIN POWDER FOR INTRAVENOUS USE

50

Member State

EU/EEA




Ehf. 1000MG VIAL CONCENTRATE FOR SOLUTION FOR INFUSION

Slovenia Actavis Group Ptc Ehf.

Vankomicin Actavis VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Slovenia FarmaPlus AS Vankomicin FarmaPlus



INTRAVENOUS USE

Slovenia FarmaPlus AS Vankomicin FarmaPlus



INTRAVENOUS USE

Slovenia Fresenius Kabi Deutschland Gmbh

Vankomicin Kabi VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Slovenia Fresenius Kabi Deutschland Gmbh

Vankomicin Kabi VANCOMYCIN 500MG VIAL


INTRAVENOUS USE


Vankomicin Lek VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE


Vankomicin Lek VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

51

Member State

EU/EEA




INJECTION Slovenia Pfizer Luxembourg

Sarl Vankomicin Pfizer VANCOMYCIN

1000MG VIAL POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Slovenia Pfizer Luxembourg Sarl

Vankomicin Pfizer VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Spain Cnp Pharma Gmbh Vancomicina CNP VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Spain Cnp Pharma Gmbh Vancomicina CNP VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Spain Hospira Productos Farmacéuticos Y Hospitalarios, S.L.

Vancomicina Hospira VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INJECTION


Spain Hospira Productos Farmacéuticos Y Hospitalarios, S.L.

Vancomicina Hospira VANCOMYCIN 500MG VIAL



Spain Accord Healthcare S.L.U.

Vancomicina IV Accord

VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INJECTION

INTRAVENOUS USE

Spain Accord Healthcare S.L.U.

Vancomicina IV Accord



INTRAVENOUS USE

Spain Fresenius Kabi Vancomicina Kabi VANCOMYCIN POWDER FOR INTRAVENOUS USE

52

Member State

EU/EEA




España S.A.U. 1000MG VIAL CONCENTRATE FOR SOLUTION FOR INFUSION

Spain Fresenius Kabi España S.A.U.



INTRAVENOUS USE

Spain Kern Pharma, S.L. Vancomicina Kern Pharma



INTRAVENOUS USE

Spain Kern Pharma, S.L. Vancomicina Kern Pharma



INTRAVENOUS USE

Spain Mylan Pharmaceuticals, S.L.

Vancomicina Mylan VANCOMYCIN 50MG/ML


INTRAVENOUS USE

Spain Laboratorios Normon, S.A.

Vancomicina Normon VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Spain Laboratorios Normon, S.A.

Vancomicina Normon VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Spain Pfizer, S.L. Vancomicina Pfizer VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

53

Member State

EU/EEA




INFUSION Spain Pfizer, S.L. Vancomicina Pfizer VANCOMYCIN 500MG

VIAL POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Spain Laboratorio Ramon Sala, S.L

Vancomicina Sala VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INJECTION

INTRAVENOUS USE

Spain Laboratorio Ramon Sala, S.L

Vancomicina Sala VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Sweden Pharmacodane Aps Vancocin VANCOMYCIN 125MG CAPSULE


Sweden Farmaplus A.S. Vancomycin VANCOMYCIN HYDROCHLORIDE 1G BOTTLE

POWDER FOR INFUSION

INTRAVENOUS USE

Sweden Farmaplus A.S. Vancomycin VANCOMYCIN HYDROCHLORIDE 500MG BOTTLE

POWDER FOR INFUSION

INTRAVENOUS USE

Sweden Actavis Group Ptc Ehf.



INTRAVENOUS USE







Sweden Actavis Group Ptc Vancomycin Actavis VANCOMYCIN 500MG POWDER FOR INTRAVENOUS USE

54

Member State

EU/EEA




Ehf. VIAL CONCENTRATE FOR SOLUTION FOR INFUSION

Sweden Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Sweden Cnp Pharma Gmbh Vancomycin Cnp VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Sweden Farmaplus As Vancomycin Farmaplus



INTRAVENOUS USE

Sweden Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

Sweden Hospira Enterprise Bv Vancomycin Hospira VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Sweden Mip Pharma Gmbh Vancomycin Mip VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Sweden Mip Pharma Gmbh Vancomycin Mip VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Sweden Mylan Hospital As Vancomycin Mylan VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

55

Member State

EU/EEA




Sweden Mylan Hospital As Vancomycin Mylan VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Sweden Orion Corporation Vancomycin Orion VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

Sweden Orion Corporation Vancomycin Orion VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

Sweden Sandoz A-S Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 1000MG VIAL


INTRAVENOUS USE

Sweden Sandoz A-S Vancomycin Sandoz VANCOMYCIN HYDROCHLORIDE 500MG VIAL


INTRAVENOUS USE

Sweden Xellia Pharmaceuticals Aps



INTRAVENOUS USE










INTRAVENOUS USE

56

Member State

EU/EEA




United Kingdom Flynn Pharma Ltd. Vancocin VANCOMYCIN 1G VIAL POWDER FOR ORAL SOLUTION, POWDER FOR SOLUTION FOR INFUSION


United Kingdom Flynn Pharma Ltd. Vancocin VANCOMYCIN 500MG VIAL



United Kingdom Flynn Pharma Limited Vancocin Matrigel VANCOMYCIN 125MG CAPSULE


United Kingdom Flynn Pharma Ltd. Vancocin Matrigel VANCOMYCIN 125MG CAPSULE


United Kingdom Actavis Group Ptc Ehf.



INTRAVENOUS USE




INTRAVENOUS USE







United Kingdom Co-Pharma Limited Vancomycin Co-Pharma



United Kingdom Co-Pharma Limited Vancomycin Co-Pharma



57

Member State

EU/EEA




United Kingdom Fresenius Kabi Limited




INTRAVENOUS USE

United Kingdom Fresenius Kabi Limited




INTRAVENOUS USE

United Kingdom Hikma Farmacêutica (Portugal), S.A.




INTRAVENOUS USE

United Kingdom Hikma Farmacêutica (Portugal), S.A.




INTRAVENOUS USE

United Kingdom Hospira Uk Ltd Vancomycin Hydrochloride Hospira Uk

VANCOMYCIN 1G VIAL POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION


United Kingdom Hospira Uk Ltd Vancomycin Hydrochloride Hospira Uk




United Kingdom Laboratorio Reig Jofre, S.A.

Vancomycin Laboratorio Reig Jofré

VANCOMYCIN 1G VIAL POWDER FOR ORAL SOLUTION, POWDER FOR SOLUTION FOR INFUSION


58

Member State

EU/EEA




United Kingdom Laboratorio Reig Jofre, S.A.

Vancomycin Laboratorio Reig Jofré




United Kingdom Mip Pharma Gmbh Vancomycin Mip Pharma Gmbh



INTRAVENOUS USE

United Kingdom Mip Pharma Gmbh Vancomycin Mip Pharma Gmbh



INTRAVENOUS USE

United Kingdom Morningside Healthcare Ltd

Vancomycin Morningside Healthcare

VANCOMYCIN HYDROCHLORIDE 128.15MG CAPSULE


United Kingdom Noridem Enterprises Ltd




INTRAVENOUS USE

United Kingdom Noridem Enterprises Ltd




INTRAVENOUS USE

United Kingdom Nrim Limited Vancomycin Nrim VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

United Kingdom Nrim Limited Vancomycin Nrim VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

59

Member State

EU/EEA




INFUSION United Kingdom Pfizer Limited Vancomycin Pfizer VANCOMYCIN

1000MG VIAL POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

INTRAVENOUS USE

United Kingdom Pfizer Limited Vancomycin Pfizer VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

United Kingdom Sandoz Ltd Vancomycin Sandoz Ltd



INTRAVENOUS USE

United Kingdom Sandoz Ltd Vancomycin Sandoz Ltd



INTRAVENOUS USE

United Kingdom Teva Uk Limited Vancomycin Teva Uk VANCOMYCIN 1000MG VIAL


INTRAVENOUS USE

United Kingdom Teva Uk Limited Vancomycin Teva Uk VANCOMYCIN 500MG VIAL


INTRAVENOUS USE

United Kingdom Wockhardt Uk Ltd Vancomycin Wockhardt Uk Ltd

VANCOMYCIN 1G VIAL POWDER FOR SOLUTION FOR INFUSION


United Kingdom Wockhardt Uk Ltd Vancomycin Wockhardt Uk Ltd




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Member State

EU/EEA




INFUSION United Kingdom Xellia

Pharmaceuticals Aps Vancomycin Xellia Pharmaceuticals


CAPSULE ORAL USE

United Kingdom Xellia Pharmaceuticals Aps

Vancomycin Xellia Pharmaceuticals Aps


CAPSULE ORAL USE





INTRAVENOUS USE





INTRAVENOUS USE

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Annex II

Scientific conclusions

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Scientific conclusions

Overall summary of the scientific evaluation of vancomycin-containing products (see Annex I)

Vancomycin is a glycopeptide antibiotic authorised around six decades ago. Its effect is mainly bactericidal and it is exerted mainly by the inhibition of the cell wall peptidoglycan synthesis. Vancomycin spectrum includes a wide range of pathogens including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococus pneumoniae, Listeria monocytogenes and Clostridium difficile.

Vancomycin containing products are commercially available as:

- powder for solution for injection or infusion (500 mg and 1000 mg) used by intravenous administration. For certain medicinal vancomycin-containing products, the intraperitoneal route and oral route of administration are authorised,

- and capsules, for oral administration.

Vancomycin hydrochloride is defined as the hydrochloride salt of a mixture of related glycopeptides for which the characteristics are defined in the European Pharmacopeia 1058 monograph (currently under revision). The active substance is obtained mainly by fermentation.

The antibacterial activity of vancomycin is confined to Gram-positive microorganisms. Intravenous vancomycin is mainly used for the treatment of serious infections caused by microorganisms with mechanisms of resistance to beta-lactam antibiotics, in particular methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS) and enterococci, the latter being often tolerant to β-lactam antibiotics. It is also used in patients who are allergic to penicillins and cephalosporins. Vancomycin is also administered by the oral route for the treatment of Clostridium difficile-infection (CDI).

However, increases in the rates of heteroresistance and tolerance to vancomycin, combined with its pharmacodynamic (i.e. slow bactericidal activity, variable tissue penetration) and clinical (clinical failures reported in patients with invasive infections produced by Staphylococcus aureus with a MIC above 1 mcg/mL) shortcomings have questioned the current role of vancomycin for the treatment of these infections.

The emergence of multidrug-resistant pathogens is a growing problem worldwide. In view of the importance of ensuring the availability of efficacious antibiotics for the EU patients, in the interest of public health and in order to contribute to tackling the threat posed by the spread of antimicrobial resistance, a critical review of the benefit-risk of vancomycin containing products in the approved indications, including the relevant posology, was considered needed. In addition, significant differences between the product information of vancomycin-containing medicines across the EU Member States were identified in particular in the indications, posology and method of administration, but also in other sections of the product information. Therefore, in light of the above the Spanish Medicines Agency (AEMPS) considered in the interest of the Union to refer the matter to the CHMP and request that its gives its opinion under Article 31 of Directive 2001/83/EC on the benefit-risk of vancomycin-containing products and on the need for regulatory measures to be taken.

In its assessment, the CHMP reviewed all available data, including submissions by the marketing authorisation holders during the procedure and consulted the Paediatric Committee (PDCO), the CHMP relevant working parties/groups: Infectious Disease working party (IDWP), the Pharmacokinetics working party (PKWP), the Quality Working Party (QWP), the Modelling and Simulation Working Group (MSWG)) and external experts (the European Committee on Antimicrobial Susceptibility Testing (EUCAST)). Among other issues, the CHMP discussed the need for updating the wording of the product information.

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Having reviewed all available data, and taking into account the current clinical practice and current clinical guideline recommendations, the CHMP considered that vancomycin is an important therapeutic option in the following indications:

• Treatment of: complicated skin and soft tissue infections, bone and joint infections, community acquired pneumonia, hospital acquired pneumonia including ventilator-associated pneumonia, infective endocarditis, bacteraemia that occurs in association with, or is suspected to be associated with any of the above (particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA)), perioperative antibacterial prophylaxis. Current guidelines from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID1,2) and Infectious Diseases Society of America (IDSA3) also support its role in the treatment of MRSA infections.

• Treatment of acute bacterial meningitis. The CHMP noted that the current guidelines for the treatment of acute bacterial meningitis from several learned societies (ESCMID4, IDSA5 guideline and UK joint specialist societies guidelines6, European Federation Neurological Societies (EFNS)) recommend vancomycin for both empirical treatment and etiological treatment of MRSA (alone) and penicillin-resistant Streptococcus pneumoniae (PRSP) in combination with other antibacterials in adults and children.

• Treatment of peritoneal dialysis–associated peritonitis. The CHMP noted the guidelines on the management of Peritoneal Dialysis-related peritonitis in adults from the International Society for Peritoneal Dialysis (ISPD) (Li PK et al., 20167), the ISPD recommendations for pediatric patients (Warady BA et al., 20128). In addition, the CHMP reviewed the available evidence submitted within the referral procedure including several references to published literature and a meta-analysis of a total of 64 studies (32 for initial treatment and negative culture, 28 reporting treatment for Gram-positive and 24 reporting treatment for Gram-negative) and 21 randomized clinical trials (14 for initial treatment and negative culture, 8 reporting treatment for Gram-positive and 8 reporting treatment for Gram-negative), confirming the efficacy of vancomycin for the treatment of peritonitis in peritoneal dialysis.

• Treatment of Clostridium difficile infection (CDI), for vancomycin given by oral route of administration. The CHMP noted that the European Society of Clinical Microbiology and Infection (ESCMID) issued a treatment guidance document9,10 for Clostridium difficile infection in 2009 that is currently being updated. The guidance provides treatment recommendations for initial and recurrent CDI. In the case of mild CDI clearly induced by the use of antibiotics, it is acceptable to discontinue the inducing antibiotic and observe the clinical response. Vancomycin treatment is recommended in severe or recurrent cases. Currently, there is no evidence that medical prophylaxis for CDI is efficacious and therefore there is not recommended prophylactic antibiotics.

1 ESCMID guidelines: https://www.escmid.org/escmid_publications/medical_guidelines/escmid_guidelines/

2 ESCMID guideline https://www.escmid.org/fileadmin/src/media/PDFs/4ESCMID_Library/2Medical_Guidelines/ESCMID_Guidelines/Eu_Rec_Antimicrobal.pdf 3 IDSA guideline http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Antimicrobial_Agent_Use/Vancomycin/Vancomycin/

4 Bacterial meningitis:ESCMID guideline for bacterial meningitis: http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(16)00020-3/abstract

5 IDSA: http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_by_Organ_System/Central_Nervous_System_(CNS)/Bacterial_Meningitis/ 6 Joint guideline: https://www.britishinfection.org/files/5614/5674/2938/McGill_meningitis_guidelines_Final_published_proof.pdf 7 PD-related peritonitis https://ispd.org/ispd-guidelines/ guidelines on the management of PD-related peritonitis in adults from the International Society for Peritoneal Dialysis (ISPD) (Li PK et al., 2016 http://www.pdiconnect.com/content/36/5/481.full 8 ISPD recommendations for paediatric patients (Warady BA et al., 2012) - https://ispd.org/media/pdf/Consensus__Change_20_.pdf 9https://www.escmid.org/fileadmin/src/media/PDFs/4ESCMID_Library/2Medical_Guidelines/ESCMID_Guidelines/fulltext_treatment_guidance_Clostridium_difficile_infection.pdf 10 Bauer MP. et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect 2009; 15: 1067–1079

https://www.escmid.org/escmid_publications/medical_guidelines/escmid_guidelines/

https://www.escmid.org/fileadmin/src/media/PDFs/4ESCMID_Library/2Medical_Guidelines/ESCMID_Guidelines/Eu_Rec_Antimicrobal.pdf

http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Antimicrobial_Agent_Use/Vancomycin/Vancomycin/

http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(16)00020-3/abstract

http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(16)00020-3/abstract

http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_by_Organ_System/Central_Nervous_System_(CNS)/Bacterial_Meningitis/

http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_by_Organ_System/Central_Nervous_System_(CNS)/Bacterial_Meningitis/

https://www.britishinfection.org/files/5614/5674/2938/McGill_meningitis_guidelines_Final_published_proof.pdf

https://ispd.org/ispd-guidelines/

http://www.pdiconnect.com/content/36/5/481.full

https://ispd.org/media/pdf/Consensus__Change_20_.pdf

https://www.escmid.org/fileadmin/src/media/PDFs/4ESCMID_Library/2Medical_Guidelines/ESCMID_Guidelines/fulltext_treatment_guidance_Clostridium_difficile_infection.pdf

https://www.escmid.org/fileadmin/src/media/PDFs/4ESCMID_Library/2Medical_Guidelines/ESCMID_Guidelines/fulltext_treatment_guidance_Clostridium_difficile_infection.pdf

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The following indications of vancomycin (oral route) for “treatment of staphylococcal enterocolitis” and “Decontamination of the gastrointestinal (GI) tract in immune-compromised patients when combined with an aminoglycoside” were not supported by the CHMP:

• With regards to the “treatment of staphylococcal enterocolitis”, the CHMP concluded that the MAHs did not provide data establishing the efficacy and safety of oral vancomycin in this indication. Furthermore, the CHMP noted that updated clinical guidelines for staphylococcal enterocolitis (diagnosis or treatment) do not mention this use of vancomycin. It is also noted that staphylococcal enterocolitis is a rare entity and that its diagnosis is controversial. Due to insufficient elements establishing the efficacy and safety of this the CHMP does not recommend this indication.

• Concerning the “decontamination of the GI tract in immune-compromised patients when combined with an aminoglycoside”, the CHMP reviewed the available data submitted throughout this procedure. The data submitted in support of the vancomycin use for decontamination were not deemed as sufficiently robust. Furthermore, the role of selective intestinal decontamination is controversial. As a consequence, the CHMP is of the view that the benefit-risk for vancomycin containing products in the indication “Decontamination of the gastrointestinal tract in immune-compromised patients when combined with an aminoglycoside” is not established and therefore this indication is not recommended.

The CHMP also reviewed the dosage regimen for vancomycin for the various approved indications and patient subpopulations. The most commonly used dosage regimen (1 g every 12 hours) was considered adequate by the CHMP from a pharmacokinetic and pharmacodynamic perspective for the majority of patients with normal renal function and based on the usual susceptibility of staphylococci (minimum inhibitory concentration (MIC) ≤1 mg/L). However, the CHMP noted that the 2 g/day dose often results in Ctrough values below the target of 10 to 20 mg/l; therefore in order to achieve the optimal target concentration, the CHMP agreed that the vancomycin dose should be individually adapted according to weight, age and the underlying type and severity of infection and clinical response; the initial vancomycin doses should be calculated based on the body weight.

The CHMP acknowledged that the current therapeutic guidelines stress the importance of therapeutic drug monitoring and the use of the trough vancomycin concentration as a surrogate for the target AUC. The CHMP noted that the measurement of trough serum concentrations at steady state is an accepted surrogate to check if effective vancomycin exposure has been achieved. However, having reviewed the data presented by the MAHs, the CHMP also considered the existing limitations of monitoring Ctrough in certain situations. Trough-only monitoring may be not sufficient to guide vancomycin dosing in all cases, because peak levels (Cmax) are primarily influenced by the volume of distribution. Therefore, the CHMP discussed different alternative approaches to estimate the vancomycin exposure.

Overall, the CHMP considered that, out of the discussed methods, the Bayesian interpolation seemed to be an appropriate alternative; it allows predicting many individual pharmacokinetic parameters for extrapolation, minimizes the number of measurements on a single patient and seems to develop optimal strategies for therapeutic intervention. In addition, in line with the outcome of the MSWG consultation, the CHMP concluded that Bayesian methods could be clinically useful for more accurate dose predictions as a complementary part of routine therapeutic drug monitoring (TDM), especially for the patient groups with altered pharmacokinetic (PK) profile (i.e. children, haemodynamically unstable patients, intensive care), and acknowledged that this is already in clinical use. The wording on therapeutic drug monitoring in section 4.2 of the SmPC has been amended accordingly by the CHMP. It is currently made clear that TDM frequency needs to be individualised based on the clinical situation and response to treatment; specific recommendations are made for hemodynamically stable and

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unstable patients, patients with normal renal function and patients on intermittent haemodialysis. The potential usefulness of model-based methods in the prediction of individual dose requirements to reach an adequate AUC is also addressed. A statement in the section 4.2 had been included accordingly by the CHMP.

The CHMP also reviewed the dose recommendation in paediatric population. For both infants, children aged from one month to 18 years old, the CHMP agreed that, as for adults, the vancomycin dose should be individually adapted according to weight, age and the underlying type and severity of infection and clinical response; the initial vancomycin doses should be calculated based on the body weight. The CHMP also acknowledged that some already approved vancomycin containing medicines already include some dosing recommendations for both term and preterm neonates11. For this specific group, the PDCO recommended one possible dosing regimen based on post-menstrual age (similar to the recommended dosing regimen by the British National Formulary (BNF) for children), but overall CHMP agreed that no universal recommendations on the dosage regimen in neonates could be made and that for establishing the dosing regimen in this population, the advice of a physician experienced in the management of neonates should be sought. The SmPC has been amended accordingly, including the dosing regimen in children based on post-menstrual age as a possible way of dosing vancomycin in this population.

Regarding the administration of vancomycin as a continuous infusion in paediatric patients, PDCO confirmed that it is being used in some countries for neonates (and children) with severe infections such as patients with central nervous system infections and/or associated bacteremia. In these cases, continuous infusions were used due to a failure of response to treatment or to a persistence of sub-therapeutic vancomycin levels despite optimizing dosing and frequency during intermittent vancomycin administration. However, continuous vancomycin infusions have a few disadvantages such as that there may be compatibility issues with other IV medications or solutions that are given concurrently; practical problems associated with reduced line availability when infusions are given over a 24-h period; increased risk of infusing a bolus dose of vancomycin when the intravenous solution is changed or when another medication is infused into the same intravenous tubing which is filled with vancomycin 24 h/day etc. Moreover, existing data (including comparative) on the use of a continuous vs. an intermittent infusion are not conclusive.

As a consequence, the CHMP could not recommend any concrete dosing recommendations for continuous infusion in the SmPC of vancomycin for IV use.

The CHMP reviewed also the optimal way of expressing the strength and dose of vancomycin-containing products. CHMP was of the opinion that, given the fact that the use of milligram to prescribe this product was established in EU clinical practice, it is essential that the convention of labelling vancomycin products by mass, i.e. milligrams, is retained. However, to ensure that the established therapeutic dose in terms of IU (potency) is maintained, and as indicated in the Question and Answer on expression/declaration of potency in quantitative and qualitative composition for vancomycin products (EMA/CHMP/QWP/667469/2015), the amount (mg) of active substance in the drug product should be adjusted to achieve the declared product strength in terms of IU. The CHMP also reviewed the limits for related substances and impurities in the active substance and in the finished products and it was concluded that the limits for related components and impurities in the drug substance and in the final drug products already authorised are qualified. The Annex 3 of the CHMP guideline on setting specifications for related impurities in antibiotics would apply to new active substances and for new sources of existing active substances. Once vancomycin monograph in the Ph.Eur. will enter into force, the limits of the impurities in the drug substance and final drug products will need to be revised accordingly, where applicable.

11 http://www.medicines.org.uk/emc/medicine/20836

http://www.medicines.org.uk/emc/medicine/20836

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The CHMP also reviewed the existing data on adverse reactions observed with the use of vancomycin and which confirm that the use of vancomycin for parenteral use is associated with nephrotoxicity and ototoxicity, infusion related adverse reactions like vein and tissue toxicity as well as hypersensitivity reactions. CHMP agreed that these risks can be minimised by appropriate warnings and recommendations in the product information.

Finally, revisions were made to sections 5.1 and 5.2 to reflect current pharmacokinetic and pharmacodynamic data, and to sections 1 and 2 to reflect the amount of active substance in the finished product (based on the potency expressed in IU), and the dose and strength of vancomycin containing products (to be expressed in milligrams). The CHMP noted that no update of the EUCAST breakpoints is warranted at this time.

In conclusion, the CHMP is of the opinion that the benefit-risk balance of the vancomycin-containing products included in the scope of this procedure remains positive under normal conditions of use, taking into account the agreed changes to the product information as set out in Annex III to the opinion.

The Committee, as a consequence, recommends the variation to the terms of the marketing authorisations for vancomycin-containing products.

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Grounds for the variation to the terms of the marketing authorisation, as applicable

Whereas,

• Vancomycin-containing medicinal products has an increasingly important role in the treatment of Gram-positive bacterial infections,

• the existing product information including the indications, dosage recommendations and pharmacokinetic and pharmacodynamic information for vancomycin-containing products in the EU need to be revised in accordance with the latest available information,

• the CHMP carried out a benefit-risk evaluation of vancomycin containing products under Article 31 of Directive 2001/83/EC, reviewing all available data, including responses submitted by the marketing authorisation holders during the procedure and recommendations from the Paediatric Committee (PDCO), the CHMP relevant working parties/groups: Infectious Disease working party (IDWP), the Pharmacokinetics working party (PKWP), the Quality Working Party (QWP), the Modelling and Simulation Working Group (MSWG)) and external experts (the European Committee on Antimicrobial Susceptibility Testing (EUCAST),

• the CHMP considered that vancomycin represent a crucial therapeutic option in the context of the treatment of serious infections (complicated skin and soft tissue infections, bone and joint infections, community acquired pneumonia, hospital acquired pneumonia including ventilator-associated pneumonia, infective endocarditis, acute bacterial meningitis, bacteraemia that occurs in association with, or is suspected to be associated with, any of the above, perioperative antibacterial prophylaxis, peritoneal dialysis–associated peritonitis and treatment of Clostridium difficile infection) caused by Gram-positive pathogens, particularly those caused by MRSA,

• the CHMP considered the available data to be sufficient to support revisions of the indication for both oral use and parenteral use, as well as the posology in adults and paediatrics populations, in line with clinical experience and current therapeutic guidelines,

• the CHMP considered that the risks of nephrotoxicity, ototoxicity, infusion related adverse reactions and hypersensitivity reactions observed with vancomycin for intravenous use can be minimised by appropriate warnings and recommendations in the product information,

• the CHMP considered that the pharmacokinetic and pharmacodynamic data in the product information need to be updated,

• the CHMP considered that the amount of active substance in the finished product is determined and consistently based on the potency expressed in IU, and that the dose and strength of vancomycin containing products should continue to be expressed in milligrams,

The Committee, as a consequence, concluded that the benefit-risk balance of the vancomycin containing products included in the scope of this procedure remains positive under normal conditions of use, taking into account the agreed changes to the product information.

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ANNEX III

Amendments to relevant sections of the summary of product characteristics and the package leaflets

Note:

These amendments to the relevant sections of the Product Information are the outcome of the referral procedure.

The product information may be subsequently updated by the Member State competent authorities, in liaison with the Reference Member State, as appropriate, in accordance with the procedures laid down in Chapter 4 of Title III of Directive 2001/83/EC.

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SUMMARY OF PRODUCT CHARACTERISTICS

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Capsules 1. NAME OF THE MEDICINAL PRODUCT

[For all vancomycin 125 mg capsule]

<{(Invented) vancomycin 125mg capsule}> [For all vancomycin 250 mg capsule]

<{(Invented) vancomycin 250mg capsule}>

2. QUALITATIVE AND QUANTITATIVE COMPOSITION


[The following wording to be reflected in this section] Each capsule contains 125mg vancomycin hydrochloride equivalent to 125,000IU vancomycin.


[The following wording to be reflected in this section] Each capsule contains 250mg vancomycin hydrochloride equivalent to 250,000IU vancomycin.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

[This section should read as follows:]

Vancomycin capsules are indicated in patients 12 years and older for the treatment of Clostridium difficile infection (CDI) (see sections 4.2, 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration


Posology

Adults and adolescents aged 12 to less than 18 years old


The recommended vancomycin dose is 125 mg every 6 hours for 10 days for the first episode of non-severe CDI. This dose can be increased to 500 mg every 6 hours for 10 days in case of severe or complicated disease. The maximum daily dose should not exceed 2 g.

In patients with multiple recurrences, consideration may be given to treat the current episode of CDI with vancomycin, 125 mg four times daily for 10 days followed by either tapering the dose, i.e., gradually decreasing it until 125 mg per day or a pulse regimen, i.e., 125–500 mg/day every 2–3 days for at least 3 weeks.

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Treatment duration with vancomycin may need to be tailored to the clinical course of individual patients. Whenever possible the antibacterial suspected to have caused CDI should be discontinued. Adequate replacement of fluid and electrolytes should be instituted.

Monitoring vancomycin serum concentrations after oral administration in patients with inflammatory intestinal disorders should be performed (see section 4.4).

Special populations

Renal impairment

Due to the very low systemic absorption, dose adjustment is unlikely, unless substantial oral absorption may occur in case of inflammatory intestinal disorders or Clostridium difficile-induced pseudomembranous colitis (see section 4.4).

Paediatric population

Vancomycin capsules are not appropriate for the treatment of children under the age of 12 years or for adolescents unable to swallow them. Below 12 years, age-appropriate formulation should be used.

Method of administration

For oral use.

The capsule should not be open and should be taken with plenty of water.

4.3 Contraindications


Hypersensitivity to the active substance or to any of the excipients (see section 4.4).

4.4 Special warnings and precautions for use


Oral Use Only

This preparation is for oral use only and is not systemically absorbed. Orally administered Vancomycin capsules are not effective for other types of infections.

Potential for Systemic Absorption

Absorption may be enhanced in patients with inflammatory disorders of the intestinal mucosa or Clostridium difficile-induced pseudomembranous colitis. These patients may be at risk for the development of adverse reactions, especially if there is a concomitant renal impairment. The greater the renal impairment, the greater the risk of developing the adverse reactions associated with the parenteral administration of vancomycin. Monitoring of serum vancomycin concentrations of patients with inflammatory disorders of the intestinal mucosa should be performed.

Nephrotoxicity

Serial monitoring of renal function should be performed when treating patients with underlying renal dysfunction or patients receiving concomitant therapy with an aminoglycoside or other nephrotoxic drugs.

Ototoxicity

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Serial tests of auditory function may be helpful in order to minimise the risk of ototoxicity in patients with an underlying hearing loss, or who are receiving concomitant therapy with an ototoxic agent such as an aminoglycoside.

Drug interactions with anti-motility agents and proton pump inhibitors

Anti-motility agents should be avoided and proton pump inhibitor use should be reconsidered.

Development of Drug-Resistant Bacteria

Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

4.8 Undesirable effects


Summary of the Safety profile

The absorption of vancomycin from the gastrointestinal tract is negligible. However, in severe inflammation of the intestinal mucosa, especially in combination with renal insufficiency, side effects that occur when vancomycin is administered parenterally may appear. Therefore, the below mentioned adverse reactions and frequencies related to parenteral vancomycin administration are included.

When vancomycin is administered parenterally, the most common adverse reactions are phlebitis, pseudo-allergic reactions and flushing of the upper body (“red-neck syndrome”) in connection with too rapid intravenous infusion of vancomycin.

Tabulated List of Adverse reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions listed below are defined using the following MedDRA convention and system organ class database:

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).

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System organ class

Frequency Adverse reaction

Blood and the lymphatic system disorders:

Rare Reversible neutropenia1, agranulocytosis, eosinophilia, thrombocytopenia, pancytopenia.

Immune system disorders:

Rare Hypersensitivity reactions, anaphylactic reactions2

Ear and labyrinth disorders:

Uncommon Transient or permanent loss of hearing4

Rare Vertigo, tinnitus3, dizziness

Cardiac disorders

Very rare Cardiac arrest

Vascular disorders:

Common Decrease in blood pressure

Rare Vasculitis

Respiratory, thoracic and mediastinal disorders:

Common Dyspnoea, stridor

Gastrointestinal disorders:

Rare Nausea

Very rare Pseudomembranous enterocolitis

Not known Vomiting, Diarrhoea

Skin and subcutaneous tissue disorders:

Common Flushing of the upper body (“red man syndrome”), exanthema and mucosal inflammation, pruritus, urticaria

Very rare Exfoliative dermatitis, Stevens-Johnson syndrome, Lyell's syndrome, Linear IgA bullous dermatosis5

Not known Eosinophilia and systemic symptoms (DRESS syndrome),

AGEP (Acute Generalized Exanthematous Pustulosis)

Renal and urinary disorders:

Common Renal insufficiency manifested primarily by increased serum creatinine and serum urea

Rare Interstitial nephritis, acute renal failure.

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Not known Acute tubular necrosis

General disorders and administration site conditions:

Common Phlebitis, redness of the upper body and face.

Rare Drug fever, shivering, Pain and muscle spasm of the chest and back muscles

Description of selected adverse drug reactions

Reversible neutropenia usually starting one week or more after onset of intravenous therapy or after total dose of more than 25 g.

Intravenous vancomycin should be infused slowly. During or shortly after rapid infusion anaphylactic/anaphylactoid reactions including wheezing may occur. The reactions abate when administration is stopped, generally between 20 minutes and 2 hours. Necrosis may occur after intramuscular injection.

Tinnitus, possibly preceding onset of deafness, should be regarded as an indication to discontinue treatment.

Ototoxicity has primarily been reported in patients given high doses, or in those on concomitant treatment with other ototoxic medicinal product like aminoglycoside, or in those who had a pre-existing reduction in kidney function or hearing.

If a bullous disorder is suspected, the drug should be discontinued and specialised dermatological assessment should be carried out.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties


[the following paragraphs should be reflected in this section:]

(…)

Mechanism of action

Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units. The drug is bactericidal for dividing microorganisms. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis. The drug is bactericidal for dividing microorganisms.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc

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Mechanism of resistance

Acquired resistance to glycopeptides is most common in enterococci and is based on acquisition of various van gene complexes which modifies the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine which bind vancomycin poorly. In some countries, increasing cases of resistance are observed particularly in enterococci; multi-resistant strains of Enterococcus faecium are especially alarming.

Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in “intermediate” susceptibility, which is most commonly heterogeneous. Also, methicillin-resistant staphylococcus strains (MRSA) with reduced susceptibility for vancomycin were reported. The reduced susceptibility or resistance to vancomycin in Staphylococcus is not well understood. Several genetic elements and multiple mutations are required.

There is no cross-resistance between vancomycin and other classes of antibiotics. Cross-resistance with other glycopeptide antibiotics, such as teicoplanin, does occur. Secondary development of resistance during therapy is rare.

Susceptibility testing breakpoints

The prevalence of acquired 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. This information only provides approximate guidance on the chance whether micro-organisms are susceptible to vancomycin.

Minimum inhibitory concentration breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Clostridium difficile1

Susceptible

≤ 2 mg/L

Resistant

> 2 mg/L

1 The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility.

5.2 Pharmacokinetic properties


Absorption

Vancomycin is not usually absorbed into the blood after oral administration. However, absorption may be enhanced in patients with inflammatory disorders of the intestinal mucosa or with Clostridium difficile-induced pseudomembranous colitis. This may lead to vancomycin accumulation in patients with co-existing renal impairment.

Elimination

An oral dose is excreted almost exclusively in the faeces. During multiple dosing of 250 mg every 8 hours for 7 doses, faecal concentrations of vancomycin, in volunteers, exceeded 100 mg/kg in the majority of samples. No blood concentrations were detected and urinary recovery did not exceed 0.76%.

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Powder for concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT

[For all vancomycin 500 mg powder for concentrate for solution for infusion]

<{(Invented) vancomycin 500mg powder for concentrate for solution for infusion}>



2. QUALITATIVE AND QUANTITATIVE COMPOSITION

[For all vancomycin 500 mg powder for concentrate for solution for infusion, the following wording to be reflected in this section]

Each vial contains 500 mg vancomycin hydrochloride equivalent to 500,000 IU vancomycin.

[For all vancomycin 1000 mg powder for concentrate for solution for infusion, the following wording to be reflected in this section]

Each vial contains 1000 mg contains vancomycin hydrochloride equivalent to 1,000,000 IU vancomycin.

(….)

4. CLINICAL PARTICULARS

4.1 Therapeutic indications


[For vancomycin powder for concentrate for solution for infusion for parenteral administration, the indications should be as follows:]

Intravenous administration

Vancomycin is indicated in all age groups for the treatment of the following infections (see sections 4.2, 4.4 and 5.1):

- complicated skin and soft tissue infections (cSSTI)

- bone and joint infections

- community acquired pneumonia (CAP)

- hospital acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP)

- infective endocarditis

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[For parenteral formulations authorised for the following indications:]

- acute bacterial meningitis

- bacteraemia that occurs in association with, or is suspected to be associated with, any of the above.

Vancomycin is also indicated in all age groups for the perioperative antibacterial prophylaxis in patients that are at high risk of developing bacterial endocarditis when undergoing major surgical procedures.

[For parenteral formulations authorised for intraperitoneal use, the indication should be as follows:]

Intraperitoneal administration

Vancomycin is indicated in all age groups for the treatment of peritoneal dialysis–associated peritonitis (see sections 4.2, 4.4 and 5.1).

[For parenteral formulations authorised for oral use, the indication should be as follows:]

Oral administration

Vancomycin is indicated in all age groups for the treatment of Clostridium difficile infection (CDI) (see sections 4.2, 4.4 and 5.1).

[The below wording should be introduced in this section for all vancomycin containing products]

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration


Posology

Where appropriate, vancomycin should be administered in combination with other antibacterial agents.


The initial dose should be based on total body weight. Subsequent dose adjustments should be based on serum concentrations to achieve targeted therapeutic concentrations. Renal function must be taken into consideration for subsequent doses and interval of administration.

Patients aged 12 years and older

The recommended dose is 15 to 20 mg/kg of body weight every 8 to 12 h (not to exceed 2 g per dose).

In seriously ill patients, a loading dose of 25–30 mg/kg of body weight can be used to facilitate rapid attainment of target trough serum vancomycin concentration.

Infants and children aged from one month to less than 12 years of age:

The recommended dose is 10 to 15 mg/kg body weight every 6 hours (see section 4.4).

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Term neonates (from birth to 27 days of post-natal age) and preterm neonates (from birth to the expected date of delivery plus 27 days)

For establishing the dosing regimen for neonates, the advice of a physician experienced in the management of neonates should be sought. One possible way of dosing vancomycin in neonates is illustrated in the following table: (see section 4.4)

PMA (weeks) Dose (mg/kg) Interval of administration (h)

<29 15 24

29-35 15 12

>35 15 8

PMA: post-menstrual age [(time elapsed between the first day of the last menstrual period and birth (gestational age) plus the time elapsed after birth (post-natal age)].

[For parenteral formulations authorised for perioperative antibacterial prophylaxis, include the wording as follows:]

Peri-operative prophylaxis of bacterial endocarditis in all age groups

The recommended dose is an initial dose of 15 mg/kg prior to induction of anaesthesia.Depending on the duration of surgery, a second vancomycin dose may be required.

Duration of treatment

Suggested treatment duration is shown in table below. In any case, the duration of treatment should be tailored to the type and severity of infection and the individual clinical response.

Indication Treatment duration

Complicated skin and soft tissue infections

-Non necrotizing 7 to 14 days

- Necrotizing 4 to 6 weeks*

Bone and joint infections 4 to 6 weeks**

Community-acquired pneumonia 7 to 14 days

Hospital-acquired pneumonia, including ventilator-associated pneumonia

7 to 14 days

Infective endocarditis 4 to 6 weeks***

Acute bacterial meningitis (For parenteral formulations authorised for Acute bacterial meningitis)

10 to 21 days

*Continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours **Longer courses of oral suppression treatment with suitable antibiotics should be considered for prosthetic joint infections ***Duration and need for combination therapy is based on valve-type and organism

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Special populations

Elderly

Lower maintenance doses may be required due to the age-related reduction in renal function.

Renal impairment

In adult and paediatric patients with renal impairment, consideration should be given to an initial starting dose followed by serum vancomycin trough levels rather than to a scheduled dosing regimen, particularly in patients with severe renal impairment or those who undergo renal replacement therapy (RRT) due to the many varying factors that may affect vancomycin levels in them.

In patients with mild or moderate renal failure, the starting dose must not be reduced. In patients with severe renal failure, it is preferable to prolong the interval of administration rather than administer lower daily doses.

Appropriate consideration should be given to the concomitant administration of medicinal products that may reduce vancomycin clearance and/or potentiate its undesirable effects (see section 4.4).

Vancomycin is poorly dialyzable by intermittent hemodialysis. However, use of high-flux membranes and continuous renal replacement therapy (CRRT) increases vancomycin clearance and generally requires replacement dosing (usually after the haemodialysis session in case of intermittent haemodialysis).

Adults

Dose adjustments in adult patients could be based on glomerular filtration rate estimated (eGFR) by the following formula:

Men: [Weight (kg) x 140 - age (years)]/ 72 x serum creatinine (mg/dl)

Women: 0.85 x value calculated by the above formula.

The usual starting dose for adult patients is 15 to 20 mg/kg that could be administered every 24 hours in patients with creatinine clearance between 20 to 49 ml/min. In patients with severe renal impairment (creatinine clearance below 20 ml/min) or those on renal replacement therapy, the appropriate timing and amount of subsequent doses largely depend on the modality of RRT and should be based on serum vancomycin trough levels and on residual renal function (see section 4.4). Depending on the clinical situation, consideration could be given to withhold the next dose while awaiting the results of vancomycin levels.

In the critically ill patient with renal insufficiency, the initial loading dose (25 to 30 mg/kg) should not be reduced.


Dose adjustments in paediatric patients aged 1 year and older could be based on glomerular filtration rate estimated (eGFR) by the revised Schwartz formula:

eGFR (mL/min/1.73m2 ) = (height cm x 0.413)/ serum creatinine (mg/dl)

eGFR (mL/min/1.73m2)= (height cm x 36.2/serum creatinine (µmol/L)

For neonates and infants below 1 year of age, expert advice should be sought as the revised Schwartz formula is not applicable to them.

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Orientative dosing recommendations for the paediatric population are shown in table below that follow the same principles as in adult patients.

GFR (mL/min/1.73 m2) IV dose Frequency

50-30 15 mg/kg 12 hourly

29-10 15 mg/kg 24 hourly

< 10

10-15 mg/kg

Re-dose based on levels*

Intermittent haemodialysis

Peritoneal dialysis

Continuous renal replacement therapy 15 mg/kg Re-dose based on levels*

*The appropriate timing and amount of subsequent doses largely depends on the modality of RRT and should be based on serum vancomycin levels obtained prior to dosing and on residual renal function. Depending on the clinical situation, consideration could be given to withhold the next dose while awaiting the results of vancomycin levels.

Hepatic impairment:

No dose adjustment is needed in patients with hepatic insufficiency.

Pregnancy

Significantly increased doses may be required to achieve therapeutic serum concentrations in pregnant women (see Section 4.6).

Obese patients

In obese patients, the initial dose should be individually adapted according to total body weight as in non-obese patients.

[For parenteral formulations authorised for intraperitoneal administration, include the wording as follows:]


Peritoneal dialysis–associated peritonitis

Adults

Intermittent therapy: the recommended dose is 15-30 mg/kg in the long-dwell, every 5-7 days.

Continuous infusion: loading dose of 30 mg/kg followed by a maintenance dose of 1.5 mg/kg/bag in all exchanges.


Intermittent therapy: initial dose of 30 mg/kg in the long-dwell, followed by 15 mg/kg every 3-5 days during the long-dwell (the second dose should be time-based on a blood level obtained 2–4 days after the initial dose, see section 4.4).

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Continuous infusion: loading dose of 1000 mg/L per litter of dialysate followed by 25 mg/L (after 3-6 h of loading dose) in all exchanges.

Supplemental doses may be needed for patients on Automated Peritoneal Dialysis (APD) because rapid exchanges in APD may lead to inadequate time to achieve therapeutic levels when vancomycin is given via intraperitoneal intermittently.

[For parenteral formulations authorised for oral use, the following should be reflected in this section]

Oral Administration

Patients aged 12 years and older

Treatment of Clostridium difficile infection (CDI):

The recommended vancomycin dose is 125 mg every 6 hours for 10 days for the first episode of non-severe CDI. This dose can be increased to 500 mg every 6 hours for 10 days in case of severe or complicated disease. The maximum daily dose should not exceed 2 g.

In patients with multiple recurrences, consideration may be given to treat the current episode of CDI with vancomycin, 125 mg four times daily for 10 days followed by either tapering the dose, i.e., gradually decreasing it until 125 mg per day or a pulse regimen, i.e., 125–500 mg/day every 2–3 days for at least 3 weeks.

Neonates, infants and children less than 12 years old

The recommended vancomycin dose is 10 mg/kg orally every 6 hours for 10 days. The maximum daily dose should not exceed 2 g.

Treatment duration with vancomycin may need to be tailored to the clinical course of individual patients. Whenever possible the antibacterial suspected to have caused CDI should be discontinued. Adequate replacement of fluid and electrolytes should be ensured.

[The below should be introduced in section 4.2 for all vancomycin products powder for concentrate]

Monitoring of vancomycin serum concentrations

The frequency of therapeutic drug monitoring (TDM) needs to be individualized based on the clinical situation and response to treatment, ranging from daily sampling that may be required in some hemodynamically unstable patients to at least once weekly in stable patients showing a treatment response. In patients with normal renal function, the serum concentration of vancomycin should be monitored on the second day of treatment immediately prior to the next dose.

In patients on intermittent haemodialysis, vancomycin levels should be usually obtained before the start of the haemodialysis session.

After oral administration, monitoring vancomycin serum concentrations in patients with inflammatory intestinal disorders should be performed (see section 4.4).

Therapeutic trough (minimum) vancomycin blood levels should normally be 10-20 mg/l, depending on the site of infection and susceptibility of the pathogen. Trough values of 15-20 mg/l are usually recommended by clinical laboratories to better cover susceptible-classified pathogens with MIC ≥1 mg/L (see sections 4.4 and 5.1).

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Model-based methods may be useful in the prediction of individual dose requirements to reach an adequate AUC. The model-based approach can be used both in calculating the personalized starting dose and for dose adjustments based on TDM results (see section 5.1).



Intravenous vancomycin is usually administered as an intermittent infusion and the dosing recommendations presented in this section for the intravenous route correspond to this type of administration.

Vancomycin shall only be administered as slow intravenous infusion of at least one hour duration or at a maximum rate of 10 mg/min (whichever is longer) which is sufficiently diluted (at least 100 ml per 500 mg or at least 200 ml per 1000 mg) (see section 4.4).

Patients whose fluid intake must be limited can also receive a solution of 500 mg/50 ml or 1000 mg/100 ml, although the risk of infusion-related undesirable effects can be increased with these higher concentrations.

For information about the preparation of the solution, please see section 6.6.

Continuous vancomycin infusion may be considered, e.g., in patients with unstable vancomycin clearance.



Intraperitoneal antibiotics should be added to the dialysate using sterile technique.

[For parenteral formulations authorised for oral administration, the following should be reflected in this section]

Oral administration

[This section must include instructions for preparation and administration of the oral solution. In addition, appropriate information should be given under Method of administration and in section 6.6.]

4.3 Contraindications


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

Vancomycin should not be administered intramuscularly due to the risk of necrosis at the site of administration.

4.4 Special warnings and precautions for use


Hypersensitivity reactions

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Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8). In case of hypersensitivity reactions, treatment with vancomycin must be discontinued immediately and the adequate emergency measures must be initiated.

In patients receiving vancomycin over a longer-term period or concurrently with other medications which may cause neutropenia or agranulocytosis, the leukocyte count should be monitored at regular intervals. All patients receiving vancomycin should have periodic haematologic studies, urine analysis, liver and renal function tests.

Vancomycin should be used with caution in patients with allergic reactions to teicoplanin, since cross hypersensitivity, including fatal anaphylactic shock, may occur.

Spectrum of antibacterial activity

Vancomycin has a spectrum of antibacterial activity limited to Gram-positive organisms. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a high suspicion that the most likely pathogen(s) would be suitable for treatment with vancomycin.

The rational use of vancomycin should take into account the bacterial spectrum of activity, the safety profile and the suitability of standard antibacterial therapy to treat the individual patient.

Ototoxicity

Ototoxicity, which may be transitory or permanent (see section 4.8) has been reported in patients with prior deafness, who have received excessive intravenous doses, or who receive concomitant treatment with another ototoxic active substance such as an aminoglycoside. Vancomycin should also be avoided in patients with previous hearing loss. Deafness may be preceded by tinnitus. Experience with other antibiotics suggests that deafness may be progressive despite cessation of treatment. To reduce the risk of ototoxicity, blood levels should be determined periodically and periodic testing of auditory function is recommended.

The elderly are particularly susceptible to auditory damage. Monitoring of vestibular and auditory function in the elderly should be carried out during and after treatment. Concurrent or sequential use of other ototoxic substances should be avoided.

Infusion-related reactions

Rapid bolus administration (i.e. over several minutes) may be associated with exaggerated hypotension (including shock and, rarely, cardiac arrest), histamine like responses and maculopapular or erythematous rash (“red man’s syndrome” or “red neck syndrome”). Vancomycin should be infused slowly in a dilute solution (2.5 to 5.0 mg/ml) at a rate no greater than 10 mg/min and over a period not less than 60 minutes to avoid rapid infusion-related reactions. Stopping the infusion usually results in a prompt cessation of these reactions.

The frequency of infusion-related reactions (hypotension, flushing, erythema, urticaria and pruritus) increases with the concomitant administration of anaesthetic agents (see section 4.5). This may be reduced by administering vancomycin by infusion over at least 60 minutes, before anaesthetic induction.

Severe bullous reactions

Stevens-Johnson syndrome (SJS) has been reported with the use of vancomycin (see section 4.8). If symptoms or signs of SJS (e.g. progressive skin rash often with blisters or mucosal lesions) are present, vancomycin treatment should be discontinued immediately and specialised dermatological assessment be sought.

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Administration site related reactions

Pain and thrombophlebitis may occur in many patients receiving intravenous vancomycin and are occasionally severe. The frequency and severity of thrombophlebitis can be minimized by administering the medicinal product slowly as a dilute solution (see section 4.2) and by changing the sites of infusion regularly.

The efficacy and safety of vancomycin has not been established for the intrathecal, intralumbar and intraventricular routes of administration.


The administration of vancomycin by intraperitoneal injection during continuous ambulatory peritoneal dialysis has been associated with a syndrome of chemical peritonitis.

Nephrotoxicity

Vancomycin should be used with care in patients with renal insufficiency, including anuria, as the possibility of developing toxic effects is much higher in the presence of prolonged high blood concentrations. The risk of toxicity is increased by high blood concentrations or prolonged therapy.

Regular monitoring of the blood levels of vancomycin is indicated in high dose therapy and longer-term use, particularly in patients with renal dysfunction or impaired faculty of hearing as well as in concurrent administration of nephrotoxic or ototoxic substances, respectively (see section 4.2).


The current intravenous dosing recommendations for the paediatric population, in particular for children below 12 years of age, may lead to sub-therapeutic vancomycin levels in a substantial number of children. However, the safety of increased vancomycin dosing has not been properly assessed and higher doses than 60 mg/kg/day cannot be generally recommended.

Vancomycin should be used with particular care in premature neonates and young infants, because of their renal immaturity and the possible increase in the serum concentration of vancomycin. The blood concentrations of vancomycin should therefore be monitored carefully in these children. Concomitant administration of vancomycin and anaesthetic agents has been associated with erythema and histamine-like flushing in children. Similarly, concomitant use with nephrotoxic agents such as aminoglycoside antibiotics, NSAIDs (e.g., ibuprofen for closure of patent ductus arteriosus) or amphotericin B is associated with an increased risk of nephrotoxicity (see section 4.5) and therefore more frequent monitoring of vancomycin serum levels and renal function is indicated.


For the intraperitoneal treatment of peritoneal dialysis–associated peritonitis (PDP) in children with residual renal function, intermittent therapy should only be indicated provided that vancomycin serum levels can be monitored in a timely manner.

Use in the elderly

The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted (see section 4.2).

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Drug interactions with anaesthetic agents

Anaesthetic induced myocardial depression may be enhanced by vancomycin. During anaesthesia, doses must be well diluted and administered slowly with close cardiac monitoring. Position changes should be delayed until the infusion is completed to allow for postural adjustment (see section 4.5).

Pseudomembranous enterocolitis

In case of severe persistent diarrhoea the possibility of pseudomembranous enterocolitis that might be life-threatening has to be taken into account (see section 4.8). Anti-diarrhoeic medicinal products must not be given.

Superinfection

Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

[For parenteral formulations authorised for oral use, include the wording as follows:]

Oral administration

Intravenous administration of vancomycin is not effective for the treatment of Clostridium difficile infection. Vancomycin should be administered orally for this indication.

Testing for Clostridium difficile colonization or toxin is not recommended in children younger than 1 year due to high rate of asymptomatic colonisation unless severe diarrhoea is present in infants with risk factors for stasis such as Hirschsprung disease, operated anal atresia or other severe motility disorders. Alternative aetiologies should always be sought and Clostridium difficile enterocolitis be proven.

Potential for Systemic Absorption

Absorption may be enhanced in patients with inflammatory disorders of the intestinal mucosa or with Clostridium difficile-induced pseudomembranous colitis. These patients may be at risk for the development of adverse reactions, especially if there is a concomitant renal impairment. The greater the renal impairment, the greater the risk of developing the adverse reactions associated with the parenteral administration of vancomycin. Monitoring of serum vancomycin concentrations of patients with inflammatory disorders of the intestinal mucosa should be performed.

Nephrotoxicity

Serial monitoring of renal function should be performed when treating patients with underlying renal dysfunction or patients receiving concomitant therapy with an aminoglycoside or other nephrotoxic drugs.

Ototoxicity

Serial tests of auditory function may be helpful in order to minimise the risk of ototoxicity in patients with an underlying hearing loss, or who are receiving concomitant therapy with an ototoxic agent such as an aminoglycoside.

Drug interactions with anti-motility agents and proton pump inhibitors

Anti-motility agents should be avoided and proton pump inhibitor use should be reconsidered.

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Development of Drug-Resistant Bacteria

Oral vancomycin use increases the chance of vancomycin-resistant Enterococci populations in the gastrointestinal tract. As a consequence, prudent use of oral vancomycin is advised.

4.8. Undesirable effects


Summary of the Safety profile

The most common adverse reactions are phlebitis, pseudo-allergic reactions and flushing of the upper body (“red-neck syndrome”) in connection with too rapid intravenous infusion of vancomycin.


The absorption of vancomycin from the gastrointestinal tract is negligible. However, in severe inflammation of the intestinal mucosa, especially in combination with renal insufficiency, adverse reactions that occur when vancomycin is administered parenterally may appear.

Tabulated List of Adverse reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions listed below are defined using the following MedDRA convention and system organ class database:

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).

System organ class

Frequency Adverse reaction

Blood and the lymphatic system disorders:

Rare Reversible neutropenia1, agranulocytosis, eosinophilia, thrombocytopenia, pancytopenia.

Immune system disorders:

Rare Hypersensitivity reactions, anaphylactic reactions2

Ear and labyrinth disorders:

Uncommon Transient or permanent loss of hearing4

Rare Vertigo, tinnitus3, dizziness

Cardiac disorders

Very rare Cardiac arrest

Vascular disorders:

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Common Decrease in blood pressure

Rare Vasculitis

Respiratory, thoracic and mediastinal disorders:

Common Dyspnoea, stridor

Gastrointestinal disorders:

Rare Nausea

Very rare Pseudomembranous enterocolitis

Not known Vomiting, Diarrhoea

Skin and subcutaneous tissue disorders:

Common Flushing of the upper body (“red man syndrome”), exanthema and mucosal inflammation, pruritus, urticaria

Very rare Exfoliative dermatitis, Stevens-Johnson syndrome, Lyell's syndrome, Linear IgA bullous dermatosis5

Not known Eosinophilia and systemic symptoms (DRESS syndrome),

AGEP (Acute Generalized Exanthematous Pustulosis)

Renal and urinary disorders:

Common Renal insufficiency manifested primarily by increased serum creatinine and serum urea

Rare Interstitial nephritis, acute renal failure.

Not known Acute tubular necrosis

General disorders and administration site conditions:

Common Phlebitis, redness of the upper body and face.

Rare Drug fever, shivering, Pain and muscle spasm of the chest and back muscles

Description of selected adverse drug reactions

Reversible neutropenia usually starting one week or more after onset of intravenous therapy or after total dose of more than 25 g.

During or shortly after rapid infusion anaphylactic/anaphylactoid reactions including wheezing may occur. The reactions abate when administration is stopped, generally between 20 minutes and 2 hours. Vancomycin should be infused slowly (see sections 4.2 and 4.4). Necrosis may occur after intramuscular injection.

Tinnitus, possibly preceding onset of deafness, should be regarded as an indication to discontinue treatment.

Ototoxicity has primarily been reported in patients given high doses, or in those on concomitant treatment with other ototoxic medicinal product like aminoglycoside, or in those who had a pre-existing reduction in kidney function or hearing.

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If a bullous disorder is suspected, the drug should be discontinued and specialised dermatological assessment should be carried out.


The safety profile is generally consistent among children and adult patients. Nephrotoxicity has been described in children, usually in association with other nephrotoxic agents such as aminoglycosides.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

5.1 Pharmacodynamic properties


Mechanism of action

Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units. The drug is slowly bactericidal for dividing microorganisms. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis.

Pharmacokinetic/ Pharmacodynamic relationship

Vancomycin displays concentration-independent activity with the area under the concentration curve (AUC) divided by the minimum inhibitory concentration (MIC) of the target organism as the primary predictive parameter for efficacy. On basis of in vitro, animal and limited human data, an AUC/MIC ratio of 400 has been established as a PK/PD target to achieve clinical effectiveness with vancomycin. To achieve this target when MICs are ≥ 1.0 mg/l, dosing in the upper range and high trough serum concentrations (15-20 mg/l) are required (see section 4.2).

Mechanism of resistance

Acquired resistance to glycopeptides is most common in enterococci and is based on acquisition of various van gene complexes which modifies the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine which bind vancomycin poorly. In some countries, increasing cases of resistance are observed particularly in enterococci; multi-resistant strains of Enterococcus faecium are especially alarming.

Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in “intermediate” susceptibility, which is most commonly heterogeneous. Also, methicillin-resistant staphylococcus strains (MRSA) with reduced susceptibility for vancomycin were reported. The reduced susceptibility or resistance to vancomycin in Staphylococcus is not well understood. Several genetic elements and multiple mutations are required.

There is no cross-resistance between vancomycin and other classes of antibiotics. Cross-resistance with other glycopeptide antibiotics, such as teicoplanin, does occur. Secondary development of resistance during therapy is rare.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc

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Synergism

The combination of vancomycin with an aminoglycoside antibiotic has a synergistic effect against many strains of Staphylococcus aureus, non-enterococcal group D-streptococci, enterococci and streptococci of the Viridans group. The combination of vancomycin with a cephalosporin has a synergistic effect against some oxacillin-resistant Staphylococcus epidermidis strains, and the combination of vancomycin with rifampicin has a synergistic effect against Staphylococcus epidermidis and a partial synergistic effect against some Staphylococcus aureus strains. As vancomycin in combination with a cephalosporin may also have an antagonistic effect against some Staphylococcus epidermidis strains and in combination with rifampicin against some Staphylococcus aureus strains, preceding synergism testing is useful.

Specimens for bacterial cultures should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to vancomycin.

Susceptibility testing breakpoints

Vancomycin is active against gram-positive bacteria, such as staphylococci, streptococci, enterococci, pneumococci, and clostridia. Gram-negative bacteria are resistant.

The prevalence of acquired 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. This information only provides approximate guidance on the chance whether micro-organisms are susceptible to vancomycin.

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Susceptible Resistant Staphylococcus aureus1 ≤ 2 mg/L > 2 mg/L Coagulase-negative staphylococci1 ≤ 4 mg/L > 4 mg/L Enterococcus spp. ≤ 4 mg/L > 4 mg/L Streptococcus groups A, B, C and G

≤ 2 mg/L > 2 mg/L

Streptococcus pneumoniae ≤ 2 mg/L > 2 mg/L Gram positive anaerobes ≤ 2 mg/L > 2 mg/L

1S. aureus with vancomycin MIC values of 2 mg/L are on the border of the wild type distribution and there may be an impaired clinical response.

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Commonly susceptible species Gram positive

Enterococcus faecalis Staphylococcus aureus Methicillin-resistant Staphylococcus aureus coagulase-negative Staphylococci Streptococcus spp. Streptococcus pneumoniae Enteroccocus spp. Staphylococcus spp.

Anaerobic species Clostridium spp. except Clostridium innocuum Eubacterium spp. Peptostreptococcus spp.

Species for which acquired resistance may be a problem

Enterococcus faecium

Inherently resistant All Gram negative bacteria Gram positive aerobic species

Erysipelothrix rhusiopathiae, Heterofermentative Lactobacillus, Leuconostoc spp Pediococcus spp.

Anaerobic species Clostridium innocuum

The emergence of resistance towards vancomycin differs from one hospital to another and a local microbiological laboratory should therefore be contacted for relevant local information.

5.2 Pharmacokinetic properties


Absorption

Vancomycin is administered intravenously for the treatment of systemic infections.

In the case of patients with normal renal function, intravenous infusion of multiple doses of 1g vancomycin (15 mg/kg) for 60 minutes produces approximate average plasma concentrations of 50-60 mg/L, 20-25 mg/L and 5-10 mg/L, immediately, 2 hours and 11 hours after completing the infusion, respectively. The plasma levels obtained after multiple doses are similar to those achieved after a single dose.

91


If vancomycin is administered during a peritoneal dialysis intraperitoneally, approximately 30-65% reach the systemic cycle during the first 6 hours. After intraperitoneal administration of 30 mg/kg serum levels of approximately 10 mg/l are reached.


Vancomycin is not usually absorbed into the blood after oral administration. However, absorption may occur after oral administration in patients with (pseudomembranous) colitis. This may lead to vancomycin accumulation in patients with co-existing renal impairment.

Distribution

The volume of distribution is about 60 L/1.73 m2 body surface. At serum concentrations of vancomycin of 10 mg/l to 100 mg/l, the binding of the drug to plasma proteins is approximately 30-55%, measured by ultra-filtration.

Vancomycin diffuses readily across the placenta and is distributed into cord blood. In non-inflamed meninges, vancomycin passes the blood-brain barrier only to a low extent.

Biotransformation

There is very little metabolism of the drug. After parenteral administration it is excreted almost completely as microbiologically active substance (approx. 75-90% within 24 hours) through glomerular filtration via the kidneys.

Elimination

The elimination half-life of vancomycin is 4 to 6 hours in patients with normal renal function and 2.2-3 hours in children. Plasma clearance is about 0.058 L/kg/h and kidney clearance about 0.048 L/kg/h. In the first 24 hours, approximately 80 % of an administered dose of vancomycin is excreted in the urine through glomerular filtration. Renal dysfunction delays the excretion of vancomycin. In anephric patients, the mean half-life is 7.5 days. Due to ototoxicity of vancomycin therapy-adjuvant monitoring of the plasma concentrations is indicated in such cases.

Biliary excretion is insignificant (less than 5% of a dose).

Although the vancomycin is not eliminated efficiently by haemodialysis or peritoneal dialysis, there have been reports of an increase in vancomycin clearance with haemoperfusion and haemofiltration.


After oral administration, only a fraction of the administered dose is recovered in the urine. In contrast, high concentrations of vancomycin are found in the faeces (>3100 mg/kg with doses of 2 g/day).

Linerarity/non-linearity

Vancomycin concentration generally increases proportionally with increasing dose. Plasma concentrations during multiple dose administration are similar to those after the administration of a single dose.

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Characteristics in specific groups

Renal impairment

Vancomycin is primarily cleared by glomerular filtration. In patients with impaired renal function the terminal elimination half- life of vancomycin is prolonged and the total body clearance is reduced. Subsequently, optimal dose should be calculated in line with dosing recommendations provided in section 4.2. Posology and method of administration.

Hepatic impairment

Vancomycin pharmacokinetics is not altered in patients with hepatic impairment.

Pregnant Women:

Significantly increased doses may be required to achieve therapeutic serum concentrations in pregnant women (see Section 4.6).

Overweight patients

Vancomycin distribution may be altered in overweight patients due to increases in volume of distribution, in renal clearance and possible changes in plasma protein binding. In these subpopulations vancomycin serum concentration were found higher than expected in male healthy adults (see section 4.2).


Vancomycin PK has shown wide inter-individual variability in preterm and term neonates. In neonates, after intravenous administration, vancomycin volume of distribution varies between 0.38 and 0.97 L/kg, similar to adult values, while clearance varies between 0.63 and 1.4 ml/kg/min. Half-life varies between 3.5 and 10 h and is longer than in adults, reflecting the usual lower values for clearance in the neonate.

In infants and older children, the volume of distribution ranges between 0.26-1.05 L/kg while clearance varies between 0.33-1.87 ml/kg/min.

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PACKAGE LEAFLET

Note: The existing package leaflet shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the wording below.

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<{(Invented) vancomycin 125mg capsule}> [For all vancomycin 250 mg capsule]

<{(Invented) vancomycin 250mg capsule}>

[to be completed nationally]

1. What Vancomycin is and what it is used for

Vancomycin is an antibiotic that belongs to a group of antibiotics called “glycopeptides”. Vancomycin works by eliminating certain bacteria that cause infections.

Vancomycin is used in adults and adolescents from 12 years of age for the treatment of infections of the mucosa of the small and the large intestines with damage to the mucosae (pseudomembranous colitis), caused by the Clostridium difficile bacterium.

2. What you need to know before you take [product name]

Do not take Vancomycin

If you are allergic to vancomycin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

If you have an inflammatory disorder of the digestive tract (you may be at risk of side effects, especially if you also have a kidney disorder).

Vancomycin capsules are not appropriate for children under 12 years or for adolescents unable to swallow them. Other forms of this medicine may be more suitable for children; ask your doctor or pharmacist.

3. How to take [product name]

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Adults and adolescents (from 12 years and older)

The recommended dose is 125 mg every 6 hours. In some cases, your doctor may decide to give a higher daily dose of up to 500 mg every 6 hours. The maximum daily dose should not exceed 2 g.

If you suffered other episodes (infection of the mucosa) before you may need different dose and different duration of the therapy.


For oral use.

Swallow the capsules whole with water.

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The usual duration of the therapy is 10 days but it may be different depending on the individual response to treatment for every patient.

4. Possible side effects


Like all medicines, this medicine can cause side effects, although not everybody gets them.

Vancomycin can cause allergic reactions, although serious allergic reactions (anaphylactic shock) are rare. Tell your doctor immediately if you get any sudden wheeziness, difficulty in breathing, redness on the upper part of the body, rash or itching.

Uptake of vancomycin from the gastrointestinal tract is negligible. Therefore adverse events following intake of capsules are unlikely.

However, if you have an inflammatory disorder of the digestive tract, especially if you also have a kidney disorder, similar side effects as those that occur when vancomycin is given by infusion may appear. Therefore, the side effects and frequencies which are reported for vancomycin given as infusion are included.

Common side effects (may affect up to 1 in 10 people):

- Fall in blood pressure

- Breathlessness, noisy breathing (a high pitched sound resulting from obstructed air flow in the upper airway)

- Rash and inflammation of the lining of the mouth, itching, itching rash, hives

- Kidney problems which may be detected primarily by blood tests

- Redness of upper body and face, inflammation of a vein

Uncommon side effects (may affect up to 1 in 100 people):

- Temporary or permanent loss of hearing

Rare side effects (may affect up to 1 in 1,000 people):

- Decrease in white blood cells, red blood cells and platelets (blood cells responsible for blood clotting)

Increase in some of the white blood cells in the blood. - Loss of balance, ringing in your ears, dizziness

- Blood vessel inflammation

- Nausea (feeling sick)

- Inflammation of the kidneys and kidney failure

- Pain in the chest and back muscles

- Fever, chills

Very rare side effects (may affect up to 1 in 10,000 people):

96

- Sudden onset of severe allergic skin reaction with skin flaking blistering or peeling skin. This may be associated with a high fever and joint pains

- Cardiac arrest

- Inflammation of the bowel which causes abdominal pain and diarrhea, which may contain blood

Not known (frequency cannot be estimated from the available data):

- Being sick (throwing up), diarrhoea - Confusion, drowsiness, lack of energy, swelling, fluid retention, decreased urine - Rash with swelling or pain behind the ears, in the neck, groin, under the chin and armpits (swollen

lymph nodes), abnormal blood and liver function tests - Rash with blisters and fever. Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

6. Contents of the pack and other information

Other sources of information

Advice/medical education

Antibiotics are used to cure bacterial infections. They are ineffective against viral infections.

If your doctor has prescribed antibiotics, you need them precisely for your current illness.

Despite antibiotics, some bacteria may survive or grow. This phenomenon is called resistance: some antibiotic treatments become ineffective.

Misuse of antibiotics increases resistance. You may even help bacteria become resistant and therefore delay your cure or decrease antibiotic efficacy if you do not respect appropriate:

- dosage

- schedules

- duration of treatment

Consequently, to preserve the efficacy of this drug:

1 - Use antibiotics only when prescribed.

2 - Strictly follow the prescription.

3 - Do not re-use an antibiotic without medical prescription, even if you want to treat a similar illness.

4 - Never give your antibiotic to another person; maybe it is not adapted to her/his illness.

5 - After completion of treatment, return all unused drugs to your chemist's shop to ensure they will be disposed of correctly.

97





[to be completed nationally]

1. What Vancomycin is and what it is used for

Vancomycin is an antibiotic that belongs to a group of antibiotics called “glycopeptides”. Vancomycin works by eliminating certain bacteria that cause infections.

Vancomycin powder is made into a <solution for infusion> <or> <oral solution>.

[for vancomycin powder for concentrate for infusion authorised for intravenous use]

Vancomycin is used in in all age groups by infusion for the treatment of the following serious infections:

- Infections of the skin and tissues below the skin.

- Infections of bone and joints.

- An infection of the lungs called "pneumonia".

- Infection of the inside lining of the heart (endocarditis) and to prevent endocarditis in patients at risk when undergoing major surgical procedures

- Infection in central nervous system.

- Infection in the blood linked to the infections listed above.

[For parenteral formulations authorised for intraperitoneal use:]

- In patients receiving peritoneal dialysis, vancomycin is used in adults and children for the treatment of infections related to peritoneal dialysis.

[for vancomycin powder for concentrate for infusion authorised for oral use]

Vancomycin can be given orally in adults and children for the treament of infection of the mucosa of the small and the large intestines with damage to the mucosae (pseudomembranous colitis), caused by the Clostridium difficile bacterium.

2. What you need to know before you use Vancomycin

Do not use Vancomycin

98

• If you are allergic to vancomycin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor or hospital pharmacist or nurse before using Vancomycin if:

- You suffered a previous allergic reaction to teicoplanin because this could mean you are also allergic to vancomycin.

- You have a hearing disorder, especially if you are elderly (you may need hearing tests during treatment).

- You have kidney disorder (you will need to have your blood and kidneys tested during treatment).

- You are receiving vancomycin by infusion for the treatment of the diarrhoea associated to Clostridium difficile infection instead of orally.

Talk to your doctor or hospital pharmacist or nurse during treatment with Vancomycin if:

- You are receiving vancomycin for a long time (you may need to have your blood, hepatic and kidneys tested during treatment).

- You develop any skin reaction during the treatment.

- You develop severe or prolonged diarrhoea during or after using vancomycin, consult your doctor immediately. This may be a sign of bowel inflammation (pseudomembranous colitis) which can occur following treatment with antibiotics.

Children

Vancomycin will be used with particular care in premature infants and young infants, because their kidneys are not fully developed and they may accumulare vancomycin in the blood. This age group may need blood tests for controlling vancomycin levels in blood.

Concomitant administration of vancomycin and anaesthetic agents has been associated with skin redness (erythema) and allergic reactions in children. Similarly, concomitant use with other medicines such as aminoglycoside antibiotics, nonsteroidal anti-inflammatory agents (NSAIDs, e.g., ibuprofen) or amphotericin B (medicine for fungal infection) can increase the risk of kidney damage and therefore more frequent blood and renal test may be necessary.

3. How to use [product name]

You will be given Vancomycin by medical staff while you are in hospital. Your doctor will decide how much of this medicine you should receive each day and how long the treatment will last.

Dosage

The dose given to you will depend on:

- your age,

- your weight,

- the infection you have,

- how well your kidneys are working,

99

- your hearing ability,

- any other medicines you may be taking.


Adults and adolescents (from 12 years and older)

The dosage will be calculated according to your body weight. The usual infusion dose is 15 to 20 mg for each kg of body weight. It is usually given every 8 to 12 hours. In some cases, your doctor may decide to give an initial dose of up to 30 mg for each kg of body weight. The maximum daily dose should not exceed 2 g.

Use in children

Children aged from one month to less than 12 years of age

The dosage will be calculated according to your body weight. The usual infusion dose is 10 to 15 mg for each kg of body weight. It is usually given every 6 hours.

Preterm and term newborn infants (from 0 to 27 days)

The dosage will be calculated according to post-menstrual age (time elapsed between the first day of the last menstrual period and birth (gestational age) plus the time elapsed after birth (post-natal age).

The elderly, pregnant women and patients with a kidney disorder, including those on dialysis, may need a different dose.



Adults and children

When using for the treatment of infections related to peritoneal dialysis, your doctor will decide exactly how much vancomycin you need.

[For parenteral formulations authorised for oral use:]

Oral administration

Adults and adolescents (from 12 to 18 years)

The recommended dose is 125 mg every 6 hours. In some cases, your doctor may decide to give a higher daily dose of up to 500 mg every 6 hours. The maximum daily dose should not exceed 2 g.

If you suffered other episodes (infection of the mucosa) before you may need different dose and different duration of the therapy.

Use in children

Neonates, infants and children less than 12 years old

The recommended dose is 10 mg for each kg of body weight. It is usually given every 6 hours. The maximum daily dose should not exceed 2 g.

100


Intravenous infusion means that the medicinal product flows from an infusion bottle or bag through a tube to one of your blood vessels and into your body. Your doctor, or nurse, will always give vancomycin into your blood and not in the muscle.

Vancomycin will be given into your vein for at least 60 minutes.


If given for the treatment of of infections related to peritoneal dialysis, vancomycin will be added to the dialysate solution in the long-dwell exchange.


If given for treatment of gastric disorders (so called Pseudomembranous colitis), the medicinal product must be administrated as a solution for oral use (you will take the medicine by mouth).

Duration of treatment

The length of treatment depends on the infection you have and may last a number of weeks.

The duration of the therapy may be different depending on the individual response to treatment for every patient.

During the treatment, you might have blood tests, be asked to provide urine samples and possibly have hearing tests to look for signs of possible side effects.

4. Possible side effects


Like all medicines, this medicine can cause side effects, although not everybody gets them.

Vancomycin can cause allergic reactions, although serious allergic reactions (anaphylactic shock) are rare. Tell your doctor immediately if you get any sudden wheeziness, difficulty in breathing, redness on the upper part of the body, rash or itching.


The absorption of vancomycin from the gastrointestinal tract is negligible. However, if you have an inflammatory disorder of the digestive tract, especially if you also have a kidney disorder, side effects that occur when vancomycin is administered by infusion may appear.

Common side effects (may affect up to 1 in 10 people):

- Fall in blood pressure

- Breathlessness, noisy breathing (a high pitched sound resulting from obstructed air flow in the upper airway)

- Rash and inflammation of the lining of the mouth, itching, itching rash, hives

101

- Kidney problems which may be detected primarily by blood tests

- Redness of upper body and face, inflammation of a vein

Uncommon side effects (may affect up to 1 in 100 people):

- Temporary or permanent loss of hearing

Rare side effects (may affect up to 1 in 1,000 people):

- Decrease in white blood cells, red blood cells and platelets (blood cells responsible for blood clotting)

Increase in some of the white cells in the blood.

- Loss of balance, ringing in your ears, dizziness

- Blood vessel inflammation

- Nausea (feeling sick)

- Inflammation of the kidneys and kidney failure

- Pain in the chest and back muscles

- Fever, chills

Very rare side effects (may affect up to 1 in 10,000 people):

- Sudden onset of severe allergic skin reaction with skin flaking blistering or peeling skin. This may be associated with a high fever and joint pains

- Cardiac arrest

- Inflammation of the bowel which causes abdominal pain and diarrhea, which may contain blood

Not known (frequency cannot be estimated from the available data):

- Being sick (throwing up), diarrhoea

- Confusion, drowsiness, lack of energy, swelling, fluid retention, decreased urine

- Rash with swelling or pain behind the ears, in the neck, groin, under the chin and armpits (swollen lymph nodes), abnormal blood and liver function tests

- Rash with blisters and fever.

Reporting of side effects

If you get any side effects, talk to your doctor, hospital pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

6. Contents of the pack and other information

Other sources of information

Advice/medical education

Antibiotics are used to cure bacterial infections. They are ineffective against viral infections.

102

If your doctor has prescribed antibiotics, you need them precisely for your current illness.

Despite antibiotics, some bacteria may survive or grow. This phenomenon is called resistance: some antibiotic treatments become ineffective.

Misuse of antibiotics increases resistance. You may even help bacteria become resistant and therefore delay your cure or decrease antibiotic efficacy if you do not respect appropriate:

- dosage

- schedules

- duration of treatment

Consequently, to preserve the efficacy of this drug:

1 - Use antibiotics only when prescribed.

2 - Strictly follow the prescription.

3 - Do not re-use an antibiotic without medical prescription, even if you want to treat a similar illness.

vancomycin article 31-1440 - european...

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