uk/h/1284/01/dc - medicines and healthcare products regulatory

PAR Cefixime 200mg Film-Coated Tablets UK/H/1284/01/DC

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Public Assessment Report

Decentralised Procedure

Cefixime 200mg Film-coated Tablet

Cefixime

UK/H/1284/01/DC

UK licence no: PL 22805/0019

Applicant: Orchid Europe Limited


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LAY SUMMARY On the 11th December 2009 the MHRA granted Orchid Europe Limited a Marketing Authorisation (licence) for the medicinal product Cefixime 200mg Film-coated Tablets. This is a prescription-only medicine (POM). Cefixime 200mg can be used to treat:

- infection of the middle ear - sinus infections - throat infection - infection causing sudden worsening of long-standing bronchitis - serious lung infections (pneumonia) acquired outside of hospital - infections in the urinary tract

Cefixime is an antibacterial agent of the cephalosporin class. Like other cephalosporins, cefixime exerts antibacterial activity by binding to and inhibiting the action of penicillin-binding proteins involved in the synthesis of bacterial cell walls. This leads to the breaking open of the bacterial cell by the destruction of its wall and cell death. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Cefixime 200mg Film-coated Tablets outweigh the risks. Hence, a Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 12 Module 4: Labelling Page 14 Module 5: Scientific Discussion Page 24 I Introduction II. Quality aspects III. Non-clinical aspects IV. Clinical aspects V. Overall conclusion and Benefit-Risk Assesment Module 6 Steps taken after initial procedure


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Module 1

Product Name

Cefixime 200mg film-coated tablets

Type of Application

Generic, Article 10.1

Active Substance

Cefixime

Form

Film-Coated Tablet

Strength

200mg

MA Holder

Orchid Europe Ltd

Building 3, Chiswick Park, 566 Chiswick High Road, Chiswick, London, W4 5YA, United Kingdom

RMS

UK

CMS

BG, DE, IE, IT and PL

Procedure Number

UK/H/1284/01/DC

Timetable

Day 210 – 1st November 2009


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Module 2 SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cefixime 200 mg Film-coated tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Film coated tablet contains 223.81 mg Cefixime trihydrate equivalent to 200 mg Cefixime (anhydrous) For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet White, circular, biconvex film coated tablets debossed with ‘C’ on one side and plain surface on the other side.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Cefixime is indicated for the treatment of the following infections when caused by susceptible organisms (see sections 4.4 and 5.1): Acute exacerbations of chronic bronchitis Community-acquired Pneumonia Lower urinary tract infections Pyelonephritis In the treatment of: Otitis media Sinusitis Pharyngitis The use of cefixime should be reserved for infections in which the causative organism is known or suspected to be resistant to other commonly used antibacterial agents or when treatment failure with other commonly used antibacterial agents may carry significant risk. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration Adults The recommended dose for adults is 200-400 mg daily according to the severity of infection, taken as a single dose (400 mg may also be taken as two divided doses) (see section 5.1). Elderly patients Elderly patients may be given the same dose as recommended for adults. Renal function should be assessed and dosage should be adjusted in severe renal impairment (See above and section 4.4). Adolescents ≥ 12 years of age Adolescents ≥ 12 years of age may be given the same dose as recommended for adults. Children from 6 months to 11 years of age It is recommended that children from 6 months to 11 years of age be given cefixime as an oral suspension because 200 mg cannot be adequately dosed for this age group. The recommended dosage for children in this age group is 8 mg / kg body weight / day administered as a single dose or in two divided doses. Children less than 6 months of age The safety and efficacy of cefixime has not been established in children less than 6 months of age. Renal insufficiency


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Cefixime may be administered in the presence of impaired renal function in adult patients. Normal dose and schedule may be given in adult patients with creatinine clearances of 20 ml/min or greater. In patients whose creatinine clearance is less than 20 ml/min, it is recommended that a dose of 200 mg once daily should not be exceeded. The dose and regimen for patients who are maintained on chronic ambulatory peritoneal dialysis or haemodialysis should follow the same recommendation as that for patients with creatinine clearances of less than 20 ml/min. There are insufficient data regarding use of cefixime in the pediatric and adolescent age group in the presence of renal insufficiency: the use of cefixime in these patient-groups is not recommended. Method of administration Cefixime tablets are for oral administration only. Cefixime tablets should be taken with a sufficient amount of water. Cefixime may be taken with or without food (see section 5.2). Duration of treatment The usual course of treatment is 7 days. This may be continued for up to 14 days if required.

4.3 Contraindications

Hypersensitivity to cefixime, other cephalosporin antibiotics or to any of the excipients. Previous, immediate and/or severe hypersensitivity reaction to penicillin or any beta-lactam antibiotic.

4.4 Special warnings and precautions for use

Cefixime should be given with caution to patients who have shown hypersensitivity to other drugs. Cephalosporins should be given with caution to penicillin-sensitive patients, as there is some evidence of partial cross-allergenicity between the penicillins and cephalosporins. Patients have had severe reactions (including anaphylaxis) to both classes of drugs. Special care is indicated in patients who have experienced any allergic reaction to penicillins or any other beta-lactam antibiotics as cross-reactions may occur (for contraindications due to known hypersensitivity reactions see section 4.3). If severe hypersensitivity reactions or anaphylactic reactions occur after administration of cefixime, the use of cefixime should be discontinued immediately and appropriate emergency measures should be initiated. Renal insufficiency Cefixime should be administered with caution in adult patients with creatinine clearance < 20 ml / min (see sections 4.2 and 5.2). There are insufficient data regarding use of cefixime in the pediatric and adolescent age group in the presence of renal insufficiency: the use of cefixime in these patient-groups is not recommended. Prolonged use of cefixime may result in the overgrowth of non-susceptible organisms. Treatment with broad spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated diarrhoea. Pseudomembranous colitis is associated with the use of broad-spectrum antibiotics (including macrolides, semi-synthetic penicillins, lincosamides and cephalosporins including cefixime); it is therefore important to consider its diagnosis in patients who develop diarrhoea in association with the use of antibiotics. In patients who develop severe diarrhoea during or after use of cefixime, the risk of life threatening pseudo-membranous colitis should be taken into account (see section 4.8). The use of cefixime should be discontinued and appropriate treatment measures should be established. Management of pseudomembranous colitis should include sigmoidoscopy, appropriate bacteriologic studies, fluids, electrolytes and protein supplementation. If the colitis does not improve after the drug has been discontinued, or if the symptoms are severe, oral vancomycin is the drug of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should be excluded. The use of medicinal products inhibiting the intestinal peristalsis is contra-indicated.

4.5 Interaction with other medicinal products and other forms of interaction

A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets, but not with tests based on enzymatic glucose oxidase reactions.


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A false positive direct Coombs’ test has been reported during treatment with cephalosporin antibiotics, therefore it should be recognized that a positive Coombs’ test may be due to the drug. In common with other cephalosporins, increases in prothrombin time have been noted in a few patients. Care should therefore be taken in patients receiving anticoagulation therapy.

4.6 Pregnancy and lactation

Pregnancy: For cefixime, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women. Cefixime should not be used in pregnant mothers unless considered essential by the physician. Lactation: It is unknown whether cefixime is excreted in human breast milk. Animal studies have shown excretion of cefixime in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with cefixime should be made taking into account the benefit of breast-feeding to the child and the benefit of cefixime therapy to the woman. However, until further clinical experience is available, cefixime should not be prescribed to breast-feeding mothers.

4.7 Effects on ability to drive and use machines

Cefixime has no known influence on the ability to drive and use machines. However, side effects may occur (See also section 4.8), which may influence the ability to drive and use machines.

4.8 Undesirable effects

In this section, the following convention has been used for the classification of undesirable effects in terms of frequency:

• Common: ≥1/100 to <1/10,

• Uncommon: ≥1/1,000 to <1/100,

• Rare: ≥1/10,000 to <1/1,000 and

• Very rare: <1/10,000

MedDRA System Organ Class

Adverse Drug Reaction Frequency

Superinfection bacterial, superinfection fungal

Rare Infections and infestations

Antibiotic-associated colitis (see section 4.4)

Very rare

Eosinophilia Rare Blood and lymphatic system disorders

Leucopenia, agranulocytosis, pancytopenia, thrombocytopenia, haemolytic anaemia

Very rare

Hypersensitivity Rare Immune system disorders

Anaphylactic shock, serum sickness Very rare

Metabolism and nutrition disorders

Anorexia Rare

Headache Uncommon Vertigo Rare

Nervous system disorders Psychomotor hyperactivity Very rare

Diarrhoea Common Abdominal pain, nausea, vomiting Uncommon

Gastrointestinal disorders

Flatulence Rare


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MedDRA System Organ Class

Adverse Drug Reaction Frequency

Hepatobiliary disorders

Hepatitis, cholestatic jaundice Very rare

Rash Uncommon Angioneurotic oedema, pruritus Rare

Skin and subcutaneous tissue disorders Stevens-Johnson syndrome, toxic

epidermal necrolysis Very rare

Renal and urinary disorders

Interstitial nephritis Very rare

General disorders and administration site conditions

Mucosal inflammation, pyrexia Rare

Hepatic enzyme increased (transaminase, alkaline phosphatase)

Uncommon

Blood urea increased Rare

Investigations

Blood creatinine increased Very rare 4.9 Overdose

There is no experience with overdoses with cefixime. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ATC code: J01DD08 Mode of Action Cefixime is an antibacterial agent of the cephalosporin class. Like other cephalosporins, cefixime exerts antibacterial activity by binding to and inhibiting the action of penicillin-binding proteins involved in the synthesis of bacterial cell walls. This leads to bacterial cell lysis and cell death. PK/PD relationship The time that the plasma concentration of cefixime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in PK/PD studies. Mechanisms of resistance Bacterial resistance to cefixime may be due to one or more of the following mechanisms: · Hydrolysis by extended-spectrum beta-lactamases and / or by chromosomally-encoded

(AmpC) enzymes that may be induced or de-repressed in certain aerobic gram-negative bacterial species

· Reduced affinity of penicillin-binding proteins · Reduced permeability of the outer membrane of certain gram-negative organisms restricting

access to penicillin-binding proteins · Drug efflux pumps More than one of these mechanisms of resistance may co-exist in a single bacterial cell. Depending on the mechanism(s) present, bacteria may express cross-resistance to several or all other beta-lactams and / or antibacterial drugs of other classes. Breakpoints Clinical minimum inhibitory concentration (MIC) breakpoints established by EUCAST (May 2009) for cefixime are:

• H.influenzae: sensitive ≤ 0.12 mg/L, resistant > 0.12 mg/L

• M.catarrhalis: sensitive ≤ 0.5 mg/L, resistant > 1.0 mg/L

• Neisseria gonorrhoeae: sensitive ≤ 0.12 mg/L, resistant > 0.12 mg/L


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• Enterobacteriaceae: sensitive ≤ 1.0 mg/L, resistant > 1.0 mg/L (for uncomplicated urinary tract infections only). The breakpoints for Enterobacteriaceae will detect reduced susceptibility mediated by most clinically important beta-lactamases in Enterobacteriaceae. Occasional ESBL-producing strains will be reported susceptible. For purposes of infection control, epidemiology and surveillance, laboratories may wish to use specific tests to screen for and confirm ESBL-production.

• Non-species related breakpoints: insufficient data.

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

Commonly susceptible species Aerobes, Gram positive: Streptococcus pneumoniae (Penicillin-susceptible) Streptococcus pyogenes Aerobes, Gram negative: Escherichia coli %

Haemophilus influenzae Klebsiella species %

Moraxella catarrhalis Proteus mirabilis%

Species for which resistance may be a problem Enterobacter species Resistant species Clostridium difficile Bacteroides fragilis Enterococci Pseudomonas species Staphylococcus aureus+

Streptococcus pneumoniae (Penicillin resistant) % Extended spectrum beta-lactamase (ESBL) producing isolates are always resistant + Cefixime has poor activity against staphylococci (regardless of susceptibility to methicillin)

5.2 Pharmacokinetic properties

Absorption: The absolute oral bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly modified by the presence of food. Cefixime may therefore be given without regard to meals. Distribution: Serum protein binding is well characterized for human and animal sera; cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of cefixime is only concentration dependent in human serum at very high concentrations which are not seen following clinical dosing. From in vitro studies, serum or urine concentrations of 1 mg/L or greater were considered to be adequate for most common pathogens against which cefixime is active. Typically, the peak serum levels following the recommended adult or paediatric doses are between 1.5 and 3 mg/L. Little or no accumulation of cefixime occurs following multiple dosing. Metabolism and elimination: Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine. Transfer of 14C-labelled cefixime from lactating rats to their nursing offspring through breast milk was quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data


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are available on secretion of cefixime in human breast milk. Placental transfer of cefixime was small in pregnant rats dosed with labeled cefixime. Special age groups: The pharmacokinetics of cefixime in healthy elderly (age > 64 years) and young volunteers (11-35) compared the administration of 400 mg doses once daily for 5 days. Mean Cmax and AUC values were slightly greater in the elderly. Elderly patients may be given the same dose as the general population (see section 4.2).

5.3 Preclinical safety data

There are no findings from chronic toxicity investigations suggesting that any side effects unknown to date could occur in humans. Furthermore, in vivo and in vitro studies did not yield any indication of a potential to cause mutagenicity. Long-term studies on carcinogenicity have not been conducted. Reproduction studies have been performed in mice and rats at doses up to 400 times the human dose and have revealed no evidence of impaired fertility or harm to the foetus due to cefixime. In the rabbit, at doses up to 4 times the human dose, there was no evidence of a teratogenic effect; there was a high incidence of abortion and maternal death, which is an expected consequence of the known sensitivity of rabbits to antibiotic-induced changes in the population of the microflora of the intestine.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

• Calcium Hydrogen Phosphate, Anhydrous

• Starch, Pregelatinised

• Cellulose, Microcrystalline

• Silica, Colloidal Anhydrous

• Magnesium stearate

• Opadry White Y-1-7000

Opadry White Y-1-7000 contains: Hypromellose (E 464) Macrogol 400 (E 1520) Titanium Dioxide (E 171)

6.2 Incompatibilities Not applicable

6.3 Shelf life

2 years 6.4 Special precautions for storage

Do not store above 25oC Keep blister in the outer carton.

6.5 Nature and contents of container

The product is packed in: PVC/ PVdC/ Al blister pack: 6s, 7s, 10s - One blister packed in a carton along with a PIL 12s, 14s, 20s - Two blisters packed in a carton along with a PIL 30s - Three blisters packed in a carton along with a PIL 40s - Four blisters packed in a carton along with a PIL 100s - Ten blisters packed in a carton along with a PIL Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements. 7 MARKETING AUTHORISATION HOLDER


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Orchid Europe Limited Building 3, Chiswick Park, 566 Chiswick High Road, Chiswick, London, W4 5YA, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 22805/0019 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/12/2009

10 DATE OF REVISION OF THE TEXT 11/12/2009


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Module 3


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Module 4

Labelling


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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Cefixime 200mg film-coated tablets, in the treatment of infection, could be approvable. This decentralised application concerns a generic version of cefixime submitted under Article 10.1. The originator product is Suprax 200mg Tablets, authorised on 12/08/1998 to Rhone-Poulenc Rorer, UK. The UK reference product was originally authorised on 24/04/1990 to Cynamid GB, PL 00095/0212 and subsequently, a COA was granted to M & B (RPR group), PL 00012/0316 on 12/08/1998.

With the UK as the Reference Member State in this Decentralised Procedure, Orchid Europe Ltd is applying for the Marketing Authorisation for Cefixime 200mg film-coated tablets in BG, DE, IE, IT and PL Cefixime is an antibacterial agent of the cephalosporin class. Like other cephalosporins, cefixime exerts antibacterial activity by binding to and inhibiting the action of penicillin-binding proteins involved in the synthesis of bacterial cell walls. This leads to the breaking open of the bacterial cell by the destruction of its wall and to cell death. The submitted dossier is of an acceptable standard. The RMS has been assured that acceptable standards of GMP are in place for this product type at all sites responsible for the manufacture and assembly of this product. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates, of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.


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ABOUT THE PRODUCT Name of the product in the Reference Member State

Cefixime 200mg Film-Coated Tablet

Name(s) of the active substance(s) (INN) Cefixime Pharmacotherapeutic classification (ATC code)

J01DD08

Pharmaceutical form and strength(s) Film-Coated Tablet and 200mg Reference numbers for the Mutual Recognition Procedure

UK/H/1284/01/DC

Reference Member State United Kingdom Member States Concerned BG, DE, IE, IT and PL Marketing Authorisation Number(s) PL 22805/0019 Name and address of the authorisation holder Orchid Europe Ltd

Building 3, Chiswick Park, 566 Chiswick High Road, Chiswick, London, W4 5YA, United Kingdom


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SCIENTIFIC OVERVIEW AND DISCUSSION II. QUALITY ASPECTS DRUG SUBSTANCE INN: cefixime Chemical Name:

Structure:

Molecular Formula: C16H15N5O7S2,3H2O Molecular Weight: 507.5 Appearance: A white or almost white powder, slightly hygroscopic, soluble in methanol, slightly soluble in water, sparingly soluble in ethanol and practically insoluble in ethyl acetate. All aspects of the manufacture and control of the active substance cefixime anhydrous are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.


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DRUG PRODUCT Other ingredients Other ingredients consist of the pharmaceutical excipients colloidal anhydrous silica, calcium hydrogen phosphate anhydrous, Opadry Y-1-7000 White, pregelatinised starch, cellulose microcrystalline and magnesium stearate. All excipients comply with their respective European Pharmacopoeia monographs except Opadry Y-1-7000 White which complies with an in-house specification. Satisfactory Certificates of Analysis have been provided for all excipients. Magnesium stearate is from a vegetable source. None of the other excipients are of human origin. Pharmaceutical Development Suitable pharmaceutical development data have been provided for this application. The physico-chemical properties of the drug product have been compared with that of the originator product. These data demonstrate that the proposed product can be considered a generic medicinal product of Suprax 200mg Tablets. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory, based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results are satisfactory.

Finished product specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used.

Container-Closure System The finished product is packed in PVC/ PVdC/Aluminium blister packs. Specifications and Certificates of Analysis for all packaging materials have been provided. These are satisfactory. All primary packaging complies with EU legislation regarding contact with food. Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years has been set for the unopened product, with the storage instructions ‘Do not store above 25 ◦ C’ and ‘Keep blisters in the outer carton’. Bioequivalence/bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study. Bio-analytical methods used have been satisfactorily validated. Satisfactory bioequivalence is seen between the test and reference product. SPC, PIL, Labels The SPC, PIL and labels are pharmaceutically acceptable.


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A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Conclusion It is recommended that Marketing Authorisation is granted for this application. The requirements for a generic product of the originator product have been met with respect to qualitative and quantitative content of the active substance. In addition, similar physico-chemical properties have been demonstrated for the proposed and originator product. III. PRE-CLINICAL ASPECTS This application claims to be a generic medicinal product of Suprax 200mg Tablets, which has been licensed within the EU for over 10 years. No new preclinical data have been supplied with this application. However, a preclinical expert report summarising relevant non-clinical studies has been included in the dossier. This is satisfactory. IV. CLINICAL ASPECTS 1. Introduction 1.1. Type of Application and Regulatory Background This is a decentralised application made under EU Directive 2001/83/EC as amended, Article 10(1) generic application for marketing authorisation for Cefixime 200mg Film-coated Tablets. The originator product in EU is Suprax tablets 200mg, authorised on 12/08/1998 to Rhone-Poulenc Rorer, UK. The UK reference product was originally authorised on 24/04/1990 to Cynamid GB, PL 00095/0212 and subsequently a COA was granted to M & B (RPR group), PL 00012/0316 on 12/08/1998. 1.2. Clinical Background Cefixime is a third-generation cephalosporin antibacterial that is given by mouth to adult and paediatric patients in the treatment of infections of the respiratory tract and urinary tract (and in the treatment of gonorrhoea, unlicensed) when caused by susceptible bacteria. Cefixime has a half-life of about 4 hours and may be administered once or twice daily. Some clinicians recommend cefixime because of the relatively long half-life in cases where the compliance of the patient is a concern. Cefixime is given by mouth in adult doses of 200 to 400 mg daily as a single dose or in two divided doses. Children over 6 months and under 50 kg may be given 8 mg/kg daily as an oral suspension either as a single dose or in two divided doses. Cefixime does not offer any advantages (other than the convenience of dose regime) over other equally effective, less expensive antibiotics available for the treatment of infections of the respiratory and urinary tracts. In addition, use of cefixime is limited as an empirical therapy because it is inactive against staphylococci, enterococci and Pseudomonas


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aeruginosa and most anaerobic bacteria. Cefixime should not be used alone if a mixed aerobic-anaerobic bacterial infection is suspected. The usual duration of therapy depends on the type of infection but is usually for about 72hrs after the patient becomes afebrile (has no fever) or evidence of eradication is obtained. There are several regimes of therapy duration. 1.3. Indications Cefixime is indicated for the treatment of the following infections when caused by susceptible organisms (see sections 4.4 and 5.1 of SPC):

Acute exacerbations of chronic bronchitis Community-acquired Pneumonia Lower urinary tract infections Pyelonephritis

In the treatment of: Otitis media Sinusitis Pharyngitis The use of cefixime should be reserved for infections in which the causative organism is known or suspected to be resistant to other commonly used antibacterial agents or when treatment failure with other commonly used antibacterial agents may carry significant risk.

Consideration should be given to official guidance on the appropriate use of antibacterial agents. 1.4. Posology and method of administration Adults The recommended dose for adults is 200-400 mg daily according to the severity of infection, taken as a single dose (400 mg may also be taken as two divided doses) (see section 5.1 of SPC). Elderly patients Elderly patients may be given the same dose as recommended for adults. Renal function should be assessed and dosage should be adjusted in severe renal impairment (See above and section 4.4 of SPC). Adolescents ≥ 12 years of age Adolescents ≥ 12 years of age may be given the same dose as recommended for adults. Children from 6 months to 11 years of age It is recommended that children from 6 months to 11 years of age be given cefixime as an oral suspension because 200 mg cannot be adequately dosed for this age group. The recommended dosage for children in this age group is 8 mg / kg body weight / day administered as a single dose or in two divided doses. Children less than 6 months of age The safety and efficacy of cefixime has not been established in children less than 6 months of age.


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Renal insufficiency Cefixime may be administered in the presence of impaired renal function in adult patients. Normal dose and schedule may be given in adult patients with creatinine clearances of 20 ml/min or greater. In patients whose creatinine clearance is less than 20 ml/min, it is recommended that a dose of 200 mg once daily should not be exceeded. The dose and regimen for patients who are maintained on chronic ambulatory peritoneal dialysis or haemodialysis should follow the same recommendation as that for patients with creatinine clearances of less than 20 ml/min. There are insufficient data regarding use of cefixime in the pediatric and adolescent age group in the presence of renal insufficiency: the use of cefixime in these patient-groups is not recommended. Method of administration Cefixime tablets are for oral administration only. Cefixime tablets should be taken with a sufficient amount of water. Cefixime may be taken with or without food (see section 5.2 of SPC). Duration of treatment The usual course of treatment is 7 days. This may be continued for up to 14 days if required. 2. Clinical Pharmacology 2.1. Pharmacokinetics Cefixime is a well known active substance and the pharmacokinetic characteristics have been studied in the past. The applicant has submitted a bioequivalence study in support of claims of essential similarity. 2.2. Bioequivalence Administrative details Study title A randomized, open label, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Cefixime 200 mg tablets of Orchid Healthcare, India and Suprax™ (Cefixime 200 mg) tablets of Rhone-Poulenc Rorer Pharma Specialities, France, in healthy human adult male subjects under fasting conditions. Study number: 1020/06 GCP certification The applicant states that the bioequivalence study was done in accordance with ICH GCP guidelines. The study was reviewed beforehand by an independent ethics committee. Informed consent was obtained from participants. Test Product Name and strength: Cefixime tablets 200mg, batch number E6017, manufactured May 2006 Reference Product Name and strength: Suprax tablets (cefixime) 200mg, lot number 279 of Rhone-Poulenc, France Acceptability criteria: marketed in an EU country, “the same” as UK reference product.


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The study design is acceptable (randomised, two-way, two-period, single dose crossover study in healthy fasted volunteers) Number of subjects studied (initial protocol, final, note any interim analyses) 28 healthy adult male subjects were enrolled for the study. Subjects were admitted to the test facility 13 hours prior to drug administration to permit monitored fasting. Subjects were given either with the test or reference product (with 240mL of water) in each period as determined by the randomization schedule. Dose administered (test/reference): 200mg The randomisation scheme appears random. Blood samples were collected within 1 hour before dosing and 1.00, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 14.00, 16.00 and 24.00 hours post-dosing in both periods. Subjects left the test house at 24 hours post dosing. Plasma cefixime concentration was analysed using a validated HPLC method with a generated standard curve for cefixime concentration up to 5.5 mg/L. This is acceptable. The duration of sampling following dosing was adequate for AUCt > 80% of AUCinf. The sampling frequency around Tmax was adequate for accurate Cmax estimation There was a wash out period of 7 days between dosings. This is adequate to prevent carry-over. Zero baseline plasma concentrations were recorded at period 2 Pre-defined bioequivalence acceptance criteria The protocol defines acceptance criteria of 0.8 – 1.25 for both AUC and Cmax. This is satisfactory. Data was analysed using an SAS package (version 9.1). Log-transformed pharmacokinetic parameters (Cmax and AUC) were analysed using a GLM ANOVA model. The protocol appears adequate. 28 subjects were enrolled into the study. 2 subjects dropped out. One subject had detectable cefixime in his blood at the start of period 2 and so was withdrawn. Withdrawals and other protocol deviations were managed according to protocol. One subject was noted to have developed eosinophilia during the study but this resolved. No other adverse event was recorded. The applicant analysed the results from 25 subjects for the pharmacokinetics. Results Arithemetic mean of

test ± S.D. Arithemetic mean of reference ± S.D.

Cmax (mg/L) 3.01 ± 0.84 3.02 ± 0.84 AUCt (mg.h/L) 25.7 ± 7.6 26.3 ± 7.3 AUC∞ (mg.h/L) 26.4 ± 7.8 27.0 ± 7.5 Tmax (h) 4.44 4.48


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The measured PK parameters in line with published values in standard reference texts: Cmax = 2.7mg/L at 3 to 4hrs post dose, half life = 2.5 to 3.5hrs (Therapeutic Drugs. Ed: C. Dollery. Published by Churchill Livingstone, Edinburgh, 1999) Bioequivalence results for log-transformed test/reference ratios with 90% Confidence Intervals: Cmax 1.00 (0.95 – 1.05) AUCt 0.98 (0.92 – 1.03) AUC∞ 0.98 (0.92 – 1.03)

The 90% confidence intervals for test/reference lie within the acceptance criteria. Appearance of individual plasma concentration – time curves has been inspected. These are acceptable. Assessor's Conclusion on Bioequivalence: the bioequivalence study has returned results consistent with bioequivalence. 2.3. Pharmacodynamics The pharmacodynamic characteristics of Cefixime have been well-studied in the past. There would be no particular concerns for a generic medicinal product. 3. Clinical Efficacy No new data have been submitted and none are required. 4. Clinical Safety No new data have been submitted and none are required. 5. Expert Reports A clinical overall summary, written by an appropriately qualified physician, has been provided and is a satisfactory, non-critical summary of Module 5. 6. Conclusion The medical assessor recommended that marketing authorisation was granted for this product. Module 1 – Administrative information MAA forms The MAA form is medically satisfactory. Summary of Product Characteristics (SPC) The SPC is medically satisfactory and consistent with that for the reference product. Patient Information Leaflet (PIL) The PIL is medically satisfactory and consistent with the SPC. Packaging The packaging is medically satisfactory.


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V . OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Cefixime 200mg Film-coated Tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY No new or unexpected safety concerns arise from this application. The SPC and PIL are satisfactory and consistent with that of the reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. Extensive clinical experience with cefixime is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

uk/h/1284/01/dc - medicines and healthcare products regulatory

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