Public Assessment Report Decentralised Procedure … · PAR Cefalexin 250 and 500mg Capsules, Hard UK/H/1578/001-2/DC 6 4.3 Contraindications Hypersensitivity to the cephalosporin

Public Assessment Report

Decentralised Procedure

CEFALEXIN 250MG CAPSULES HARD CEFALEXIN 500MG CAPSULES HARD

Procedure No: UK/H/1578/001-2/DC

UK Licence No: PL 30306/0082-3

ACTAVIS GROUP PTC EHF

PAR Cefalexin 250 and 500mg Capsules, Hard UK/H/1578/001-2/DC

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LAY SUMMARY The MHRA granted Actavis Group PTC ehf Marketing Authorisations (licences) for the medicinal products Cefalexin 250 and 500mg Capsules Hard on 26th March 2009. These are prescription-only medicines to treat infections caused by bacteria (germs). These include infections of: - the lungs and breathing airways (bronchitis and mild to moderate pneumonia) - the skin and soft tissue (such as wound infection) The active ingredient, cefalexin, which is an antibiotic. Antibiotics work by killing the bacteria (germs) that can cause an infection. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Cefalexin 250 and 500mg Capsules Hard outweigh the risks, hence Marketing Authorisations have been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 3 Module 2: Summary of Product Characteristics Page 4 Module 3: Product Information Leaflets Page 22 Module 4: Labelling Page 24 Module 5: Scientific Discussion Page 28 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6 Steps taken after initial procedure


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Module 1

Product Name

Cefalexin 250 and 500mg Capsules, Hard

Type of Application

Article 10.1

Active Substance

Cefalexin monohydrate

Form

Hard Capsules

Strength

250 and 500mg

MA Holder

Actavis Group PTC ehf, Reykjavíkurvegur 76-78, IS-220 Hafnarfjörður, Iceland

Reference Member State (RMS)

UK

CMS

250 and 500mg: Finland, Ireland and Norway 500mg: Italy

Procedure Number

UK/H/1578/001-2/DC

Timetable

Day 210 – 23rd February 2009


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Cefalexin 250mg capsules, hard 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains, as active ingredient, cefalexin monohydrate equivalent to 250mg of cefalexin base. Excipients: Brilliant blue (E133) and sunset yellow (E110). For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Capsule, hard. 250mg capsules, consist of green coloured opaque cap and opaque white coloured body, size “2” hard gelatine capsules, imprinted with black “-” on cap and body, filled with white to off white granular powder.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Cefalexin is a semi-synthetic cephalosporin antibiotic for oral administration. Cefalexin is indicated for the treatment of the following infections (see also sections 4.4 and 5.1). Exacerbation of chronic bronchitis Mild to moderate community-acquired pneumonia Uncomplicated upper and lower urinary tract infections Skin and soft tissue infections Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology The recommended dose for adults is 1-4g daily in divided doses. Most infections will respond to a dosage of 500mg every 8 hours. For skin and soft tissue infections, streptococcal pharyngitis, and mild, uncomplicated urinary tract infections, the usual dosage is 250mg every 6 hours or 500mg every 12 hours. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cefalexin greater than 4g are required, parenteral cephalosporins, in appropriate doses, should be considered. Patients with impaired renal function Reduce dosage if renal function is markedly impaired (section 4.4). Elderly patients The recommended dose for adults should be used in elderly patients except those with impaired renal function (see section 4.4). Children The recommended daily dosage for children is 25-50mg/kg body weight divided in 3 doses. In severe infections, the dosage may be doubled. In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose should be administered for at least 10 days. Method of administration Cefalexin is administered orally.


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4.3 Contraindications Hypersensitivity to the cephalosporin group of antibiotics or to any of the excipients.

4.4 Special warnings and precautions for use

Before instituting therapy with cefalexin, every effort should be made to determine whether the patient has had previous hypersensitivity reactions to the cephalosporins, penicillins or other medicinal products. Cefalexin should be given cautiously to penicillin-sensitive patients. There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and cephalosporins. Patients have had severe reactions (including anaphylaxis) to both medicinal products. Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics, including macrolides, semi-synthetic penicillins, and cephalosporins. It is important, therefore, to consider its diagnosis in patients who develop diarrhoea in association with the use of antibiotics. Such colitis may range in severity from mild to life-threatening. Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken. If an allergic reaction to cefalexin occurs, the drug should be discontinued and the patient treated with the appropriate agents. Prolonged use of cefalexin 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. Cefalexin should not be used in infections in which Haemophilus influenzae is, or is likely to be, implicated. Cefalexin should be administered with caution in the presence of markedly impaired renal function. Careful clinical and laboratory studies should be made because safe dosage may be lower than that usually recommended. If dialysis is required for renal failure, the daily dose of cefalexin should not exceed 500 mg. Positive direct Coombs' tests have been reported during treatment with the cephalosporin antibiotics. In haematological studies, or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side, or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognised that a positive Coombs' test may be due to the medicinal product. A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions, or with copper sulphate test tablets. Cefalexin capsules, hard contain colouring agents brilliant blue (E133) and sunset yellow (E110), which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

As with other beta-lactam medicinal products, renal excretion of Cefalexin is inhibited by probenecid. Concurrent administration with certain other drug substances, such as aminoglycosides, other cephalosporins, or furosemide, and similar potent diuretics, may increase the risk of nephrotoxicity. In a single study of 12 healthy subjects given single 500mg doses of cefalexin and metformin, plasma metformin Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin renal clearance decreased by an average of 14%. No side effects were reported in 12 healthy subjects in this study. No information is available about the interaction of cefalexin and metformin following multiple dose administration. The clinical significance of this study is unclear, particularly as no cases of “lactic acidosis” have been reported in association with concomitant metformin and cefalexin treatment.

4.6 Pregnancy and lactation

Pregnancy There are no adequate and well controlled studies in pregnant women. Although animal studies have shown no evidence of teratogenicity, caution should be exercised when prescribing cefalexin during pregnancy (see section 5.3).


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Lactation Cefalexin is excreted in human milk. Caution should be exercised when cefalexin is administered to a nursing woman.

4.7 Effects on ability to drive and use machines

There are no known effects of cephalexin on a patient's ability to drive or use machinery. However when driving vehicles or operating machines it should be taken into account that occasionally dizziness or confusion may occur.

4.8 Undesirable effects

Adverse events that have been reported in cefalexin trials are categorised below, according to system organ class and frequency. Frequencies are defined as: 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). Undesirable effects for cefalexin occur at a frequency of 3-6%. Investigations Uncommon: Increase in ASAT and ALAT (reversible) Frequency not known: Positive direct Coombs test. False positive reaction to glucose in the urine Blood and lymphatic system disorders Uncommon: Eosinophilia Rare: Neutropenia, thrombocytopenia, haemolytic anaemia Nervous system disorders Rare: Headache, dizziness Gastrointestinal disorders Common: Diarrhoea, nausea. Rare: Abdominal pain, vomiting, dyspepsia, pseudomembranous colitis Renal and urinary disorders Rare: Reversible interstitial nephritis Skin and subcutaneous tissue disorders Uncommon: Rash, urticaria, pruritus Rare: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis (Lyell’s

syndrome), angioedema Musculoskeletal and connective tissue disorders Frequency not known: Arthralgia, arthritis Infections and infestations Rare: Genital and anal pruritus, vaginitis Frequency not known: Vaginal candidiasis General disorders and administration site conditions Rare: Tiredness Frequency not known: Fever Immune system disorders Rare: Anaphylactic reaction Hepatobiliary disorders Rare: Hepatitis, cholestatic icterus


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Psychiatric disorders Frequency not known: Hallucinations, agitation, confusion

4.9 Overdose Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhoea, and haematuria.

In the event of severe overdosage, general supportive care is recommended, including close clinical and laboratory monitoring of haematological, renal and hepatic functions, and coagulation status until the patient is stable. Forced diuresis, peritoneal dialysis, haemodialysis, or charcoal haemoperfusion have not been established as beneficial for an overdose of Cefalexin. It would be extremely unlikely that one of these procedures would be indicated. Unless 5 to 10 times the normal total daily dose has been ingested, gastro-intestinal decontamination should not be necessary. There have been reports of haematuria, without impairment of renal function, in children accidentally ingesting more than 3.5g of cefalexin in a day. Treatment has been supportive (fluids) and no sequelae have been reported.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: First generation cephalosporin, ATC code: J01DB01. Mode of Action Cefalexin is an antibacterial agent of the cephalosporin class. Like other cephalosporins cefalexin 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. Mechanisms of resistance Bacterial resistance to cefalexin 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 pencillin-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 medicinal products of other classes. Breakpoints Minimum inhibitory concentration (MIC) breakpoints established by the British Society of Antimicrobial Chemotherapy for beta-haemolytic Streptococci and Streptococcus pneumoniae are: susceptible ≤ 2mg /l, resistant ≥2.5mg/l. 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: Staphylococcus aureus (methicillin susceptible) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes


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Aerobes, Gram negative: Escherichia coli Moraxella catarrhalis Anaerobes: Peptostreptococcus species Species for which resistance may be a problem Gram-negative aerobes: Citrobacter species Enterobacter species Morganella morganii. Inherently resistant species Gram-negative aerobes: Haemophilus influenzae

5.2 Pharmacokinetic properties

Cefalexin is acid stable and may be given without regard to meals. It is rapidly absorbed after oral administration. Following doses of 250mg, 500mg, and 1g, average peak serum levels of approximately 9, 18, and 32mg/l, respectively, were obtained at 1 hour. Measurable levels were present 6 hours after administration. Cefalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the medicinal product was excreted unchanged in the urine within 8 hours. During this period, peak urine concentrations following the 250mg, 500mg, and 1g doses were approximately 1,000, 2,200, and 5,000mg/l, respectively. Cefalexin is almost completely absorbed from the gastro-intestinal tract, and 75-100% is rapidly excreted in active form in the urine. Absorption is slightly reduced if the drug is administered with food. The half-life is approximately 60 minutes in patients with normal renal function. Haemodialysis and peritoneal dialysis will remove cefalexin from the blood. Peak blood levels are achieved one hour after administration, and therapeutic levels are maintained for 6-8 hours. Approximately 80% of the active drug is excreted in the urine within 6 hours. No accumulation is seen with dosages above the therapeutic maximum of 4g/day. The half-life may be increased in neonates due to their renal immaturity, but there is no accumulation when given at up to 50mg/kg/day.

5.3 Preclinical safety data

The daily oral administration of cefalexin to rats in doses of 250 or 500mg/kg prior to and during pregnancy, or to rats and mice during the period of organogenesis only, had no adverse effect on fertility, foetal viability, foetal weight, or litter size. Cefalexin showed no enhanced toxicity in weanling and newborn rats as compared with adult animals. The oral LD50 of cefalexin in rats is 5,000mg/kg.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Capsule content Cellulose microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell Sodium laurilsulfate Sunset yellow (E110) Brilliant blue (E133) Titanium dioxide (E171) Gelatin


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Black printing ink (containing shellac, propylene glycol, potassium hydroxide and iron oxide, black (E172))

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

1 year 6.4 Special precautions for storage

Do not store above 25°C 6.5 Nature and contents of container

Blister strips consisting of PVC/Aclar/Aluminium blister film. Pack sizes: Cefalexin caps. 250mg: 14 and 28 capsules. Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf Reykjavíkurvegur 76-78 IS-220 Hafnarfjörður Iceland

8 MARKETING AUTHORISATION NUMBER(S)

PL 30306/0082 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26/03/2009 10 DATE OF REVISION OF THE TEXT

26/03/2009


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1 NAME OF THE MEDICINAL PRODUCT Cefalexin 500mg capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains, as active ingredient, cefalexin monohydrate equivalent to 500mg of cefalexin base. Excipients: Brilliant blue (E133) and sunset yellow (E110). For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Capsule, hard. 500mg capsules, consist of green coloured opaque cap and opaque light green coloured body, size “0” hard gelatine capsules, imprinted with black “-” on cap and body, filled with white to off white granular powder.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Cefalexin is a semi-synthetic cephalosporin antibiotic for oral administration. Cefalexin is indicated for the treatment of the following infections (see also sections 4.4 and 5.1). Exacerbation of chronic bronchitis Mild to moderate community-acquired pneumonia Uncomplicated upper and lower urinary tract infections Skin and soft tissue infections Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology The recommended dose for adults is 1-4g daily in divided doses. Most infections will respond to a dosage of 500mg every 8 hours. For skin and soft tissue infections, streptococcal pharyngitis, and mild, uncomplicated urinary tract infections, the usual dosage is 250mg every 6 hours or 500mg every 12 hours. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cefalexin greater than 4g are required, parenteral cephalosporins, in appropriate doses, should be considered. Patients with impaired renal function Reduce dosage if renal function is markedly impaired (section 4.4). Elderly patients The recommended dose for adults should be used in elderly patients except those with impaired renal function (see section 4.4). Children The recommended daily dosage for children is 25-50mg/kg body weight divided in 3 doses. In severe infections, the dosage may be doubled. In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose should be administered for at least 10 days. Method of administration Cefalexin is administered orally.

4.3 Contraindications

Hypersensitivity to the cephalosporin group of antibiotics or to any of the excipients.


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4.4 Special warnings and precautions for use Before instituting therapy with cefalexin, every effort should be made to determine whether the patient has had previous hypersensitivity reactions to the cephalosporins, penicillins or other medicinal products. Cefalexin should be given cautiously to penicillin-sensitive patients. There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and cephalosporins. Patients have had severe reactions (including anaphylaxis) to both medicinal products. Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics, including macrolides, semi-synthetic penicillins, and cephalosporins. It is important, therefore, to consider its diagnosis in patients who develop diarrhoea in association with the use of antibiotics. Such colitis may range in severity from mild to life-threatening. Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken. If an allergic reaction to cefalexin occurs, the drug should be discontinued and the patient treated with the appropriate agents. Prolonged use of cefalexin 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. Cefalexin should not be used in infections in which Haemophilus influenzae is, or is likely to be, implicated. Cefalexin should be administered with caution in the presence of markedly impaired renal function. Careful clinical and laboratory studies should be made because safe dosage may be lower than that usually recommended. If dialysis is required for renal failure, the daily dose of cefalexin should not exceed 500 mg. Positive direct Coombs' tests have been reported during treatment with the cephalosporin antibiotics. In haematological studies, or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side, or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognised that a positive Coombs' test may be due to the medicinal product. A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions, or with copper sulphate test tablets. Cefalexin capsules, hard contain colouring agents brilliant blue (E133) and sunset yellow (E110), which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

As with other beta-lactam medicinal products, renal excretion of Cefalexin is inhibited by probenecid. Concurrent administration with certain other drug substances, such as aminoglycosides, other cephalosporins, or furosemide, and similar potent diuretics, may increase the risk of nephrotoxicity. In a single study of 12 healthy subjects given single 500mg doses of cefalexin and metformin, plasma metformin Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin renal clearance decreased by an average of 14%. No side effects were reported in 12 healthy subjects in this study. No information is available about the interaction of cefalexin and metformin following multiple dose administration. The clinical significance of this study is unclear, particularly as no cases of “lactic acidosis” have been reported in association with concomitant metformin and cefalexin treatment.

4.6 Pregnancy and lactation

Pregnancy There are no adequate and well controlled studies in pregnant women. Although animal studies have shown no evidence of teratogenicity, caution should be exercised when prescribing cefalexin during pregnancy (see section 5.3). Lactation Cefalexin is excreted in human milk. Caution should be exercised when cefalexin is administered to a nursing woman.


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4.7 Effects on ability to drive and use machines

There are no known effects of cephalexin on a patient's ability to drive or use machinery. However when driving vehicles or operating machines it should be taken into account that occasionally dizziness or confusion may occur.

4.8 Undesirable effects

Adverse events that have been reported in cefalexin trials are categorised below, according to system organ class and frequency. Frequencies are defined as: 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). Undesirable effects for cefalexin occur at a frequency of 3-6%. Investigations Uncommon: Increase in ASAT and ALAT (reversible) Frequency not known: Positive direct Coombs test. False positive reaction to glucose in the urine Blood and lymphatic system disorders Uncommon: Eosinophilia Rare: Neutropenia, thrombocytopenia, haemolytic anaemia Nervous system disorders Rare: Headache, dizziness Gastrointestinal disorders Common: Diarrhoea, nausea. Rare: Abdominal pain, vomiting, dyspepsia, pseudomembranous colitis Renal and urinary disorders Rare: Reversible interstitial nephritis Skin and subcutaneous tissue disorders Uncommon: Rash, urticaria, pruritus Rare: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis (Lyell’s

syndrome), angioedema Musculoskeletal and connective tissue disorders Frequency not known: Arthralgia, arthritis Infections and infestations Rare: Genital and anal pruritus, vaginitis Frequency not known: Vaginal candidiasis General disorders and administration site conditions Rare: Tiredness Frequency not known: Fever Immune system disorders Rare: Anaphylactic reaction Hepatobiliary disorders Rare: Hepatitis, cholestatic icterus Psychiatric disorders Frequency not known: Hallucinations, agitation, confusion


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4.9 Overdose Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhoea, and haematuria.

In the event of severe overdosage, general supportive care is recommended, including close clinical and laboratory monitoring of haematological, renal and hepatic functions, and coagulation status until the patient is stable. Forced diuresis, peritoneal dialysis, haemodialysis, or charcoal haemoperfusion have not been established as beneficial for an overdose of Cefalexin. It would be extremely unlikely that one of these procedures would be indicated. Unless 5 to 10 times the normal total daily dose has been ingested, gastro-intestinal decontamination should not be necessary. There have been reports of haematuria, without impairment of renal function, in children accidentally ingesting more than 3.5g of cefalexin in a day. Treatment has been supportive (fluids) and no sequelae have been reported.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: First generation cephalosporin, ATC code: J01DB01. Mode of Action Cefalexin is an antibacterial agent of the cephalosporin class. Like other cephalosporins cefalexin 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. Mechanisms of resistance Bacterial resistance to cefalexin 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 pencillin-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 medicinal products of other classes. Breakpoints Minimum inhibitory concentration (MIC) breakpoints established by the British Society of Antimicrobial Chemotherapy for beta-haemolytic Streptococci and Streptococcus pneumoniae are: susceptible ≤ 2mg /l, resistant ≥2.5mg/l. 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: Staphylococcus aureus (methicillin susceptible) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Aerobes, Gram negative: Escherichia coli Moraxella catarrhalis


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Anaerobes: Peptostreptococcus species Species for which resistance may be a problem Gram-negative aerobes: Citrobacter species Enterobacter species Morganella morganii. Inherently resistant species Gram-negative aerobes: Haemophilus influenzae

5.2 Pharmacokinetic properties

Cefalexin is acid stable and may be given without regard to meals. It is rapidly absorbed after oral administration. Following doses of 250mg, 500mg, and 1g, average peak serum levels of approximately 9, 18, and 32mg/l, respectively, were obtained at 1 hour. Measurable levels were present 6 hours after administration. Cefalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the medicinal product was excreted unchanged in the urine within 8 hours. During this period, peak urine concentrations following the 250mg, 500mg, and 1g doses were approximately 1,000, 2,200, and 5,000mg/l, respectively. Cefalexin is almost completely absorbed from the gastro-intestinal tract, and 75-100% is rapidly excreted in active form in the urine. Absorption is slightly reduced if the drug is administered with food. The half-life is approximately 60 minutes in patients with normal renal function. Haemodialysis and peritoneal dialysis will remove cefalexin from the blood. Peak blood levels are achieved one hour after administration, and therapeutic levels are maintained for 6-8 hours. Approximately 80% of the active drug is excreted in the urine within 6 hours. No accumulation is seen with dosages above the therapeutic maximum of 4g/day. The half-life may be increased in neonates due to their renal immaturity, but there is no accumulation when given at up to 50mg/kg/day.

5.3 Preclinical safety data

The daily oral administration of cefalexin to rats in doses of 250 or 500mg/kg prior to and during pregnancy, or to rats and mice during the period of organogenesis only, had no adverse effect on fertility, foetal viability, foetal weight, or litter size. Cefalexin showed no enhanced toxicity in weanling and newborn rats as compared with adult animals. The oral LD50 of cefalexin in rats is 5,000mg/kg.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Capsule content Cellulose microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell Sodium laurilsulfate Sunset yellow (E110) Brilliant blue (E133) Titanium dioxide (E171) Gelatin Black printing ink (containing shellac, propylene glycol, potassium hydroxide and iron oxide, black (E172))

6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

1 year 6.4 Special precautions for storage

Do not store above 25°C 6.5 Nature and contents of container

Blister strips consisting of PVC/Aclar/Aluminium blister film. Pack sizes: Cefalexin caps. 500mg: 8, 14, 20, 21, 30, 40 and 100 capsules. Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf Reykjavíkurvegur 76-78 IS-220 Hafnarfjörður Iceland

8 MARKETING AUTHORISATION NUMBER(S)

PL 30306/0083 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26/03/2009 10 DATE OF REVISION OF THE TEXT

26/03/2009


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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 considered that the applications for Cefalexin 250 and 500mg Capsules Hard (PL 30306/0082-83 UK/H/1578/001-2/DC) could be approved. The products are prescription-only medicines for the treatment of the following infections:

• Exacerbation of chronic bronchitis • Mild to moderate community-acquired pneumonia • Uncomplicated upper and lower urinary tract infections • Skin and soft tissue infections

These applications were submitted using the decentralised procedure (DCP), according to Article 10.1 of 2001/83 EC, as amended. With the UK as RMS, the marketing authorisation holder (Actavis Group PTC ehf) was applying for product licences in Finland, Ireland and Norway for the 250 and 500mg tablets, and Italy for the 500mg tablets. The reference medicinal products are Keflex 250 and 500mg Capsules (Eli Lilly, UK), which have been granted licences in at least one EU country for the last 10 years. Cefalexin is a semi-synthetic cephalosporin antibiotic and has bactericidal activity resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death. Cefalexin is stable to a broad range of bacterial β-lactamases and is active against both gram-positive and gram-negative species. No new preclinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. No new clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports issued by an EU regulatory authority. The decentralised procedure was completed successfully on 23rd February 2009. National licences were subsequently granted in the UK on 26th March 2009.


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

Cefalexin 250mg Capsules Hard Cefalexin 500mg Capsules Hard

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

First-generation cephalosporin (J01 D B01)

Pharmaceutical form and strength(s) 250mg and 500mg hard capsules Reference numbers for the Mutual Recognition Procedure

UK/H/1578/001-2/DC

Reference Member State United Kingdom Member States concerned 250mg and 500mg: Finland, Ireland and Norway

500mg: Italy Marketing Authorisation Number(s) PL 30306/0082-3 Name and address of the authorisation holder Actavis Group PTC ehf, Reykjavíkurvegur 76-

78, IS-220 Hafnarfjörður, Iceland


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN/Ph.Eur name: Cefalexin monohydrate Chemical name: (6R,7R)-7-[[(2R)-2-Amino-2-phenylacetyl]amino]-3-methyl-8-oxo-5-

thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid monohydrate Structural formula:

H2O,NH2

NH

H N

S

CH3O

H HO

CO2H

Molecular formula: C16H17N3O4S, H2O Appearance: White or almost white crystalline powder, sparingly soluble in water,

practically insoluble in alcohol. Molecular weight: 365.4 Cefalexin monohydrate is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of active cefalexin monohydrate are covered by a European Directorate for the Quality of Medicines Certificate of Suitability. The packaging used to store active cefalexin monohydrate is stated on the certificate of suitability. A suitable retest period has been stated on the certificate of suitability, based on data submitted by the active substance manufacturer. P. Medicinal Product Other Ingredients Other ingredients consist of pharmaceutical excipients cellulose microcrystalline, magnesium stearate, sodium laurilsulfate, sunset yellow (E110), brilliant blue (E133), titanium dioxide (E171), gelatine and black printing ink (E172 – consisting of shellac, propylene glycol, potassium hydroxide and iron oxide black). With the exception of the gelatin capsules, all excipients comply with their European Pharmacopoeia monograph. Gelatin capsules are controlled to a suitable in-house specification. With the exception of gelatin, none of the excipients contain materials of animal or human origin. All suppliers of gelatin have provided European Directorate on the Quality of Medicines Certificates of Suitability to show that gelatin is produced in-line with current guidelines concerning the minimisation of TSE/BSE.


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Pharmaceutical Development The objective of the development programme was to formulate stable, efficacious and tolerable hard capsules containing cefalexin monohydrate that can be considered generic medicinal products of Keflex 250 and 500mg Capsules (Eli Lilly, UK). A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution profiles and impurity profiles have been provided for the proposed and originator products. Manufacturing Process Satisfactory batch formulae have been provided for both strengths of product, along with an appropriate account of the manufacturing process. Supporting validation data have been provided for pilot-scale batches along with a commitment to validate the first three commercial-scale batches as they become available. Finished Product Specification The finished product specifications proposed for both strengths are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for all working standards used. Container-Closure System Both strengths of tablets are packaged in aluminium/polyvinylchloride/aclar blisters and aluminium/aluminium blisters, both of which are contained in cardboard boxes. Pack sizes for the 250mg strength are 14 and 28 tablets, and 8, 14, 20, 21, 30, 40 and 100 tablets for the 500mg strength. The marketing authorisation holder does not intend to market all pack sizes at the current time, but has committed to submitting the mock-ups for any pack sizes to the regulatory authorities before marketing them in that country. Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability of the product Stability studies were performed in accordance with current guidelines on batches of all strengths of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 1 year, with the storage conditions “Do not store above 25°C”. Suitable post approval stability commitments have been provided to follow-up the batches from the current studies and to place the first three commercial-scale batches of each strength on stability, followed by one batch per year. Bioequivalence/bioavailability Satisfactory certificates of analysis have been provided for the test and reference batches used in the bioequivalence study.


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Summary of Product Characteristics (SPC), Patient Information Leaflet (PIL), Labels The SPC, PIL and labels are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA, along with readability testing results of the leaflet. 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. MAA forms The MAA forms are pharmaceutically satisfactory. Expert report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion The grant of marketing authorisations is recommended. III.2 PRE-CLINICAL ASPECTS The applicant has provided no new preclinical data. As the pharmacodynamic, pharmacokinetic and toxicological properties of cefalexin monohydrate are well-known, no new preclinical data are required. The preclinical overview, based on a literature review, has been written by an appropriately qualified person and is a suitable summary of the preclinical aspects of the dossier. No environmental risk assessment has been submitted. The lack of an environmental risk assessment is justified as the product is a generic version of an already approved one and it is not likely to change the total market of cefalexin. There are no objections to approval of these products from a non-clinical point of view. III.3 CLINICAL ASPECTS Pharmacokinetics In support of these applications, the marketing authorisation holder has submitted the following bioequivalence study: An open-label, randomised, two-period, two-treatment, two-sequence, single-dose, crossover study to compare the pharmacokinetics of Cefalexin 500mg Capsules (Test) versus Keflex 500mg Capsules (Reference – Eli Lilly, UK) in healthy male volunteers under fasted conditions. Volunteers were dosed with either treatment with blood samples taken measurement of pharmacokinetic parameters pre- and up to 10 hours post dose. The two treatment arms were separated by a 7-day washout period. The results are presented below for the active substance cefalexin monohydrate:

Test Reference Ratio (Test/Reference)

90% Confidence Interval (Parametric)

Cmax (µg/ml) 22.228 23.0798 96.309 89.545-103.585 AUC0-t (µg*.hr/ml) 46.3177 45.2131 102.443 97.643-107.478 AUC 0-∞ (µg*.hr/ml) 47.5581 46.2294 102.874 98.144-107.833


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The 90% confidence intervals for cefalexin monohydrate lie within the acceptance criteria specified in the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), meaning that bioequivalence has been shown between the test and reference products. As these products meet all the criteria as specified in the Note for Guidance on the investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence study on the 500mg strength can be extrapolated to the 250mg strength tablets. Pharmacodynamics No new data on the pharmacodynamics of cefalexin monohydrate are submitted and none are required for these types of applications. Efficacy No new data on the efficacy of cefalexin monohydrate are submitted and none are required for these types of applications. Safety No new data on the safety of cefalexin monohydrate are submitted and none are required for these types of applications. Summary of product characteristics (SPC), Patient information leaflet (PIL) and Labels The SPCs, PIL and labels are medically acceptable and consistent with those for the reference products, where applicable. Conclusion The grant of marketing authorisations is recommended. IV OVERALL CONCLUSION AND RISK-BENEFIT ASSESSMENT QUALITY The important quality characteristics of Cefalexin 250 and 500mg Capsules Hard 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 risk-benefit balance. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY Bioequivalence has been demonstrated between the applicant’s Cefalexin 500mg Capsules and the originator products Keflex 500mg Capsules (Eli Lilly, UK). As these products meet all the criteria as specified in the Note for Guidance on the investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence study on the 500mg strength can be extrapolated to the 250mg strength capsules. No new or unexpected safety concerns arise from these applications. The SPC, PIL and labelling are satisfactory and consistent with those for Cefalexin Capsules.


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RISK-BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant’s products and the innovator products are interchangeable. Extensive clinical experience with cefalexin monohydrate 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

Documents

Public Assessment Report Decentralised Procedure … · PAR Cefalexin 250 and 500mg Capsules, Hard UK/H/1578/001-2/DC 6 4.3 Contraindications Hypersensitivity to the cephalosporin