Public Assessment Report. Decentralised Procedure

Transcription

1 Public Assessment Report Decentralised Procedure AMOXICILLIN 125 MG/ 5 ML POWDER FOR ORAL SUSPENSION AMOXICILLIN 250 MG/ 5 ML POWDER FOR ORAL SUSPENSION Procedure No: UK Licence No: PL 25298/ BROWN & BURK UK LTD

2 LAY SUMMARY On 14 December 2011, the Netherlands and the UK agreed to grant Marketing Authorisations to Brown & Burk UK Ltd for the medicinal products Amoxicillin 125 mg/ 5 ml and Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension (PL 25298/0003-4; UK/H/3242/001-2/DC). The licences were granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After a subsequent national phase, Marketing Authorisations were granted in the UK on 13 January These are prescription-only medicines (POM) used in adults and children above the age of 6 months to treat infections of the chest (bronchitis or pneumonia) and ears (acute otitis media) and cystitis. They can also be used as part of treatment to prevent infections of the heart lining (endocarditis). Amoxicillin belongs to a group of antibiotics called penicillins. Penicillins work by killing the bacteria that can cause infections. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for Oral Suspension outweigh the risks, hence Marketing Authorisations have been granted. 2

3 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 23 Module 4: Labelling Page 25 Module 5: Scientific Discussion Page 29 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Page 37 3

4 Module 1 Product Name Amoxicillin 125 mg/ 5 ml Powder for Oral Suspension Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension Type of Application Generic, Article 10 (1) Active Substances Amoxicillin Form Powder for oral suspension Strength 125 mg/ 5 ml and 250 mg/ 5 ml MA Holder Brown & Burk UK Ltd, 5, Marryat Close, Hounslow West Middlesex, TW4 5DQ, UK Reference Member State UK (RMS) Concerned Member State The Netherlands (CMS) Procedure Number Timetable Day December

5 Module 2 Summary of Product Characteristics 1 NAME OF THE MEDICINAL PRODUCT Amoxicillin 125 mg/ 5 ml Powder for Oral Suspension 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Amoxicillin suspension contains 125 mg amoxicillin per 5 ml dose. The amoxicillin is present as the trihydrate. Contains 295 mg /5 ml sorbitol (E420) For excipients see PHARMACEUTICAL FORM Powder for oral suspension White to pale yellow free flowing powder for oral suspension. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Amoxicillin Suspension is indicated for the treatment of the following infections caused by susceptible bacteria in adults and children above the age of 6 months (see sections 4.2, 4.4 and 5.1): Acute otitis media Acute exacerbations of chronic bronchitis Community acquired pneumonia Cystitis Endocarditis: Prophylaxis of endocarditis associated with procedures such as dental extraction, where indicated in patients at risk of developing bacterial endocarditis. Consideration should be given to official guidelines on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Treatment of Infection: Adult dosage (including elderly patients): Oral: Standard adult dosage: 250 mg-500 mg three times daily, increasing to 1 g three times daily for more severe infections. High dosage therapy (maximum recommended oral dosage 6 g daily in divided doses): A dosage of 3 g twice daily is recommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract. Short course therapy: Simple acute urinary tract infection: two 3 g doses with hours between the doses. Dosage in impaired renal function: The dose should be reduced in patients with severe renal function impairment. In patients with a creatinine clearance of less than 30 ml/min a reduction in the total daily dose by an increase in the dosage interval and/or a reduction in subsequent doses is recommended (see section 4.4 and 5.2). The following adjustments are recommended: Glomerular filtration rate > 30 ml/min: No adjustment necessary. Glomerular filtration rate ml/min: Amoxicillin. max. 500 mg b.d 5

6 Glomerular filtration rate < 10 ml/min: Amoxicillin. max. 500 mg/day In case of hemodialysis: 500 mg should be administered at the end of the procedure. Dosage in impaired hepatic function: Dose with caution and monitor hepatic function at regular intervals Prophylaxis for endocarditis 3g amoxicillin given as a single dose one hour preceding the surgical procedure. National guidelines should be followed. Children weighing < 40 kg: The daily dosage for children is mg/kg/day in two to three divided doses* (not exceeding 3 g/day) depending on the indication, severity of the disease and the susceptibility of the pathogen (see special dosage recommendations below and sections 4.4, 5.1 and 5.2). *PK/PD data indicate that dosing three times daily is associated with enhanced efficacy, thus twice daily dosing is only recommended when the dose is in the upper range. Children weighing more than 40 kg should be given the usual adult dosage. Special dosage recommendation Indication Acute otitis media Prophylaxis for endocarditis Dose regimen and duration of treatment In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, dosage regimens should be guided by national/local recommendations. 50 mg amoxicillin/kg body weight given as a single dose, one hour preceding the surgical procedure. Renal impairment in children under 40 kg: Creatinine clearance ml/min Dose Interval between administration > 30 Usual dose No adjustment necessary Half of usual dose < 10 Half of usual dose 12 h 24 h In case of haemodialysis: one usual dose should be administered at the end of the procedure. Administration: Oral Treatment should be continued for 2 to 3 days following the disappearance of symptoms. It is recommended that atleast 10 days treatment be given for any infection caused by beta-haemolytic streptococci in order to achieve eradication of the organism. Parenteral therapy is indicated if the oral route is considered impracticable or unsuitable, and particularly for the urgent treatment of severe infection. For instructions on reconstitution of the medicinal product before administration see section Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. 6

7 History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). 4.4 Special warnings and precautions for use Before treatment with amoxicillin is started, thorough enquiries should be made concerning earlier hypersensitivity reactions to penicillins and cephalosporins (see sections 4.3 and 4.8). The possibility of cross-sensitivity (10-15%) with cephalosporins should be taken into account. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and alternative therapy instituted. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. Treatment of urinary tract infections may be a problem due to a very high resistance rate of Escherichia coli reported for amoxicillin in some European countries (see section 5.1). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters a regular check of patency should be maintained (see Section 4.9). It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods. Dosage should be adjusted in patients with renal impairment (see 4.2). The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires amoxicillin discontinuation and contra-indicates any subsequent administration of amoxicillin. Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). This medicine contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine. 7

8 This medicine also contains sodium benzoate (E211), which may increase the risk of jaundice in newborn babies. 4.5 Interaction with other medicinal products and other forms of interaction In common with other broad spectrum antibiotics, amoxicillin may reduce the efficacy of oral contraceptives and patients should be warned accordingly. Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods. There have been cases of increased international normalised ratio in patients treated with acenocoumarol or warfarin when receiving concurrent treatment with amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Adjustments in the dose of oral anticoagulants may be necessary. 4.6 Fertility, pregnancy and lactation Pregnancy: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Amoxicillin passes the placenta and foetal plasma concentrations are approximately 25-30% of the maternal plasma concentrations. Data on a limited number of exposed pregnancies indicate no adverse effects of amoxicillin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Caution should be exercised when prescribing to pregnant women. Lactation: Amoxicillin diffuses into the breast milk (approx. 10% of the corresponding serum concentration) and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should also be considered. A decision must be made as to whether to discontinue breast-feeding, or to discontinue/abstain from Amoxicillin suspension therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility: No fertility data are available. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000,<1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000). The majority of side effects listed below are not unique to amoxicillin and may occur when using other pencillins. Unless otherwise stated, the frequency of adverse events has been derived from more than 30 years of post-marketing reports. 8

9 Infections and infestations Very Rare: Blood and lymphatic system disorders Very rare: Immune system disorders Very rare: Nervous system disorders Very rare: Gastrointestinal disorders Clinical Trial Data *Common: *Uncommon: Post-marketing Data Very rare: Hepato-biliary disorders Very rare: Skin and subcutaneous tissue disorders Clinical Trial Data *Common: *Uncommon: Post-marketing Data Very rare: Mucocutaneous Candidiasis Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin (see Section 4.4) Severe allergic reactions, including angioneurotic oedema, anaphylaxis (see Section 4.4), serum sickness and hypersensitivity vasculitis. Hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses. Diarrhoea and nausea. Vomiting. Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis). Black hairy tongue Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. The significance of a rise in AST and/or ALT is unclear. Skin rash Urticaria and pruritus Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (See also Immune system disorders). Renal and urinary tract disorders Very rare: Interstitial nephritis. Very rare: Crystalluria (see Section 4.9). *The incidence of these AE's was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin. 9

10 4.9 Overdose Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to the water/electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4). Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4) Amoxicillin may be removed from the circulation by haemodialysis. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties General properties Pharmacotherapeutic Group: Penicillins with extended spectrum, ATC classification: J01CA04 Mode of action Amoxicillin is bactericidal against susceptible organisms during the stage of active multiplication. It acts through the inhibition of one or more enzymes (often referred to as penicillin-binding proteins, PBP s) in the biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell wall. PK/PD relationship Amoxicillin demonstrates a time-dependent pattern of bactericidal activity (%T > MIC is considered to be the major determinant of efficacy). Mechanisms of resistance Bacteria may be resistant to amoxicillin owing to: production of beta-lactamases that hydrolyse aminopenicillins alterations in penicillin-binding proteins impermeability of the bacteria to the drug drug efflux pumps. Complete cross-resistance occurs with ampicillin and amoxicillin Breakpoints (EUCAST) Organism Susceptibility Breakpoints (μg/ml) Susceptible Intermediate Resistant Haemophilus influenzae 1 - > 1 Moraxella catharrhalis 1 - > 1 Enterococcus 4 8 > 8 Streptococcus A, B, C, G > 0.25 Streptococcus > 2 pneumoniae 2 Enterobacteriaceae > 8 Gram-negative anaerobes > 2 Gram-positive Anaerobes 4 8 > 8 Non-species related breakpoints > 8 1 Breakpoint values in the table are based on Benzylpenicillin breakpoints. 2 Breakpoint values in the table are based on ampicillin breakpoints. 3 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 10

11 Susceptibility: The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive Enterococcus faecalis $ Streptococcus agalactiae Streptococcus bovis Streptococcus pyogenes * Staphylococcus aureus (penicillin-sensitive strains only) Anaerobes Peptostreptococci Others Borrelia Species for which acquired resistance may be a problem Aerobic Gram-positive Corynebacterium spp Enterococcus faecium $ Streptococcus pneumoniae * + Streptococcus viridans Aerobic Gram-negative Escherichia coli + Haemophilus influenzae * Haemophilus para-influenzae * Moraxella catarrhalis + Proteus mirabilis Anaerobes Prevotella Fusobacterium spp Inherently resistant organisms Aerobic Gram-negative Acinetobacter spp Citrobacter spp Enterobacter spp Klebsiella spp Legionella Morganella morganii Proteus vulgaris Providencia spp Pseudomonas spp Serratia spp Anaerobes Bacteroides fragilis Others Chlamydia Mycoplasma Rickettsia * Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + pathogens resistance prevalence is > 50% $ Naturally intermediate species 5.2 Pharmacokinetic properties Absorption: 11

12 After oral administration, amoxicillin is rapidly and almost completely (85-90%) absorbed. The absorption of amoxicillin is unaffected by taking with food. Maximum plasma concentrations are reached after 1-2 hours. Bioavailability (as assessed by pharmacokinetic parameters AUC and / or recovery in urine) is linearly proportional to the dose of amoxicillin between 250 mg and 750 mg. Distribution: Protein binding for amoxicillin is approximately 17%. Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. Amoxicillin can penetrate inflamed meninges and enter the cerebrospinal fluid. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk. Biotransformation: About 7-25% of the administered dose is metabolised to inactive penicilloic acid. Elimination: Excretion is primarily via the kidneys, mostly (approx. 80%) by tubular secretion, the rest (20%) by glomerular filtration. The plasma half-life of amoxicillin is 1 to 1.5 hours with normal renal function, in premature infants, newborns and infants up to 6 months 3-4 hours. In impaired renal function (creatinine clearance 15 ml / min. or below) the half-life increase, to 8.5 hours in anuria. Hepatic impairment does not affect the half-life. In preterm infants with gestational age weeks, the total body clearance after intravenous dosing of amoxicillin, day 3 of life, ranged between ml/min, very similar to the inulin clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Consequently, due to the decreased CL, the exposure is expected to be elevated in this group of patients, although this increase in exposure may in part be diminished by decreased bioavailability when given orally. 5.3 Preclinical safety data There are no non clinical data of relevance to the prescriber which are additional to that already included in other sections of this SPC. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients The powder contains: Di-sodium Edetate Sodium Benzoate (E211) Sodium Saccharin (E954) Colloidal Silicon Dioxide (E551) Xanthan Gum (E415) Orange Flavour Raspberry Flavour Golden Caramel Sorbitol (E420) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 24 months (once reconstituted: 14 days) 6.4 Special precautions for storage Store powder in a dry place. Once dispensed, Amoxicillin Suspension should be used within 14 days. If dilution of the reconstituted product is required, water should be used. 6.5 Nature and contents of container 150 ml HDPE bottle containing 100ml of product. 150 ml HDPE bottle containing powder for suspension and a dosing syringe of 5 ml. 12

13 Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. Add sufficient quantity of water (approx ml) to reconstitute the product. Close the cap securely. Shake the bottle vigorously to dissolve the content. The product appears pale yellow to yellow colored suspension with fruity aromatic odor after reconstitution. 7 MARKETING AUTHORISATION HOLDER Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex TW4 5DQ UK 8 MARKETING AUTHORISATION NUMBER(S) PL 25298/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13/01/ DATE OF REVISION OF THE TEXT 13/01/

14 1 NAME OF THE MEDICINAL PRODUCT Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Amoxicillin suspension contains 250 mg amoxicillin per 5 ml dose. The amoxicillin is present as the trihydrate. Contains 590 mg /5 ml sorbitol (E420) For excipients see PHARMACEUTICAL FORM Powder for oral suspension White to pale yellow free flowing powder for oral suspension. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Amoxicillin Suspension is indicated for the treatment of the following infections caused by susceptible bacteria in adults and children above the age of 6 months (see sections 4.2, 4.4 and 5.1): Acute otitis media Acute exacerbations of chronic bronchitis Community acquired pneumonia Cystitis Endocarditis: Prophylaxis of endocarditis associated with procedures such as dental extraction, where indicated in patients at risk of developing bacterial endocarditis. Consideration should be given to official guidelines on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Treatment of Infection: Adult dosage (including elderly patients): Oral: Standard adult dosage: 250 mg-500 mg three times daily, increasing to 1 g three times daily for more severe infections. High dosage therapy (maximum recommended oral dosage 6 g daily in divided doses): A dosage of 3 g twice daily is recommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract. Short course therapy: Simple acute urinary tract infection: two 3 g doses with hours between the doses. Dosage in impaired renal function: The dose should be reduced in patients with severe renal function impairment. In patients with a creatinine clearance of less than 30 ml/min a reduction in the total daily dose by an increase in the dosage interval and/or a reduction in subsequent doses is recommended (see section 4.4 and 5.2). The following adjustments are recommended: Glomerular filtration rate > 30 ml/min: No adjustment necessary. Glomerular filtration rate ml/min: Amoxicillin. max. 500 mg b.d Glomerular filtration rate < 10 ml/min: Amoxicillin. max. 500 mg/day In case of hemodialysis: 500 mg should be administered at the end of the procedure. Dosage in impaired hepatic function 14

15 Dose with caution and monitor hepatic function at regular intervals Prophylaxis for endocarditis 3g amoxicillin given as a single dose one hour preceding the surgical procedure. National guidelines should be followed. Children weighing < 40 kg: The daily dosage for children is mg/kg/day in two to three divided doses* (not exceeding 3 g/day) depending on the indication, severity of the disease and the susceptibility of the pathogen (see special dosage recommendations below and sections 4.4, 5.1 and 5.2). *PK/PD data indicate that dosing three times daily is associated with enhanced efficacy, thus twice daily dosing is only recommended when the dose is in the upper range. Children weighing more than 40 kg should be given the usual adult dosage. Special dosage recommendation Indication Acute otitis media Prophylaxis for endocarditis Dose regimen and duration of treatment In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, dosage regimens should be guided by national/local recommendations. 50 mg amoxicillin/kg body weight given as a single dose, one hour preceding the surgical procedure. Renal impairment in children under 40 kg: Creatinine clearance ml/min Dose Interval between administration > 30 Usual dose No adjustment necessary Half of usual dose < 10 Half of usual dose 12 h 24 h In case of haemodialysis: one usual dose should be administered at the end of the procedure. Administration: Oral Treatment should be continued for 2 to 3 days following the disappearance of symptoms. It is recommended that atleast 10 days treatment be given for any infection caused by beta-haemolytic streptococci in order to achieve eradication of the organism. Parenteral therapy is indicated if the oral route is considered impracticable or unsuitable, and particularly for the urgent treatment of severe infection. For instructions on reconstitution of the medicinal product before administration see section Contraindications Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). 4.4 Special warnings and precautions for use Before treatment with amoxicillin is started, thorough enquiries should be made concerning earlier hypersensitivity reactions to penicillins and cephalosporins (see sections 4.3 and 4.8). 15

16 The possibility of cross-sensitivity (10-15%) with cephalosporins should be taken into account. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and alternative therapy instituted. Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8). Amoxicillin should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. Treatment of urinary tract infections may be a problem due to a very high resistance rate of Escherichia coli reported for amoxicillin in some European countries (see section 5.1). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters a regular check of patency should be maintained (see Section 4.9). It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods. Dosage should be adjusted in patients with renal impairment (see 4.2). The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires amoxicillin discontinuation and contra-indicates any subsequent administration of amoxicillin. Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8). This medicine contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine. This medicine also contains sodium benzoate (E211), which may increase the risk of jaundice in newborn babies. 4.5 Interaction with other medicinal products and other forms of interaction In common with other broad spectrum antibiotics, amoxicillin may reduce the efficacy of oral contraceptives and patients should be warned accordingly. 16

17 Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods. There have been cases of increased international normalised ratio in patients treated with acenocoumarol or warfarin when receiving concurrent treatment with amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Adjustments in the dose of oral anticoagulants may be necessary. 4.6 Fertility, pregnancy and lactation Pregnancy: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Amoxicillin passes the placenta and foetal plasma concentrations are approximately 25-30% of the maternal plasma concentrations. Data on a limited number of exposed pregnancies indicate no adverse effects of amoxicillin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Caution should be exercised when prescribing to pregnant women. Lactation: Amoxicillin diffuses into the breast milk (approx. 10% of the corresponding serum concentration) and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should also be considered. A decision must be made as to whether to discontinue breast-feeding, or to discontinue/abstain from Amoxicillin suspension therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility: No fertility data are available. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000,<1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000). The majority of side effects listed below are not unique to amoxicillin and may occur when using other pencillins. Unless otherwise stated, the frequency of adverse events has been derived from more than 30 years of post-marketing reports. Infections and infestations Very Rare: Blood and lymphatic system disorders Very rare: Mucocutaneous Candidiasis Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin (see 17

18 Immune system disorders Very rare: Nervous system disorders Very rare: Gastrointestinal disorders Clinical Trial Data *Common: *Uncommon: Post-marketing Data Very rare: Hepato-biliary disorders Very rare: Skin and subcutaneous tissue disorders Clinical Trial Data *Common: *Uncommon: Post-marketing Data Very rare: Section 4.4) Severe allergic reactions, including angioneurotic oedema, anaphylaxis (see Section 4.4), serum sickness and hypersensitivity vasculitis. Hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses. Diarrhoea and nausea. Vomiting. Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis). Black hairy tongue Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. The significance of a rise in AST and/or ALT is unclear. Skin rash Urticaria and pruritus Skin reactions such as erythema multiforme, Stevens- Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (See also Immune system disorders). Renal and urinary tract disorders Very rare: Interstitial nephritis. Very rare: Crystalluria (see Section 4.9). *The incidence of these AE's was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin. 4.9 Overdose Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to the water/electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4). Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4) Amoxicillin may be removed from the circulation by haemodialysis. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties General properties Pharmacotherapeutic Group: Penicillins with extended spectrum, ATC classification: J01CA04 Mode of action 18

19 Amoxicillin is bactericidal against susceptible organisms during the stage of active multiplication. It acts through the inhibition of one or more enzymes (often referred to as penicillin-binding proteins, PBP s) in the biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell wall. PK/PD relationship Amoxicillin demonstrates a time-dependent pattern of bactericidal activity (%T > MIC is considered to be the major determinant of efficacy). Mechanisms of resistance Bacteria may be resistant to amoxicillin owing to: production of beta-lactamases that hydrolyse aminopenicillins alterations in penicillin-binding proteins impermeability of the bacteria to the drug drug efflux pumps. Complete cross-resistance occurs with ampicillin and amoxicillin Breakpoints (EUCAST) Organism Susceptibility Breakpoints (μg/ml) Susceptible Intermediate Resistant Haemophilus influenzae Moraxella catharrhalis 1 - > > 1 Enterococcus 4 8 > 8 Streptococcus A, B, > 0.25 C, G 1 Streptococcus > 2 pneumoniae 2 Enterobacteriaceae > 8 Gram-negative > 2 anaerobes Gram-positive 4 8 > 8 Anaerobes Non-species related breakpoints > 8 1 Breakpoint values in the table are based on Benzylpenicillin breakpoints. 2 Breakpoint values in the table are based on ampicillin breakpoints. 3 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. Susceptibility: The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive Enterococcus faecalis $ Streptococcus agalactiae Streptococcus bovis Streptococcus pyogenes * 19

20 Commonly susceptible species Staphylococcus aureus (penicillin-sensitive strains only) Anaerobes Peptostreptococci Others Borrelia Species for which acquired resistance may be a problem Aerobic Gram-positive Corynebacterium spp Enterococcus faecium $ Streptococcus pneumoniae * + Streptococcus viridans Aerobic Gram-negative Escherichia coli + Haemophilus influenzae * Haemophilus para-influenzae * Moraxella catarrhalis + Proteus mirabilis Anaerobes Prevotella Fusobacterium spp Inherently resistant organisms Aerobic Gram-negative Acinetobacter spp Citrobacter spp Enterobacter spp Klebsiella spp Legionella Morganella morganii Proteus vulgaris Providencia spp Pseudomonas spp Serratia spp Anaerobes Bacteroides fragilis Others Chlamydia Mycoplasma Rickettsia * Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + pathogens resistance prevalence is > 50% $ Naturally intermediate species 5.2 Pharmacokinetic properties Absorption: After oral administration, amoxicillin is rapidly and almost completely (85-90%) absorbed. The absorption of amoxicillin is unaffected by taking with food. Maximum plasma concentrations are reached after 1-2 hours. Bioavailability (as assessed by pharmacokinetic parameters AUC and / or recovery in urine) is linearly proportional to the dose of amoxicillin between 250 mg and 750 mg. Distribution: Protein binding for amoxicillin is approximately 17%. Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. Amoxicillin can penetrate inflamed meninges and enter the cerebrospinal fluid. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk. Biotransformation: About 7-25% of the administered dose is metabolised to inactive penicilloic acid. 20

21 Elimination: Excretion is primarily via the kidneys, mostly (approx. 80%) by tubular secretion, the rest (20%) by glomerular filtration. The plasma half-life of amoxicillin is 1 to 1.5 hours with normal renal function, in premature infants, newborns and infants up to 6 months 3-4 hours. In impaired renal function (creatinine clearance 15 ml / min. or below) the half-life increase, to 8.5 hours in anuria. Hepatic impairment does not affect the half-life. In preterm infants with gestational age weeks, the total body clearance after intravenous dosing of amoxicillin, day 3 of life, ranged between ml/min, very similar to the inulin clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Consequently, due to the decreased CL, the exposure is expected to be elevated in this group of patients, although this increase in exposure may in part be diminished by decreased bioavailability when given orally. 5.3 Preclinical safety data There are no non clinical data of relevance to the prescriber which are additional to that already included in other sections of this SPC. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients The powder contains: Di-sodium Edetate Sodium Benzoate (E211) Sodium Saccharin (E954) Colloidal Silicon Dioxide (E551) Xanthan Gum (E415) Orange Flavour Raspberry Flavour Golden Caramel Sorbitol (E420) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 24 months (once reconstituted: 14 days) 6.4 Special precautions for storage Store powder in a dry place. Once dispensed, Amoxicillin Suspension should be used within 14 days. If dilution of the reconstituted product is required, water should be used. 6.5 Nature and contents of container 150 ml HDPE bottle containing 100ml of product. 150 ml HDPE bottle containing powder for suspension and a dosing syringe of 5 ml. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. Add sufficient quantity of water (approx ml) to reconstitute the product. Close the cap securely. Shake the bottle vigorously to dissolve the content. The product appears pale yellow to yellow colored suspension with fruity aromatic odor after reconstitution. 7 MARKETING AUTHORISATION HOLDER Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex 21

22 TW4 5DQ UK 8 MARKETING AUTHORISATION NUMBER(S) PL 25298/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13/01/ DATE OF REVISION OF THE TEXT 13/01/

23 Module 3 23

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25 Carton: Module 4 Labelling 25

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29 Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the applications for Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for Oral Suspension (PL 25298/0003-4; ) could be approved. These applications were submitted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and the Netherlands as Concerned Member State (CMS). The products are prescription-only medicines (POM) indicated for the treatment of the following infections caused by susceptible bacteria in adults and children above the age of 6 months: acute otitis media acute exacerbations of chronic bronchitis community acquired pneumonia cystitis Endocarditis: Prophylaxis of endocarditis associated with procedures such as dental extraction, where indicated in patients at risk of developing bacterial endocarditis. These applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, cross referring to the reference products Amoxil Syrup Sucrose Free/Dye Free 125 mg/5 ml and Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK) which have been authorised in the UK since 14 May Amoxicillin is an aminopenicillin and belongs to a group of medicines called Beta-lactam antibiotics. It is bactericidal against susceptible organisms during the stage of active multiplication. It acts through the inhibition of one or more enzymes (often referred to as penicillin-binding proteins or PBPs) in the biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell wall. No new non-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. One bioequivalence study (single dose) was submitted to support these applications, comparing the test product Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension (Brown & Burk Ltd) with the reference product Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK). With the exception of the bioequivalence study, no new clinical studies were conducted, which is acceptable given that the applications were for products that are being considered as generic medicinal products of an originator product 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 Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture, assembly and batch release of this products. 29

30 The RMS and CMS considered that the applications could be approved with the end of procedure (Day 208) on 14 December After a subsequent national phase, the licences were granted in the UK on 13 January

31 II. ABOUT THE PRODUCT Name of the product in the Reference Member State Amoxicillin 125 mg/ 5 ml Powder for Oral Suspension Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension Name(s) of the active substance(s) (INN) Amoxicillin Pharmacotherapeutic classification (ATC code) Penicillins with extended spectrum (ATC code:j01ca04) Pharmaceutical form and strength(s) Powder for oral suspension, 125 mg/ 5 ml and 250 mg/ 5 ml. Reference numbers for the Decentralised procedure Reference Member State (RMS) United Kingdom Concerned Member State (CMS) The Netherlands. Marketing Authorisation Number(s) PL 25298/003-4 Name and address of the authorisation holder Brown & Burk UK Ltd, 5, Marryat Close, Hounslow West, Middlesex, TW4 5DQ, UK. 31

32 III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN: Amoxicillin trihydrate Chemical name: (2S,5R,6R)-6-[[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]- amino]- 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid trihydrate Structure: Molecular formula: C 16 H 19 N 3 O 5 S * 3H 2 0 Molecular mass: Appearance: Amoxicillin trihydrate is a white or almost white, crystalline powder. It is slightly soluble in water, very slightly soluble in ethanol, practically insoluble in fatty oils and dissolves in dilute acids and dilute solutions of alkali hydroxides. Amoxicillin trihydrate is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance amoxicillin trihydrate are covered by a European Directorate for the Quality of Medicines (EDQM) certificate of suitability. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients di-sodium edentate, sodium benzoate (E211), sodium saccharin (E954), colloidal silicon dioxide (E551), xanthan gum (E415), orange flavour, raspberry flavour, golden caramel and sorbitol (E420). All excipients used comply with their respective European Pharmacopoeia monograph with the exception of orange flavour, raspberry flavour and golden caramel which are controlled to suitable in-house specifications. Satisfactory Certificates of Analysis have been provided for all excipients. None of the excipients are of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the programme was to develop two strengths of powder formulation for oral suspension containing 125 mg/5ml and 250 mg/5ml amoxicillin as the active substance. Suitable pharmaceutical development data have been provided for these applications. Comparative in-vitro dissolution and impurity profiles have been provided for the proposed and originator products 32

33 Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at pilot scale and has shown satisfactory results. In addition the marketing authorisation holder has committed to conduct process validation on commercial scale batches prior to release of the product on the market. Finished Product Specification The finished product specifications proposed are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Container-Closure System All strengths of the finished product are packaged in: 150 ml high-density polyethylene (HDPE) bottles containing 100ml of product 150 ml high-density polyethylene (HDPE) bottles containing powder for suspension and a dosing syringe of 5 ml. It has been stated that not all pack sizes may be marketed, however, the marketing authorisation holder has committed to submitting the mock-ups for any pack size to the relevant regulatory authorities for approval before marketing. 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 the finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 24 months for the unopened product which reduces to 14 days upon reconstitution with the storage conditions Store powder in a dry place. Once dispensed, Amoxicillin Suspension should be used within 14 days. If dilution of the reconstituted product is required, water should be used. Bioequivalence/bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence studies. Summary of Product Characteristics (SmPCs), Patient Information Leaflets (PIL), Labels The SmPCs, PIL and labels are acceptable. 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, as amended. The leaflet conforms to the requirements. The test shows that the patients/users are able to act upon the information that the leaflet contains. MAA forms The MAA forms are satisfactory. 33

34 Expert report The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion There are no objections to the approval of these products from a pharmaceutical viewpoint. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of amoxicillin are well-known, no new non-clinical studies are required and none have been provided. The applicant s non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the products pharmacology and toxicology. A suitable justification has been provided for non-submission of an environmental risk assessment. As these products are intended for generic substitution with other products already on the market they are not considered to increase the environmental risk. Thus, the applicant s justification is accepted. There are no objections to the approval of these products from a non-clinical viewpoint. III.3 CLINICAL ASPECTS Pharmacokinetics In support of these applications, the marketing authorisation holder has submitted the following bioequivalence study: An open label, randomised, single-dose, two-treatment, two-sequence, two-period, crossover study to compare the pharmacokinetics of the test product Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension (Brown & Burk UK Ltd) versus the reference product Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK) in healthy adult volunteers under fasted conditions. All volunteers received a single oral dose of 250mg (5 ml) of either the test or reference product administered with 240 ml of water under fasting conditions. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 12 hours post dose. The washout period between treatment periods was at least 7 days. The pharmacokinetic results for amoxicillin are presented below (log-transformed values; mean, ratios and 90% confidence intervals): Treatment AUC 0-t ng/ml/h AUC 0- ng/ml/h C max ng/ml Test Reference *Ratio (90% CI) ( %) ( %) AUC 0- area under the plasma concentration-time curve from time zero to infinity AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration *ln-transformed values The 90% confidence intervals for AUC and C max for test versus reference product for amoxicillin are within predefined acceptance criteria specified in the Guideline on the ( %) 34

35 Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/, Corr). Thus, the data support the claim that the test product is bioequivalent to the reference product. As the 125 mg/5ml and 250 mg/5ml strengths of the product meet the criteria specified in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and conclusions of the bioequivalence study on the 250 mg/5ml strength can be extrapolated to the 125 mg/5ml strength. Pharmacodynamics No new pharmacodynamic data were submitted and none were required for these applications. Efficacy No new efficacy data were submitted and none were required for these applications. Safety With the exception of the data generated during the bioequivalence study, no new safety data were submitted and none were required for these applications. No new or unexpected safety issues were highlighted by the bioequivalence data. Summary of Product Characteristics (SmPCs), Patient Information Leaflet (PIL), Labels The SmPCs, PIL and labels are acceptable. The SmPCs are consistent with that for the originator products where appropriate. The PIL is consistent with the SmPCs and in-line with current guidelines. The labelling is in-line with current guidelines. Clinical Expert Report The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Pharmacovigilance System and Risk Management Plan The pharmacovigilance system, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for not submitting a risk management plan for these applications. Conclusion There are no objections to the approval of these applications from a clinical viewpoint. 35

36 IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for Oral Suspension 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. NON-CLINICAL No new non-clinical data were submitted and none were required for applications of this type. EFFICACY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant s Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension and its respective reference product (Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml, GlaxoSmithKline, UK). As the 125 mg/5ml and 250 mg/5ml strength of the product meets the biowaiver criteria specified in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and conclusions of the bioequivalence study on the 250 mg/5ml strength can be extrapolated to the 125 mg/5ml strength. SAFETY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. As the safety profile of amoxicillin is well-known, no additional data were required. No new or unexpected safety concerns arose from the safety data from the bioequivalence study. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory and consistent with those for the reference product, where appropriate. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant s products and the originator products are interchangeable. Extensive clinical experience with amoxicillin is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive. 36

37 Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome 37