public assessment report decentralised procedure - … · lactation: because...

Public Assessment Report

Decentralised Procedure

PHENOXYMETHYLPENICILLIN 125MG / 5ML POWDER FOR ORAL SOLUTION

PHENOXYMETHYLPENICILLIN 250MG / 5ML

POWDER FOR ORAL SOLUTION

UK/H/3831/001-2/DC UK Licence No: PL 25298/0042-3

BROWN & BURK UK LIMITED

PAR Phenoxymethylpenicillin 125mg / 5ml Powder for Oral Solution Phenoxymethylpenicillin 250mg / 5ml Powder for Oral Solution

UK/H/3831/001-2/DC

2

LAY SUMMARY

On 13th January 2012, the UK granted Brown & Burk UK Limited Marketing Authorisations (licences) for the medicines Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution. Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution contain the active ingredient phenoxymethylpenicillin potassium. Phenoxymethylpenicillin belongs to a group of antibiotics called ‘penicillins’, which work by killing the bacteria that cause infections. Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution are antibiotics (antibacterial medicines) for treating infections. Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution are used to treat a range of bacterial infections of the ear, throat, lungs, skin and soft tissues. They may also be used to prevent infections such as rheumatic fever and prevention of infection in patients without a spleen or sickle cell disease. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution outweigh the risks; hence these Marketing Authorisations have been granted.


UK/H/3831/001-2/DC

3

TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Patient Information Leaflets Page 17 Module 4: Labelling Page 19 Module 5: Scientific Discussion Page 22 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Not applicable


UK/H/3831/001-2/DC

4

Module 1

Product Name

Phenoxymethylpenicillin 125mg / 5ml Powder for Oral Solution Phenoxymethylpenicillin 250mg / 5ml Powder for Oral Solution

Type of Application

Generic, Article 10(1)

Active Substance

Phenoxymethylpenicillin potassium

Pharmaceutical Form and Strength

125mg / 5ml and 250mg / 5ml Powder for Oral Solution

MA Holder

Brown & Burk UK Limited

Reference Member State (RMS)

United Kingdom (UK)

Concerned Mmeber States (CMS)

Ireland (IE)

Procedure Number

UK/H/3831/001/DC UK/H/3831/002/DC

End of Procedure

Day 180: 16th December 2011


UK/H/3831/001-2/DC

5

Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Phenoxymethylpenicillin 125mg / 5ml Powder for Oral Solution 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 138.6mg of Phenoxymethylpenicillin potassium equivalent to phenoxymethylpenicillin 125mg. Also contains 955.5mg/5ml of Sorbitol (E420). For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral solution Phenoxymethylpenicillin 125mg is a white to off-white fine powder, which when reconstituted as directed, yields a colourless to pale yellow solution.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Phenoxymethylpenicillin is indicated for the treatment of the following infections (See Section 5.1) Streptococcal infections: Pharyngitis Scarlet fever Skin and soft tissue infections (e.g. erysipelas) Pneumococcal infections: Pneumonia Otitis media Vincent's gingivitis and pharyngitis Phenoxymethylpenicillin is also indicated for (see Section 5.1): Prophylaxis of rheumatic fever and/or chorea Prophylaxis of pneumococcal infection (e.g. in asplenia and in patients with sickle cell disease) Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

For oral administration Phenoxymethylpenicillin Solution should be taken at least 30 minutes before or 2 hours after food, as ingestion of phenoxymethylpenicillin with meals slightly reduces the absorption of the drug. Phenoxymethylpenicillin 250 mg is approximately equivalent to 400,000 units. The usual dosage recommendations are as follows: Adults: 250-500 mg every six hours. Children 1-5 years: 125 mg every six hours 6-12 years: 250 mg every six hours Prophylactic Use Prophylaxis of rheumatic fever/ chorea: 250 mg twice daily on a continuing basis Prophylaxis of pneumococcal infection (e.g. in asplenia and in sickle cell disease): Adults and children over 12 years: 500mg every 12 hours. Children 6-12 years: 250mg every 12 hours. Children below 5 years: 125mg every 12 hours. Elderly The dosage is as for adults. The dosage should be reduced if renal function is markedly impaired. Renal impairment


UK/H/3831/001-2/DC

6

The dosage should be reduced if renal function is markedly impaired. Hepatic impairment Dosage adjustment may be necessary in patients with impaired liver function when they also have renal failure. In this situation the liver may be a major excretion route For instructions on dilution of the product before administration, see section 6.6.

4.3 Contraindications

A history of a previous hypersensitivity reaction to any penicillin is a contraindication. 4.4 Special warnings and precautions for use

Phenoxymethylpenicillin should be given with caution to patients with a history of allergy, especially to other drugs. Phenoxymethylpenicillin should also be given cautiously to cephalosporin-sensitive patients, as there is some evidence of partial cross-allergenicity between the cephalosporins and penicillins. Patients have had severe reactions (including anaphylaxis) to both drugs. If the patient experiences an allergic reaction phenoxymethylpenicillin should be discontinued and treatment with the appropriate agents initiated. Particular caution should be exercised in prescribing phenoxymethylpenicillin to patients with an allergic diathesis or with bronchial asthma Oral Penicillins are not indicated in patients with a gastrointestinal disease that causes persistent diarrhoea or vomiting, because absorption may be reduced. In patients undergoing long-term phenoxymethylpenicillin treatment the complete and differential blood count, as well as the liver and kidney function, should be monitored. During long-term treatment attention should also be paid to the potential overgrowth of resistant organisms including Pseudomonas or Candida. Sustained severe diarrhoea should prompt suspicion of pseudomembranous colitis. As this condition may be life-threatening phenoxymethylpenicillin should be withdrawn immediately and treatment guided by bacteriologic studies. It should be noted that each 125mg dose contains about 1/3mmol of potassium, which may be harmful to people on low potassium diets and may cause stomach upset, diarrhoea and hyperkalaemia. High doses should be used with caution in patients receiving potassium-containing drugs or potassium sparing-diuretics. In renal impairment the safe dosage may be lower than usually recommended. Phenoxymethylpenicillin Oral Solution contains Sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

As penicillins like phenoxymethylpenicillin are only active against proliferating micro-organisms, phenoxymethylpenicillin should not be combined with bacteriostatic antibiotics. Concomitant use of uricosuric drugs (e.g. probenecid) reduces the excretion of phenoxymethylpenicillin resulting in increased plasma levels. Combined use of phenoxymethylpenicillin and oral anticoagulants (e.g. warfarin) may prolong prothrombin time. Phenoxymethylpenicillin may reduce the excretion of methotrexate causing an increased risk of toxicity. Like other antibiotics, phenoxymethylpenicillin may reduce the effectiveness of oral contraceptives. During treatment with phenoxymethylpenicillin non-enzymatic urinary glucose tests may be false-positive.


UK/H/3831/001-2/DC

7

Neomycin reduces the absorption of phenoxymethylpenicillin. Guar gum may slow the speed of absorption of Phenoxymethylpenicillin. Concurrent use of phenoxymethylpenicillin with potassium sparing diuretics(e.g Amiloride and Spironolactone) may cause hyperkalaemia, which can be life-threatening.

4.6 Fertility, pregnancy and lactation

Fertility Fertility data for phenoxymethylpenicillin are not available. Pregnancy: Safe use of phenoxymethylpenicillin during pregnancy has not been definitely established. There are no adequate or controlled studies using phenoxymethylpenicillin in pregnant women and the drug should be used during pregnancy only when clearly needed. Lactation: Because phenoxymethylpenicillin is distributed into milk, the drug should be used with caution in nursing women.

4.7 Effects on ability to drive and use machines

None stated 4.8 Undesirable effects

Although reactions have been reported much less frequently after oral than after parenteral penicillin therapy, it should be remembered that all degrees of hypersensitivity, including fatal anaphylaxis, have been observed with oral penicillin.

Very common (>1/10) Common (>1/100 to <1/10) Uncommon (>1/1,000 to <1/100) Rare (>1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data)

Infections & infestations Not known Candida, Vulvo-vaginitis

Blood and lymphatic system disorders Not known Eosinophilia, Haemolytic anaemia Leukopenia, Thrombocytopenia, Agranulocytosis

Immune system disorders Not known Erythema multiforme, Anaphylactic shock (which could be fatal with collapse)

Vascular disorders Not known Anaphylactoid shock

Gastrointestinal disorders Not known Nausea, Vomiting, Diarrhoea, Stomatitis, Glossitis

Skin and subcutaneous tissue disorders Not known Urticaria, Angioneurotic oedema, Exfoliative dermatitis

Musculoskeletal and connective tissue disorders

Not known Joint pains

General disorders and administration site conditions

Not known Fever


UK/H/3831/001-2/DC

8

4.9 Overdose

Overdosage may lead to gastrointestinal symptoms e.g. nausea, vomiting, epigastric pain, diarrhoea and in rare cases motor seizures. Serum potassium may need to be monitored in patients with compromised renal function and/or dehydration. General supportive measures are normally all that are required for treatment of overdosage of penicillins. There is no known antidote. Symtomatic and supportive therapy is recommended. Phenoxymethylpenicillin may be removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

General properties ATC classification Pharmacotherapeutic Group: Beta lactamase sensitive penicillins ATC Code: J01C E02. Mode of action Phenoxymethylpenicillin exerts a bactericidal action against penicillin-susceptible bacteria by inhibition of biosynthesis of cell wall mucopeptides. PK/PD relationship Efficacy correlates with the time that plasma levels exceed the MIC of the pathogen under treatment. Resistance Resistance to phenoxymethylpenicillin is usually mediated by one or both of: Bacterial production of β-lactamases: This family of enzymes can inactivate Phenoxymethylpenicillin by hydrolyzing the β-lactam ring The occurrence of modified penicillin-binding proteins resulting in impaired binding of phenoxymethylpenicillin. EUCAST recommendations for susceptibility testing: Staphylococcus spp: Isolates positive for β- lactamase are resistant to phenoxymethylpenicillin. Isolates negative for β- lactamase and susceptible to methicillin can be reported susceptible to phenoxymethylpenicillin. Isolates resistant to methicillin are resistant to phenoxymethylpenicillin. Streptococcus groups A, B, C and G: The β-lactam susceptibility of β-haemolytic Streptococcus groups A, B, C and G is inferred from the penicillin susceptibility. Streptococcus pneumoniae: Isolates fully susceptible to benzylpenicillin (MIC≤ 0.064 mg/ml, susceptible by Oxacillin disk screen, Screen for β- lactam resistance with the Oxacillin 1µg disk – isolates categorized as susceptible can be reported as susceptible to phenoxymethylpenicillin irrespective of the clinical condition. Isolates categorized as Oxacillin resistant can be reported to phenoxymethylpenicillin in meningitis) can be reported susceptible to phenoxymethylpenicillin, otherwise reported as phenoxymethylpenicillin resistant without further testing. The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent is at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive micro-organisms Streptococcus A,B,C,G Species for which acquired resistance may be a problem Staphylococcus aureus Streptococcus pneumoniae


UK/H/3831/001-2/DC

9

5.2 Pharmacokinetic properties Absorption Following administration by mouth absorption is usually quick, complete and rapid from the gastrointestinal tract. Peak serum concentrations of 3-6 ~g per ml have been seen following dosage of 250 mg to 500 mg by mouth. The effect of food on absorption is slight and variable. Impaired absorption is seen in patients with coeliac disease. Distribution Eighty per cent is reported to be protein bound. Phenoxymethylpenicillin is widely distributed round the body tissues and fluids and more readily penetrates inflamed tissues. It also diffuses across the placenta into foetal circulation and small amounts appear in the milk of nursing mothers. Biotransformation Some metabolism occurs in the liver and several metabolites have been found, including penicilloic acid. Elimination Excretion is by tubular secretion into urine. Small excretion occurs in bile. The plasma half-life of phenoxymethylpenicillin is about 30 minutes which may increase to four hours in renal failure.

5.3 Preclinical safety data

There are no pre-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

Sorbitol (E420) Powdarome Strawberry Premium (Nature identical flavouring and natural flavouring, maize maltodextrin, INS1520 propylene glycol) Sodium Saccharin

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

24 months.

6.4 Special precautions for storage Store powder in a dry place below 25ºC After reconstitution, phenoxymethylpenicillin oral solution must be stored between 2°C to 8°C and used within 7 days.

6.5 Nature and contents of container

150ml HDPE bottle with a 28mm screw cap which has a red-coloured ring. Each bottle contains 100ml of reconstituted solution.

6.6 Special precautions for disposal

No special requirements. Add 86.0ml of water to the powder and shake vigorously. This will make 100ml of solution. The solution should be used within 7 days of reconstitution. Shake well before use.

7 MARKETING AUTHORISATION HOLDER

Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex TW4 5DQ UK.


UK/H/3831/001-2/DC

10

8 MARKETING AUTHORISATION NUMBER(S) PL 25298/0042

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13/01/2012 10 DATE OF REVISION OF THE TEXT

13/01/2012


UK/H/3831/001-2/DC

11

1 NAME OF THE MEDICINAL PRODUCT Phenoxymethylpenicillin 250mg / 5ml Powder for Oral Solution.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 277.2mg of Phenoxymethylpenicillin potassium equivalent to phenoxymethylpenicillin 250mg Also contains 814.15mg/5ml of Sorbitol (E420). For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral solution Phenoxymethylpenicillin 250mg is a white to off-white fine powder, which when reconstituted as directed, yields a colourless to pale yellow solution.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Phenoxymethylpenicillin is indicated for the treatment of the following infections (See Section 5.1) Streptococcal infections: Pharyngitis Scarlet fever Skin and soft tissue infections (e.g. erysipelas) Pneumococcal infections: Pneumonia Otitis media Vincent's gingivitis and pharyngitis Phenoxymethylpenicillin is also indicated for (see Section 5.1): Prophylaxis of rheumatic fever and/or chorea Prophylaxis of pneumococcal infection (e.g. in asplenia and in patients with sickle cell disease) Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

For oral administration Phenoxymethylpenicillin Solution should be taken at least 30 minutes before or 2 hours after food, as ingestion of phenoxymethylpenicillin with meals slightly reduces the absorption of the drug. Phenoxymethylpenicillin 250 mg is approximately equivalent to 400,000 units. The usual dosage recommendations are as follows: Adults: 250-500 mg every six hours. Children 1-5 years: 125 mg every six hours 6-12 years: 250 mg every six hours Prophylactic Use Prophylaxis of rheumatic fever/ chorea: 250 mg twice daily on a continuing basis Prophylaxis of pneumococcal infection (e.g. in asplenia and in sickle cell disease): Adults and children over 12 years: 500mg every 12 hours. Children 6-12 years: 250mg every 12 hours. Children below 5 years: 125mg every 12 hours. Elderly The dosage is as for adults. The dosage should be reduced if renal function is markedly impaired. Renal impairment The dosage should be reduced if renal function is markedly impaired.


UK/H/3831/001-2/DC

12

Hepatic impairment Dosage adjustment may be necessary in patients with impaired liver function when they also have renal failure. In this situation the liver may be a major excretion route For instructions on dilution of the product before administration, see section 6.6.

4.3 Contraindications

A history of a previous hypersensitivity reaction to any penicillin is a contraindication. 4.4 Special warnings and precautions for use

Phenoxymethylpenicillin should be given with caution to patients with a history of allergy, especially to other drugs. Phenoxymethylpenicillin should also be given cautiously to cephalosporin-sensitive patients, as there is some evidence of partial cross-allergenicity between the cephalosporins and penicillins. Patients have had severe reactions (including anaphylaxis) to both drugs. If the patient experiences an allergic reaction phenoxymethylpenicillin should be discontinued and treatment with the appropriate agents initiated. Particular caution should be exercised in prescribing phenoxymethylpenicillin to patients with an allergic diathesis or with bronchial asthma Oral Penicillins are not indicated in patients with a gastrointestinal disease that causes persistent diarrhoea or vomiting, because absorption may be reduced. In patients undergoing long-term phenoxymethylpenicillin treatment the complete and differential blood count, as well as the liver and kidney function, should be monitored. During long-term treatment attention should also be paid to the potential overgrowth of resistant organisms including Pseudomonas or Candida. Sustained severe diarrhoea should prompt suspicion of pseudomembranous colitis. As this condition may be life-threatening phenoxymethylpenicillin should be withdrawn immediately and treatment guided by bacteriologic studies. It should be noted that each 125mg dose contains about 1/3mmol of potassium, which may be harmful to people on low potassium diets and may cause stomach upset, diarrhoea and hyperkalaemia. High doses should be used with caution in patients receiving potassium-containing drugs or potassium sparing-diuretics. In renal impairment the safe dosage may be lower than usually recommended. Phenoxymethylpenicillin Oral Solution contains Sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

As penicillins like phenoxymethylpenicillin are only active against proliferating micro-organisms, phenoxymethylpenicillin should not be combined with bacteriostatic antibiotics. Concomitant use of uricosuric drugs (e.g. probenecid) reduces the excretion of phenoxymethylpenicillin resulting in increased plasma levels. Combined use of phenoxymethylpenicillin and oral anticoagulants (e.g. warfarin) may prolong prothrombin time. Phenoxymethylpenicillin may reduce the excretion of methotrexate causing an increased risk of toxicity. Like other antibiotics, phenoxymethylpenicillin may reduce the effectiveness of oral contraceptives. During treatment with phenoxymethylpenicillin non-enzymatic urinary glucose tests may be false-positive. Neomycin reduces the absorption of phenoxymethylpenicillin.


UK/H/3831/001-2/DC

13

Guar gum may slow the speed of absorption of Phenoxymethylpenicillin. Concurrent use of phenoxymethylpenicillin with potassium sparing diuretics(e.g Amiloride and Spironolactone) may cause hyperkalaemia, which can be life-threatening.

4.6 Fertility, pregnancy and lactation

Fertility Fertility data for phenoxymethylpenicillin are not available. Pregnancy: Safe use of phenoxymethylpenicillin during pregnancy has not been definitely established. There are no adequate or controlled studies using phenoxymethylpenicillin in pregnant women and the drug should be used during pregnancy only when clearly needed. Lactation: Because phenoxymethylpenicillin is distributed into milk, the drug should be used with caution in nursing women.

4.7 Effects on ability to drive and use machines

None stated 4.8 Undesirable effects

Although reactions have been reported much less frequently after oral than after parenteral penicillin therapy, it should be remembered that all degrees of hypersensitivity, including fatal anaphylaxis, have been observed with oral penicillin.

Very common (>1/10) Common (>1/100 to <1/10) Uncommon (>1/1,000 to <1/100) Rare (>1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data)

Infections & infestations Not known Candida, Vulvo-vaginitis

Blood and lymphatic system disorders Not known Eosinophilia, Haemolytic anaemia Leukopenia, Thrombocytopenia, Agranulocytosis

Immune system disorders Not known Erythema multiforme, Anaphylactic shock (which could be fatal with collapse)

Vascular disorders Not known Anaphylactoid shock

Gastrointestinal disorders Not known Nausea, Vomiting, Diarrhoea, Stomatitis, Glossitis

Skin and subcutaneous tissue disorders Not known Urticaria, Angioneurotic oedema, Exfoliative dermatitis

Musculoskeletal and connective tissue disorders

Not known Joint pains

General disorders and administration site conditions

Not known Fever


UK/H/3831/001-2/DC

14

4.9 Overdose

Overdosage may lead to gastrointestinal symptoms e.g. nausea, vomiting, epigastric pain, diarrhoea and in rare cases motor seizures. Serum potassium may need to be monitored in patients with compromised renal function and/or dehydration. General supportive measures are normally all that are required for treatment of overdosage of penicillins. There is no known antidote. Symtomatic and supportive therapy is recommended. Phenoxymethylpenicillin may be removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

General properties ATC classification Pharmacotherapeutic Group: Beta lactamase sensitive penicillins ATC Code: J01C E02. Mode of action Phenoxymethylpenicillin exerts a bactericidal action against penicillin-susceptible bacteria by inhibition of biosynthesis of cell wall mucopeptides. PK/PD relationship Efficacy correlates with the time that plasma levels exceed the MIC of the pathogen under treatment. Resistance Resistance to phenoxymethylpenicillin is usually mediated by one or both of: Bacterial production of β-lactamases: This family of enzymes can inactivate Phenoxymethylpenicillin by hydrolyzing the β-lactam ring The occurrence of modified penicillin-binding proteins resulting in impaired binding of phenoxymethylpenicillin. EUCAST recommendations for susceptibility testing: Staphylococcus spp: Isolates positive for β- lactamase are resistant to phenoxymethylpenicillin. Isolates negative for β- lactamase and susceptible to methicillin can be reported susceptible to phenoxymethylpenicillin. Isolates resistant to methicillin are resistant to phenoxymethylpenicillin. Streptococcus groups A, B, C and G: The β-lactam susceptibility of β-haemolytic Streptococcus groups A, B, C and G is inferred from the penicillin susceptibility. Streptococcus pneumoniae: Isolates fully susceptible to benzylpenicillin (MIC≤ 0.064 mg/ml, susceptible by Oxacillin disk screen, Screen for β- lactam resistance with the Oxacillin 1µg disk – isolates categorized as susceptible can be reported as susceptible to phenoxymethylpenicillin irrespective of the clinical condition. Isolates categorized as Oxacillin resistant can be reported to phenoxymethylpenicillin in meningitis) can be reported susceptible to phenoxymethylpenicillin, otherwise reported as phenoxymethylpenicillin resistant without further testing. The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent is at least some types of infections is questionable. Commonly susceptible species Aerobic Gram-positive micro-organisms Streptococcus A,B,C,G Species for which acquired resistance may be a problem Staphylococcus aureus Streptococcus pneumoniae


UK/H/3831/001-2/DC

15

5.2 Pharmacokinetic properties Absorption Following administration by mouth absorption is usually quick, complete and rapid from the gastrointestinal tract. Peak serum concentrations of 3-6 ~g per ml have been seen following dosage of 250 mg to 500 mg by mouth. The effect of food on absorption is slight and variable. Impaired absorption is seen in patients with coeliac disease. Distribution Eighty per cent is reported to be protein bound. Phenoxymethylpenicillin is widely distributed round the body tissues and fluids and more readily penetrates inflamed tissues. It also diffuses across the placenta into foetal circulation and small amounts appear in the milk of nursing mothers. Biotransformation Some metabolism occurs in the liver and several metabolites have been found, including penicilloic acid. Elimination Excretion is by tubular secretion into urine. Small excretion occurs in bile. The plasma half-life of phenoxymethylpenicillin is about 30 minutes which may increase to four hours in renal failure.

5.3 Preclinical safety data

There are no pre-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

Sorbitol (E420) Powdarome Strawberry Premium (Nature identical flavouring and natural flavouring, maize maltodextrin, INS1520 propylene glycol) Sodium Saccharin

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

24 months. The shelf life after reconstitution is 7 days.

6.4 Special precautions for storage

Store powder in a dry place below 25ºC After reconstitution, phenoxymethylpenicillin oral solution must be stored between 2°C to 8°C and used within 7 days.

6.5 Nature and contents of container

150ml HDPE bottle with a 28mm screw cap which has a red-coloured ring. Each bottle contains 100ml of reconstituted solution.

6.6 Special precautions for disposal

No special requirements. Add 86.0ml of water to the powder and shake vigorously. This will make 100ml of solution. The solution should be used within 7 days of reconstitution. Shake well before use.

7 MARKETING AUTHORISATION HOLDER

Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex TW4 5DQ UK.


UK/H/3831/001-2/DC

16

8 MARKETING AUTHORISATION NUMBER(S) PL 25298/0043

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 13/01/2012 10 DATE OF REVISION OF THE TEXT

13/01/2012


UK/H/3831/001-2/DC

17

Module 3 Patient Information Leaflet


UK/H/3831/001-2/DC

18


UK/H/3831/001-2/DC

19

Module 4

Labelling


UK/H/3831/001-2/DC

20


UK/H/3831/001-2/DC

21


UK/H/3831/001-2/DC

22

Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, Ireland and the UK considered that the applications for Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution could be approved. The products are prescription only medicines (POM) and are indicated for the following infections:

• Streptococcal infections: Pharyngitis Scarlet fever Skin and soft tissue infections (e.g. erysipelas)

• Pneumococcal infections:

Pneumonia Otitis media

• Vincent's gingivitis and pharyngitis

Phenoxymethylpenicillin is also indicated for:

• Prophylaxis of rheumatic fever and/or chorea • Prophylaxis of pneumococcal infection (e.g. in asplenia and in patients with

sickle cell disease) These applications for Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution are submitted as abridged applications according to Article 10(1) of Directive 2001/83/EC, claiming to be a generic medicinal products of Apsin VK Phenoxymethylpenicillin Oral Solution BP 125mg / 5ml and 250mg / 5ml, authorised in the UK to Teva UK Limited on 18th and 24th August 1988 respectively (PL 00289/5278-9R). No new non-clinical studies were conducted, which is acceptable given that the products contain a widely-used, well-known active substance. The pharmacology of phenoxymethylpenicillin potassium is well-established. No clinical studies have been performed and none are required for these applications as the proposed products are aqueous solutions at the time of administration and contain the same concentration of active substance as the already approved reference products. 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 or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.


UK/H/3831/001-2/DC

23

The RMS considers that 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 satisfactory justification has been provided for the absence of a Risk Management Plan.


UK/H/3831/001-2/DC

24

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

Phenoxymethylpenicillin 125mg / 5ml Powder for Oral Solution Phenoxymethylpenicillin 250mg / 5ml Powder for Oral Solution

Name(s) of the active substance(s) (INN) Phenoxymethylpenicillin potassium

Pharmacotherapeutic classification (ATC code)

Beta lactamase sensitive penicillins (J01C E02)

Pharmaceutical form and strength(s) 125mg / 5ml and 250mg / 5ml Powder for Oral Solution

Reference numbers for the Decentralised Procedure UK/H/3831/001/DC UK/H/3831/002/DC

Reference Member State (RMS) United Kingdom (UK)

Member States concerned (CMS) Ireland (IE)

Marketing Authorisation Number(s) PL 25298/0042 PL 25298/0043

Name and address of the authorisation holder Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex TW4 5DQ UK


UK/H/3831/001-2/DC

25

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN/Ph.Eur name: Phenoxymethylpenicillin potassium Chemical name: Potassium salt of (2S,5R,6R)-3,3-dimethyl-7-oxo-6-

[(phenoxyacetyl)amino]-4-thia-1-azobicyclo[3.2.0]heptane-2-carboxylic acid

Structural formula:

Molecular formula: C16H17KN2O5S Appearance: white or almost white crystalline powder. Solubility: Freely soluble in water, practically insoluble in ethanol (96%). Molecular weight: 388.5 Phenoxymethylpenicillin potassium complies with its European Pharmacopoeia monograph. All aspects of the manufacture of the active substance from its starting materials are controlled by a Certificate of Suitability. All potential known impurities have been identified and characterised. An appropriate specification with suitable test methods and limits is provided for the active substance. The methods of testing and limits for residual solvents are in compliance with current guidelines. Suitable Certificates of Analysis have been provided for all reference and impurity standards used. Batch analysis data are provided and comply with the proposed specification. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines. Stability studies have been performed with the active substance and no significant changes of the quality parameters were observed. On the basis of the results, the RMS agreed that a suitable re-test period could be approved.


UK/H/3831/001-2/DC

26

P. Medicinal Product Other Ingredients Other ingredients are the pharmaceutical excipients sorbitol (E420), Powdarome Strawberry Premium (nature identical flavouring and natural flavouring, maize maltodextrin and INS1520 propylene glycol) and sodium saccharin. With the exception of Powdarome Strawberry Premium, all of the excipients comply with their European Pharmacopoeia monographs. Powdarome Strawberry Premium complies with in-house specifications. None of the excipients used contain material of animal or human origin. Declarations that neither the excipients nor any material used in the production of the excipients pose a Transmissible Spongiform Encephalopathy (TSE) risk have been provided. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development programme was to produce safe, efficacious products containing phenoxymethylpenicillin potassium that could be considered generic medicinal products of Apsin VK Phenoxymethylpenicillin Oral Solution BP 125mg / 5ml and 250mg / 5ml. The applicant has provided suitable product development sections. Valid justifications for the use and amounts of each excipient have been provided. Comparative in vitro assay and impurity profiles have been provided for the proposed and reference products. This was satisfactory. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the products, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Process validation data on batches of both strengths have been provided and are satisfactory. The applicant has committed to perform process validation on future production-scale batches. Finished Product Specifications The finished product specifications proposed for the product is acceptable. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used. Container-Closure System These products are packaged in 150ml HDPE bottles with a 28mm screw cap which has a red-coloured ring. Each bottle contains 100ml of reconstituted solution. There is one bottle per pack. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the EU Directive regarding contact with food.


UK/H/3831/001-2/DC

27

Stability of the products Stability studies were performed on batches of the finished products in the packaging proposed for marketing and in accordance with current guidelines. These data support a shelf-life of 24 months with storage instructions ‘Store powder in a dry place below 25°C.’ The SmPCs also state that after reconstitution the solution must be stored between 2°C to 8°C and used within 7 days. This is satisfactory. Summary of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and Labelling The SmPCs, PIL and labelling are pharmaceutically acceptable. The UK approved SmPC texts, PIL and label mock-ups are included in modules 2, 3 and 4 of this report. User testing results have been submitted for the PIL for these products. The results indicate that the PIL 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. Quality Overall Summary The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusions It is recommended that Marketing Authorisations are granted for these applications from a quality point of view.


UK/H/3831/001-2/DC

28

III.2 NON-CLINICAL ASPECTS The pharmacodynamics, pharmacokinetics and toxicological properties of phenoxymethylpenicillin potassium are well-known. As this is a widely used, well-known active substance, the applicant has not provided any additional studies and none are required. An overview based on literature is thus, appropriate. Impurities The impurities identified in the drug substance and drug products have satisfactory proposed limits which all comply with current international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) guidelines. Non-clinical Overview The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. Environmental Risk Assessment A satisfactory justification has been provided for the absence of an Environmental Risk Assessment. Conclusions It is recommended that Marketing Authorisations are granted for these applications from a non-clinical point of view.


UK/H/3831/001-2/DC

29

III.3 CLINICAL ASPECTS This assessment report represents an evaluation of the key elements of the information provided by the company in the dossier. Clinical Pharmacology The applicant’s products are generic products of the reference products; both the test and reference product of both strengths contain the same quantitative and qualitative composition of the active ingredient. As per the Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98 Rev 1, ‘If the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution, bioequivalence studies may be waived.’ No new pharmacokinetic or pharmacodynamic data were submitted with these generic applications and none were required. The test and reference products are identical at the point of administration. Therefore, a human bioavailability study is not required for these applications. Efficacy No new efficacy data were submitted with these applications and none were required. Safety No new safety data were submitted with these applications and none were required. Summary of Product Characteristics (SmPCs), Patient Information Leaflet (PILs) and Labelling The SmPCs, PIL and labelling are clinically satisfactory and consistent with those for the reference products, where appropriate. Clinical Overview The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. MAA Forms The MAA forms are clinically satisfactory. Conclusions It is recommended that Marketing Authorisations are granted for these applications from a clinical point of view.


UK/H/3831/001-2/DC

30

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Phenoxymethylpenicillin 125mg / 5ml and 250mg / 5ml Powder for Oral Solution 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 are required for applications of this type. EFFICACY No bioequivalence studies have been performed and none are required for these applications, given the composition of the product and its intended route of administration. No new or unexpected safety concerns arise from these applications. The SmPCs, PIL and labelling are satisfactory and consistent with that for the reference products. RISK-BENEFIT ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with phenoxymethylpenicillin potassium is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


UK/H/3831/001-2/DC

31

Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

public assessment report decentralised procedure - … · lactation: because...

Documents