PHENOXYMETHYLPENICILLIN 125 MG / 5ML GRANULES FOR ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Phenoxymethyl­penicillin 125mg/5ml Granules for Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Phenoxymethyl­penicillin Potassium

138.59 mg equivalent to 125mg phenoxymethyl­penicillin per 5ml of reconstituted product

Excipients: Each 5 ml contains 2.61g of sucrose, 1.2mg of ponceau 4R (E124)

For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Granules for oral solution

Light pink powder with an odour of strawberry

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Phenoxymethyl­penicillin and potassium phenoxymethyl­penicillin are indicated in the treatment of mild to moderately severe infections associated with micro-organisms whose susceptibility to penicillin is within the range of serum levels attained with these dosage forms. The following infections will usually respond to adequate doses:

Streptococcal infections (without bacteraemia): Mild to moderate infections of the upper respiratory tract, scarlet fever and mild erysipelas.

Pneumococcal infections: Mild to moderately severe infections of the respiratory tract.

Staphylococcal infections sensitive to penicillin: Mild infections of the skin and soft tissues.

Fusospirochaetosis (Vincent’s gin­givitis and pharyngitis): Mild to moderately severe infections of the oropharynx usually respond to therapy with oral penicillin.

Prophylactic use: Prophylaxis with oral penicillin has proved effective in preventing reccurrence of rheumatic fever and chorea.

Patients with a past history of rheumatic fever receiving continuous prophylaxis may harbour penicillin-resistant organisms. In these patients, the use of another prophylactic agent should be considered.

Note: severe empyema, bacteraemia, pericarditis, meningitis and arthritis should not be treated with Phenoxymethyl­penicillin during the acute phase.

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

4.2 Posology and method of administration

Adults: 125 – 500 mg every 4 – 6 hours depending on the severity of the condition.

Prophylactic use: 125 mg twice daily is recommended for long term prophylaxis of rheumatic fever.

Children: Up to 1 year: 62.5 mg 6 hourly

1 – 5 years: 125 mg 6 hourly

6 – 12 years:250 mg 6 hourly

The Elderly: As for adults. Reduce dosage if renal function is markedly impaired.

Each dose should be administered half an hour before or at least 3 hours after a meal.

In patients with beta-haemolytic streptococcal infection, it is usual to continue treatment at the full dosage for 10 days, in order to minimise the occurrence of secondary complications such as acute nephritis and rheumatic fever.

Route of administration : Oral use

For instructions on dilution of the product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity reaction to any penicillin or to any of the excipients and should be used with caution in patients with known histories of allergy.

4.4 Special warnings and precautions for use

Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma.

All degrees of hypersensitivity, including fatal anaphylaxis, have been observed with oral penicillin. These reactions are more likely to occur in         individuals

with a history of sensitivity to penicillins, cephalosporins and other      allergens.

Enquiry should be made for such a history before therapy with a penicillin is begun.

If an allergic reaction occurs, the drug should be discontinued and the patient treated with the usual agents (e.g. Adrenaline and other pressor amines, antihistamines and corticosteroids).

Oral therapy should not be relied upon in patients with severe illness, or with nausea, vomiting, gastric dilatation, achalasia or intestinal hypermotility.

Occasionally, patients do not absorb therapeutic amounts of orally administered penicillin.

Administer with caution in the presence of markedly impaired renal function, as safe dosage may be lower than that usually recommended.

Streptococcal infections should be treated for a minimum of 10 days, and posttherapy cultures should be performed to confirm the eradication of the organisms.

Prolonged use of antibiotics may promote the overgrowth of non-susceptible organisms, including fungi. If super-infection occurs, appropriate measures should be taken.

Sucrose: Each 5ml dose contains 2.61g sucrose; this should be taken into account in patients with diabetes. May be harmful to teeth. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Ponceau 4R (E124): May cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Aminoglycosides: Neomycin is reported to reduce the absorption of phenoxymethyl­penicillin.

Anticoagulants: Penicillins may interfere with anticoagulant control.

Bacteriostatic antibiotics: Certain bacteriostatic antibiotics such as chloramphenicol, erythromycin and tetracyclines have been reported to antagonise the bactericidal activity of penicillins and concomitant use is not recommended.

Methotrexate: Use of phenoxymethyl­penicillin while taking methotrexate can cause reduced excretion of methotrexate thereby increasing the risk of toxicity.

Sulfinpyrazone: Excretion of penicillins reduced by sulfinpyrazone.

Typhoid vaccine (oral): Penicillins may inactivate oral typhoid vaccine if ingested concomitantly.

Concomitant administration of guar gum with phenoxymethyl­penicillin reduces the absorption of the latter.

Concurrent use of phenoxymethyl­penicillin with probenecid reduces the excretion of phenoxymethyl­penicillin by competing with it for renal tubular secretion.

4.6 Fertility, pregnancy and lactation

Laboratory and clinical studies have shown no evidence of teratogenicity with the use of phenoxymethyl­penicillin potassium during pregnancy. However, as with other drugs, caution should be exercised when prescribing to pregnant patients.

Phenoxymethyl­penicillin is excreted in the milk and should be used with caution in nursing mothers as it may cause an allergic reaction in the offspring.

4.7 Effects on ability to drive and use machines

No or negligible effect.

4.8 Undesirable effects

The most common reactions to oral penicillin are gastrointestinal effects and hypersensitivity reactions. Although hypersensitivity reactions have been reported much less frequently after oral than after parenteral therapy, it should be remembered that all forms of hypersensitivity, including fatal anaphylaxis have been observed with oral penicillin.

Infections and infestations

Pseudomembranous colitis has rarely (>1/10,000 to <1/1,000) been reported.

Blood and lymphatic system disorders

There have been very rare (<1/10,000) reports of changes in blood counts, including thrombocytopenia, neutropenia, leucopenia, eosinophilia and haemolytic anaemia. Coagulation disorders (including prolongation of bleeding time and defective platelet function) have also been reported.

Immune system disorders

Allergic reactions may commonly occur (>1/100 to <1/10) and typically manifest as skin reactions (See Skin and subcutaneous tissue disorders). Severe allergic reactions causing angioedema, laryngeal oedema and anaphylaxis have been reported rarely (>1/10,000 to <1/1,000).

Serum sickness-like reactions are characterised by fever, chills, arthralgia and oedema.

Nervous system disorders

Central nervous system toxicity including convulsions has been reported (especially with high doses or in severe renal impairment); paraesthesia may occur with prolonged use.

Neuropathy is an infrequent reaction and is usually associated with high doses of parenteral penicillin.

Gastrointestinal disorders

Nausea, vomiting, abdominal pain, diarrhoea are common (>1/100 to <1/10). Sore mouth and black hairy tongue (discolouration of tongue) has been reported rarely (>1/10,000 to <1/1,000).

Hepatobiliary disorders

Hepatitis and cholestatic jaundice have been reported very rarely (<1/10,000).

Skin and subcutaneous tissue disorders

Urticarial, erythematous or morbilliform rash and pruritis occur commonly (>1/100 to <1/10), while exfoliative dermatitis occurs rarely (>1/10,000 to <1/1,000).

Renal and urinary disorders

Interstitial nephritis has occurred in very rare cases (<1/10,000).

Nephropathy is an infrequent reaction and is usually associated with high doses of parenteral penicillin.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms: A large oral overdose of penicillin may cause nausea, vomiting, stomach pain, diarrhoea and rarely, major motor seizures. If other symptoms are present, consider the possibility of an allergic reaction. Hyperkalaemia may result from overdosage, particularly for patients with renal insufficiency.

Management: No specific antidote is known. Symptomatic and supportive therapy is recommended. Activated charcoal with a cathartic, such as sorbitol, may hasten drug elimination. Penicillin may be removed by haemodialysis

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

J01CE02 Antibacterials for systemic use, Beta-lactamase sensitive penicillins

Phenoxymethyl­penicillin has a mainly bactericidal action against many gram-positive bacteria and some gram-negative cocci, and against some spirochaetes and actinomycetes.

Mechanism of action

It is considered to act through interference with the final stage of synthesis of the bacterial cell wall. The action depends upon phenoxymethyl­penicillin’s a­bility to reach and bind to certain membrane bound proteins, known as penicillin-binding proteins (PBP’s) that are located beneath the cell wall. These proteins are involved in maintaining cell wall structure in cell wall synthesis, and in cell division, and appear to possess transpeptidase and carboxypeptidase activity.

Bacterial surface enzymes called autolysins also appear to be involved in the lethal effect of penicillins particularly for gram-positive bacteria. In gram-negative bacilli, osmotic rupture of cells may occur once the cell wall is weakened.

Phenoxymethyl­penicillin can also produce morphological changes in vitro including the formation of long filaments or abnormally shaped cells. Bacteria that are not growing and dividing are generally not killed by phenoxymethyl­penicillin.

PK/PD relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for phenoxymethyl­penicillin.

Mechanism(s) of resistance:

Its action is inhibited by penicillinase and other beta-lactamases that are produced by certain micro-organisms. The incidence of beta-lactamase producing organisms is increasing.

Mechanisms of resistance

The two main mechanisms of resistance to phenoxymethyl­penicillin are:

Inactivation by bacterial penicillinases and other beta-lactamases

Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance.

EUCAST clinical MIC breakpoints to separate susceptible (S) pathogens from resistant ® pathogens (version 1.0 22.11.210) are:

The susceptibility of streptococci Groups A, C and G and S. pneumoniae to phenoxymethyl­penicillin is inferred from the susceptibility to benzylpenicillin.

Staphylococci: Most staphylococci are penicillinase-producers. Penicillinase­producing strains are resistant. The benzylpenicillin breakpoint (shown) will mostly, but not unequivocally, separate beta-lactamase producers from non-producers.

Streptococcus pneumoniae: For phenoxymethyl­penicillin, report S. pneumoniae with benzylpenicillin MICs above 0.06 mg/L resistant.

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

Commonly susceptible species

Streptococcus A, C, G

Species for which acquired resistance may be a problem

Staphylococcus aureus

Streptococcus pneumoniae

Staphylococcus epidermidis

5.2 Pharmacokinetic properties

Absorption: Rapidly but incompletely absorbed after oral administration (about 60% of an oral dose is absorbed). Calcium and potassium salts are better absorbed than the free acid. Absorption appears to be reduced in patients with coeliac disease.

Absorption appears to be more rapid in fasting than non-fasting subjects.

Blood concentration: After an oral dose of 125mg, peak serum concentrations of 200 to 700ng/ml are attained in 2 hours. After an oral dose of 500mg, peak serum concentrations reach 3 to 5 micrograms/ml in 30 to 60 minutes.

Half-life: Biological half-life is about 30 minutes, increased to about 4 hours in severe renal impairment.

Distribution: Widely distributed throughout the body and enters pleural and ascitic fluids and also in cerebrospinal fluid when the meninges are inflamed;

Phenoxymethyl­penicillin crosses the placenta and is secreted in the milk; (protein binding 50 to 80% bound plasma proteins).

Metabolic reactions: Hydroxylation may occur.

Excretion: 20% to 35% of an oral dose is excreted in the urine in 24 hours.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Strawberry Flavour

Ponceau 4R (E124)

Sucrose

Saccharin Sodium

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Before reconstitution: 36 months After reconstitution: 1 week

6.4 Special precautions for storage

In the form of dry granules: Do not store above 25°C. Keep the bottle tightly closed.

After reconstitution: Store in a refrigerator (2 – 8 °C). Keep the bottle tightly closed. Use within one week of reconstitution.

6.5 Nature and contents of container

HDPE bottles and PP/HDPE child resistant caps with EPE induction seal liner.

Pack size 100 ml.