TRIMETHOPRIM 50 MG / 5ML SUSPENSION - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Trimethoprim 50 mg/5 ml Suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml contains 50 mg of Trimethoprim Ph.Eur.

Excipients with known effect

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral suspension.

A white, opalescent, viscous suspension.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Trimethoprim is indicated for the prevention and treatment of urinary tract infections in adults and children, and the treatment of other susceptible infections in adults and children caused by a wide range of trimethoprim sensitive Gm +ve and Gm -ve organisms including Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, E.coli, Enterobacter, Proteus and Streptococcus faecalis.

4.2 Posology and method of administration

Method of administration

For oral administration

Posology

Adults & Children over 12 years of age

Treatment of urinary tract infections and all other susceptible infections: 200 mg (20 ml) twice daily.

Long-term prevention of recurrent urinary tract infections: 100 mg (10 ml) at night.

Children 6 weeks to 12 years of age

Treatment of urinary tract infections is based on a dosage of 8 mg/kg body weight daily, subdivided into two equal doses. Suggested regimens are:

6 weeks – 5 months          -      25 mg (2.5 ml) twice daily

6 months – 5 years           -      50 mg (5 ml) twice daily

6 years – 12 years            -      100 mg (10 ml) twice daily

Long-term prevention of recurrent urinary tract infection is based on 2 mg/kg body weight daily given as a single dose at night. Suggested regimens are:

6 months – 5 years    -      25 mg (2.5 ml) at night

6 years – 12 years     -      50 mg (5 ml) at night

Dosage advised where there is reduced kidney function:

Monitoring of renal function and serum electrolytes should be considered particularly with longer term use, in patients with impaired renal function.

Trimethoprim should only be initiated and used in dialysis patients under close supervision from specialists in both infectious disease and renal medicine. Trimethoprim is removed by dialysis.

Monitoring trimethoprim plasma concentration may be considered with long term therapy but the value of this in individual cases should first be discussed with specialists in infectious disease and renal medicine.

Elderly

Depending on kidney function, see special dosage schedule.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Trimethoprim is contra-indicated in severe hepatic insufficiency.

Trimethoprim is contra-indicated in megaloblastic anaemia and other blood dyscrasias.

Trimethoprim should not be administered to pregnant women, premature infants or children under 4 months.

4.4 Special warnings and precautions for use

Care is necessary in administration to patients with impaired renal function.

Regular haematological tests should be performed during long term therapy.

In patients with renal impairment, care should be taken to avoid accumulation. Monitoring of renal function and serum electrolytes should be considered particularly with longer term use.

Trimethoprim should only be initiated and used in dialysis patients under close supervision from specialists in both infectious disease and renal medicine.

Trimethoprim may cause depression of haemopoiesis. Regular haematological tests should be undertaken in patients receiving long term treatment and those predisposed to folate deficiency, (e.g. the elderly), to check for possible pancytopaenia. If there is evidence of folic acid deficiency, calcium folinate should be administered and response checked by haematologic monitoring. It may be necessary to discontinue trimethoprim. Particular care should be exercised in the haematological monitoring of children on long term therapy.

Isolated cases of megaloblastic anaemia during prolonged therapy with trimethoprim in doses higher than those recommended have been reported but these are reversible with discontinuation of therapy and administration of calcium folinate.

If a patient has a known or suspected risk of acute prophyria, treatment with trimethoprim should be avoided.

Close monitoring of serum electrolytes is advised in patients at risk for hyperkalaemia (see section 4.8). Elevations in serum potassium have been observed in some patients treated with trimethoprim. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, poorly controlled diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, renin angiotensin system inhibitors (eg: ACE inhibitors or renin angiotensin receptor blockers), or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above-mentioned agents is deemed appropriate, monitoring of serum potassium is recommended (see section 4.5).

Monitoring of blood glucose is advised if co-administered with repaglinide (see section 4.5).

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

Folate antagonists and anticonvulsants: Trimethoprim may induce folate deficiency in patients predisposed to folate deficiency such as those receiving concomitant folate antagonists or anticonvulsants.

Bone marrow depressants: Trimethoprim may increase the potential for bone marrow aplasia.

Cytotoxics such as azathioprine, mercaptopurine, methotrexate, increase the risk of haematologic toxicity when given with trimethoprim. Special care is necessary in patients receiving pyrimethamine in addition to trimethoprim.

Phenytoin and Digoxin: Careful monitoring of patients treated with digoxin or phenytoin is advised as trimethoprim may increase plasma concentration of these agents by increasing their elimination half-life.

Rifampicin may decrease trimethoprim concentrations.

Diuretics: In elderly patients concurrently taking diuretics, primarily thiazides, there is an increased incidence of thrombocytopenia with purpura.

Concomitant use of drugs that may increase serum potassium levels may lead to a significant increase in serum potassium. Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, renin-angiotensin system inhibitors (eg: ACE inhibitors or renin angiotensin receptor blockers) and other potassium increasing substances (eg: heparin). Monitoring of potassium should be undertaken as appropriate (see section 4.4).

Ciclosporin: Increased risk of nephrotoxicitiy.

Procainamide: Trimethoprim increases plasma concentrations of procainamide.

Dapsone: Plasma concentrations of trimethoprim and dapsone may increase when taken together.

Repaglinide: Trimethoprim may enhance the hypoglycaemic effects of repaglinide.

Anticoagulants: Trimethoprim may potentate the anticoagulant effect of warfarin and other coumarins.

Antibacterials: Plasma concentration of trimethoprim is possibly reduced by rifampicin. Plasma concentration of both drugs may increase when trimethoprim is given with dapsone. Antimalarials: Increased antifolate effect when trimethoprim is given with pyrimethamine.

4.6. Fertility, pregnancy and lactation

Pregnancy

Trimethoprim is contra-indicated in pregnant women, premature infants or infants during the first few weeks of life.

Breastfeeding

Trimethoprim is excreted in breast milk. Effects on the suckling child are likely if therapeutic doses are administered to breast-feeding mothers. Trimethoprim is contraindicated if the breast fed infant is less than 4 months of age.

4.7. Effects on ability to drive and use machines

Not known.

4.8. Undesirable effects

The following list of undesirable effects have been reported by healthcare professionals. Sometimes it may be difficult to distinguish reactions caused by the condition being treated from adverse drug reactions, which means that not all the listed reactions were caused by drug administration.

Infections and Infestations

Common: Monilial overgrowth

Blood and lymphatic system disorders

Very rare: Leucopenia, neutropenia, thrombocytopenia, pancytopaenia, bone marrow depression, agranulocytosis, aplastic anaemia, haemolytic anaemia, eosinophilia, purpura, haemolysis.

Unknown: Megaloblastic anaemia, methaemoglobi­naemia, depression of haematopoiesis. Fatalities have been reported (especially in the elderly, or those with impairment of renal or hepatic function in whom careful monitoring is advised- refer to Section 4.3 Contraindi­cations), however the majority of haematological changes are mild and reversible when treatment is stopped.

Immune system disorders

Very rare: Hypersensitivity, anaphylaxis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus arythematosus.

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare: Hypoglycaemia, hyponatraemia, anorexia.

Close supervision is recommended when trimethoprim is used in elderly patients or in patients taking high doses as these patients may be more susceptible to hyperkalaemia and hyponatraemia.

Psychiatric disorders

Very rare: Depression, hallucinations, confusional states, agitation, anxiety, abnormal behaviour, insomnia and nightmares.

Nervous system disorders

Common: Headache

Very rare: Dyskinesias, aseptic meningitis, tremor, ataxia, dizziness, lethargy, syncope, paraesthesiae, convulsions, peripheral neuritis, vertigo, tinnitus.

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Eye disorders

Very rare: uveitis.

Respiratory, thoracic and mediastinal disorders

Very rare: Cough, shortness of breath, wheeze, epistaxis.

Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting.

Very rare: Constipation, glossitis, stomatitis, pseudomembranous colitis, pancreatitis. Unknown: Sore mouth, gastro-intestinal disturbance

Hepatobiliary disorders

Very rare: Elevation of serum transaminases, elevation of bilirubin levels, cholestatic jaundice, hepatic necrosis. Cholestatic jaundice and hepatic necrosis may be fatal.

Skin and subcutaneous tissue disorders

Common: Skin rashes, urticaria

Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, erythema nodusum, Stevens-Johnson Syndrome, toxic epidermal necrolysis, bullous dermatitis, purpura.

Unknown: Pruritis

Lyell's syndrome (toxic epidermal necrolysis) carries a high mortality.

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia and uveitis.

Renal and urinary disorders

Very rare: Impaired renal function (sometimes reported as renal failure), haematuria.

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 or search for MHRA Yellow Card in Google Play or Apple App store.

4.9. Overdose

Treatment of overdosage: Symptomatic treatment, gastric lavage and forced diuresis can be used. Depression of haematopoiesis by trimethoprim can be counteracted by intramuscular administration of calcium folinate.

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Systemic antibacterial, ATC code: J01EA01

Mechanism of action

Trimethoprim is a dihydrofolate reductase inhibitor, inhibiting the conversion of bacterial dihydrofolic acid to tetrahydrofolic acid, required for the synthesis of some amino acids.

Its effects are considerably greater on the cells of micro-organisms than on the mammalian cells. Trimethoprim may be bactericidal or bacteriostatic depending on growth conditions.

In vitro trimethoprim has effects on most Gram-positive and Gram-negative aerobic organisms, including enterobacteria such as E Coli, Proteus, Klebsiella pneumoniae, Streptococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus.

It has no effect on Mycobacterium tuberculosis, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Treponema pallidum, Brucella abortis or anaerobic bacteria.

Mechanism(s) of resistance

Resistance to trimethoprim may be due to several mechanisms. Clinical resistance is often due to plasmid mediated dihydrofolate reductases that are resistant to trimethoprim: such genes may become incorporated into the chromosome via transposons. Resistance may also be due to overproduction of dihydrofolate reductase, changes in cell permeability, or bacterial mutants which are intrinsically resistant to trimethoprim because they depend on exogenous thymidine and thymine for growth. Emergence of resistance to trimethoprim does not appear to be any higher in areas where it is used alone than in areas where trimethoprim is used in combination with sulphonamides.

Nonetheless, trimethoprim resistance has been reported in many species, and very high frequencies of resistance have been seen in some developing countries, particularly among Enterobacteriaceae.

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

The activity of trimethoprim is uncertain against enterococci. Hence the wild type population is categorized as intermediate.

5.2. Pharmacokinetic properties

Trimethoprim is readily absorbed from the gastro-intestinal tract and peak concentrations in the circulation occur about 3 hours after a dose is taken. About 45% is bound to plasma proteins. Tissue concentrations are reported to be higher than serum concentrations with particularly high concentrations in the kidneys and lungs. Concentrations in the CSF are about half that of those in blood. The half life is about 10–16 hours. 40–50% of the dose is excreted unchanged in the urine within 24 hours.

5.3. Pre-clinical safety data

Pre-clinical information has not been included because the safety profile of trimethoprim has been established after many years of clinical use. Please refer to Section 4.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sorbitol

Agar

Methyl hydroxybenzoate

Propyl hydroxybenzoate

Polysorbate 80

Saccharin Sodium

Purified water

6.2. Incompatibilities

Not applicable.

6.3. Shelf life

36 months unopened.

6.4. Special precautions for storage

Store in the original container. Keep container in the outer carton.

6.5. Nature and contents of container

Amber glass bottles with aluminium pilfer proof screw cap and expanded polyethylene liner.

Pack size: 100 ml.

6.6. Instruction for use and handling

Not applicable.

7. MARKETING AUTHORISATION HOLDER

Pinewood Laboratories Limited

Ballymacarbry

Clonmel

Co. Tipperary

Ireland

8. MARKETING AUTHORISATION NUMBER

PL 04917/0065