SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Trimethoprim Tablets BP 100 mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 100 mg of trimethoprim BP.

For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, round, flat bevelled edged tablets, engraved on one side with the company logo and with a breakline and A307 on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Trimethoprim is an antibacterial agent active in-vitro against a wide range of Gram-negative and Gram-positive organisms. It is administered orally for the following purposes.

Urinary Tract:

In the treatment of acute and chronic urinary tract infections and for prophylactic treatment of patients with a tendency to recurrent urinary infections.

Respiratory Tract:

In the treatment of acute and chronic bronchitis, bronchopneumonia and lobar pneumonia.

Trimethoprim is particularly useful for patients sensitive to sulphonamides.

4.2    Posology and method of administration

Route of administration: oral Acute infections:

Treatment should continue for a period of between three days (e.g. uncomplicated bacterial cystitis in women) and two weeks according to the nature and severity of infection. The first dose can be doubled.

Adults and children over 12 years:

For acute urinary tract and respiratory tract infections: 200mg every 12 hours. Children 6 - 12 years: 100mg every 12 hours.

Elderly: Dosage is dependent upon kidney function; see special dosage schedule.

Children under 6 years of age: Not recommended; a more suitable dosage form should be used in this age group.

Long-term treatment and prophylactic therapy:

Adults and children over 12 years: 100mg at night.

Children 6 - 12 years: 50mg at night. Where a single daily dose is required, dosage at bedtime may maximise urinary concentrations. The approximate dosage in children is 2mg trimethoprim per kg body weight per day.

Elderly: Dosage is dependent upon kidney function; see special dosage schedule

Advised dosage Schedule where there is reduced kidney function:

Creatinine Clearance	Plasma creatinine (micromol/l)	Dosage advised
Over 0.45	Men <250 Women <175	Normal
0.25 - 0.45	Men 250-600 Women 175-400	Normal for 3 days then half dose
Under 0.25	Men >600 Women >400	Half the normal dose

Trimethoprim is removed by dialysis. However, it should not be administered to dialysis patients unless plasma concentrations can be estimated regularly.

4.3 Contraindications

1.    Hypersensitivity to trimethoprim or to any of the excipients.

2.    Severe renal insufficiency where blood levels cannot be monitored regularly.

3.    Pregnant women and nursing mothers.

4.    Premature infants and neonates during the first two months of life.

5.    Blood dyscrasias.

4.4 Special warnings and precautions for use

Caution should be exercised in patients with impaired renal function (refer to Section 4.2. Posology and Method of Administration).

This product is classified as unsafe for use in porphyria.

Long term therapy requires regular haematological examination.

Special care should be taken in patients with a predisposition to folate deficiency and in elderly patients and administration of folate supplement should be considered.

Although an effect on folate metabolism is possible, interference with haematopoiesis rarely occurs at the recommended dose. If any such change is seen, folinic acid should reverse the effect. Elderly people may be more susceptible and a lower dose may be advisable.

In patients with renal impairment, care should be taken to avoid accumulation. Specialist supervision is required if used in neonates.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Antimalarials: There is an increased risk of antifolate effect when taken with pyrimethamine (in Fansidar^® and Maloprim^®).

Cytotoxics: The antifolate effect of methotrexate is increased when trimethoprim is used concurrently - avoid concurrent use. There is an increased risk of haematological toxicity with azathioprine and mercaptopurine.

Anti-arrhythmics: Procainamide plasma concentration may be increased, if taken concomitantly.

Antibacterials: Concomitant use of trimethoprim and dapsone may increase plasma concentrations of both drugs.

Anticoagulants: Trimethoprim should be used with caution in patients receiving warfarin and acenocoumarol as potentiation of the effects of these agents may occur.

Antiepileptics: Plasma concentration and antifolate effect of phenytoin is increased when taken concurrently.

Antivirals: Lamivudine and possibly zalcitabine plasma concentration may be increased if taken concurrently.

Cardiac glycosides: Plasma concentration of digoxin may be increased when taken concurrently with trimethoprim.

Bone marrow depressants - trimethoprim may increase the potential for bone marrow aplasia.

Rifampicin may increase the elimination and shorten the elimination half-life of trimethoprim.

Ciclosporin may increase the nephrotoxicity of trimethoprim.

4.6 Fertility, pregnancy and lactation

Use during pregnancy and lactation is contra-indicated. Trimethoprim should not be given to pregnant women, premature infants or infants during the first few weeks of life. Trimethoprim is a folate antagonist and there is therefore a risk of teratogenicity if used during the first trimester.

Trimethoprim crosses the placental barrier and is excreted in the breast milk. Short-term use in breast feeding is not known to be harmful.

4.7 Effects on ability to drive and use machines

None reported.

4.8 Undesirable effects

The most frequent adverse effects at usual doses are pruritus and skin rash (in about 3 to 7% of patients) and mild, gastro-intestinal adverse effects including nausea, vomiting and glossitis. These effects are generally mild and quickly reversible on withdrawal of the drug.

Blood and lymphatic system disorders

Leucopenia, megaloblastic anaemia, thrombocytopenia, agranulocytosis, hyperkalaemia (particularly in the elderly and in HIV patients), methaemoglobinaemia.

Prolonged administration may depress haematopoiesis due to an effect on folic acid metabolism. This effect may be reversed by the administration of calcium folinate.

Patients on long-term treatment and their carers should be taught to recognise the following symptoms which may be indicative of a blood disorder:

Fever, sore throat, rash, mouth ulcers, purpura or unexpected bruising or bleeding.

Medical attention should be sought in the event of such symptoms.

Immune system disorders

Other allergic effects including anaphylactic reactions, anaphylactoid reactions have been reported rarely.

Nervous system disorders Aseptic meningitis.

Gastrointestinal disorders

Nausea, vomiting, glossitis, gastrointestinal disturbances, sore mouth. Hepatobiliary disorders

Disturbances in liver enzyme values, cholestatic jaundice.

Skin and subcutaneous tissue disorders

Skin rash, exfoliative dermatitis, pruritus and urticaria have been reported occasionally. More severe skin sensitivity or allergic reactions such as photosensitivity, angioedema, erythema multiforme, Stevens Johnson syndrome and epidermal necrolysis have been reported rarely.

Musculoskeletal and connective tissue disorders Isolated cases of myalgia have occurred.

Renal and urinary disorders

Raised serum creatinine and blood urea nitrogen levels. It is not known however, whether this represents inhibition of creatinine tubular secretion or genuine renal dysfunction.

General disorders and administration site conditions Drug fever, headache.

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 of overdosage are vomiting and diarrhoea. Treatment is symptomatic and gastric lavage and forced diuresis may be employed.

Calcium folinate may be used to counteract any effect of trimethoprim on the bone marrow.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for Systemic Use; Sulfonamides and Trimethoprim; Trimethoprim and Derivatives - trimethoprim

ATC Code: J01E A01

Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds and reversibly inhibits the bacterial enzyme dihydrofolate reductase thus selectively blocking the conversion of dihydrofolic acid to its functional form, the tetrahydrofolic acid. This entails depletion of folate, an essential co-factor in the biosynthesis of nucleic acids hence interference with bacterial nucleic acid and protein production.

Dihydrofolate reductase of bacterial origin is 50 - 60 thousand times more tightly bound by trimethoprim than the corresponding mammalian enzyme.

5.2 Pharmacokinetic properties

Trimethoprim is almost completely absorbed from the gut. Following a dose of 100mg a peak plasma level of 0.9 - 1.2pg/ml is reached after 1/ - 3/ hours. About 45% is protein bound. The plasma half-life of trimethoprim is 6 -12 hours. A single 200mg dose will yield levels approximately twice as high. Trimethoprim is widely distributed throughout the body and is concentrated in a number of tissues and organs (like stomach, colon, gall bladder, haemorrhoid tissue, thyroid tissue, varicose veins, lungs, right auricle, uterus, salpinx and ovary) as a result of its lipophilic properties. Excretion of trimethoprim occurs chiefly through glomerular filtration and renal tubular secretion and thus high concentrations, usually of 50 - 100pg/ml of the active drug are found in the urine. 50 - 60% of the ingested dose is excreted by the kidneys within 24 hours, 80% of which is in the unmetabolised form.

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 the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Maize starch

Pregelatinised maize starch Magnesium stearate Sodium starch glycollate

6.2    Incompatibilities

None.

6.3    Shelf life

Opaque plastic containers:    60 months, as packaged for sale

Blister packs:    36 months, as packaged for sale

6.4    Special precautions for storage

Protect from heat, light and moisture.

Keep out of the reach of children.

6.5    Nature and contents of container

The product may be packed in the following containers:

a)    Opaque plastic containers composed of polypropylene tubes and polyethylene made tamper-evident closures in pack sizes of 9, 10, 14, 15,

20,    21, 28, 30, 50, 56, 84, 100, 250, 500 and 1000 tablets.

b)    Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene with a packing inclusion of standard polyether foam or polyethylene or polypropylene made filler in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500 and 1000 tablets.

c)    Blister packs of aluminium/opaque PVC in pack sizes of 9, 10, 14, 15, 20,

21,    28, 30, 56 and 84 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special instructions for use/handling.