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Trimethoprim 200mg Tablets

Document: spc-doc_PL 06453-0044 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Trimethoprim 200mg Tablets

2. Qualitative and Quantitative Composition

Each tablet contains Trimethoprim BP 200 mg

3. PHARMACEUTICAL FORM

Uncoated tablet

Flat white tablet, with bevelled edges and embossed with ‘TR200’ on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of susceptible infections caused by trimethoprim sensitive organisms including urinary and respiratory tract infections.

Prophylaxis of recurrent urinary tract infections.

4.2 Posology and method of administration

Acute infections:

Treatment should continue for a period of between 3 days (eg, uncomplicated bacterial cystitis in women) to 2 weeks depending on the nature and severity of the infection. The first dose may be doubled.

Adults and children over 12 years: 200mg twice daily Children 6 - 12 years: 100mg twice daily

Children under 6 years: This dosage form is not suitable for use in children younger than 6 years.

Elderly: Dosage is dependent on renal function. See special dosage schedule below.

Advised dosage schedule where there is reduced kidney function:

Creatinine Clearance (ml/sec)

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.

Long-term treatment and prevention 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: Dose depends on renal function. Refer to special dosage schedule above.

Route of administration For oral administration.

4.3 Contraindications

Severe hepatic insufficiency. Severe renal insufficiency. , unless plasma levels can be monitored regularly.Megaloblastic anaemia and other blooddyscrasias. Trimethoprim should not be administered to premature infants or children under 4 months of age. Trimethoprim should not be administered to pregnant women.

Hypersensitivity to trimethoprim or any other constituents of the medication.

4.4 Special warnings and precautions for use

Patients with marked impairment of renal function:

Trimethoprim may cause depression of haemopoiesis. Regular haematological tests should be undertaken in patients receiving long term treatment and those predisposed to folate deficiency, (eg 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.

Close monitoring of serum electrolytes is advised in patients at risk for hyperkalaemia (see section 4.8).

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

Acute porphyria.

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 risk for bone marrow aplasia. Cytotoxic agents such as azathioprine, mercaptopurine and 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 taking diuretics, particularly thiazides, there is an increased incidence of thrombocytopaenia with purpura.

Hyperkalaemia may be exacerbated by concomitant administration of diuretics, particularly potassium sparing diuretics and/or thiazide diuretics and eplerenone.

Cyclosporin: Increased risk of nephrotoxicity.

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 Pregnancy and lactation

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

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

None that are known.

4.8 Undesirable effects

The following list of undesirable effects have been reported by health care 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

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 erythematosus.

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare: Hypoglycaemia, hyponatraemia, anorexia

Close supervision is recommended when Trimoptin 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 behavior, 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 Trimoptin 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

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.

Lyell’s syndrome (toxic epidermal necrolysis) carries a high mortality. Unknown: Pruritis

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

4.9    Overdose

Treat symptomatically, gastric lavage and forced diuresis can be used. Depression of haematopoiesis by trimethoprim can be counteracted by intramuscular injections of calcium folinate.

5    PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Systemic antibacterial.

ATC Code: J01EA01 Mode 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 (R) pathogens are:

EUCAST Species-related breakpoints (Susceptible</Resistant>) Units: mg/L

Enterobacteriaceae

Staphylococcus

Enterococcus

<2/>4

<2/>4

*

<0.032/>1

*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. It is bound to plasma proteins. Tissue concentrations are reported to be higher than serum concentrations with particularly high concentrations occurring in the kidneys and lungs but concentrations in the cerebrospinal fluid are about one half of those in the blood. About 40 to 50% of a dose is excreted in the urine within 24 hours mainly as unchanged drug. Urinary concentrations are generally well above the MIC of common pathogens for more than 24 hours after the last dose.

5.3. Preclinical Safety Data

Not relevant

6. PHARMACEUTICAL PROPERTIES

6.1.


List of excipients

Lactose monohydrate Povidone K30 Crospovidone

Sodium starch glycolate (Type A) Magnesium stearate Purified water

6.2.    Incompatibilities

None reported

6.3.    Shelf Life

36 months

6.4.    Special Precautions for Storage

Store below 25oC in a dry place. Protect from light.

6.5.    Nature and contents of container

Polypropylene securitainer of 14/15/18/20/21/28/30/100/500 100 or 500 tablets with appropriate bellows or polyurethane foam wads.

Also available in a PVC blister with aluminium lidding foil containing 6, 14 and 28 tablets.

6.6.    Instruction for Use/Handling

No special instructions

Administrative Data

7.    Marketing Authorisation Holder

ATHLONE LABORATORIES LIMITED, BALLYMURRAY,

CO. ROSCOMMON,

IRELAND.

8.    Marketing Authorisation Number

PL 6453/0044

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/09/2005

10    DATE OF REVISION OF THE TEXT

01/10/13