Trimethoprim 200mg Tablets

1. Name of the medicinal product

Trimethoprim 200mg Tablets.

 

2. Qualitative and quantitative composition

Trimethoprim 200.00mg

For a full list of all excipients, see section 6.1.

 

3. Pharmaceutical form

Tablet;

White flat beveled edged tablets, engraved with “MT200”.

 

4. Clinical particulars

4.1 Therapeutic indications

Treatment of susceptible infections caused by Trimethoprim sensitive organisms including most gram-positive and gram-negative aerobic organisms, including Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumonia, Staphylococcus aureus, Eschersichia coli, Enterobacter, Proteus and Streptococcus faecalis.

Exceptions include anaerobic bacteria. Mycobacterium tuberculosis, Neisseria gonorrhoeae, pseudomonas aeruginosa and Treponema pallidum.

Prophylaxis of recurrent urinary tract infections.

Route of administration: Oral

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

 

4.2 Posology and method of administration

Posology

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: 200mg twice daily.

• Children 6-12 years: 100mg twice daily.

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

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

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:

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.

Route of administration

For oral administration.

 

4.3 Contraindications

Hypersensitivity to trimethoprim or any of the excipients.

Pregnancy.

Blood dyscrasias.

Severe hepatic insufficiency.

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

 

4.4 Special warnings and precautions for use

Administer with care to patients with impaired renal function. Regular haematological examination 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 in those with actual or potential folate deficiency (e.g. the elderly) to check for possible pancytopaenia 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. 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). 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).

Acute porphyria

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

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

Antimalarials:

Special care is necessary patients receiving pyrimethamine therapy in addition to trimethoprim. Increased antifolate effect when trimethoprim is given with pyrimethamine.

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

Cytotoxic agents such as azathioprine, mercaptopurine and methotrexate increase the risk of haematologic toxicity when given with trimethoprim.

Antibacterials:

Rifampicin may increase the elimination and shorten the elimination half-life of trimethoprim. Plasma concentration of both drugs may increase when trimethoprim is given with dapsone.

Diuretics: In elderly patients taking diuretics, particularly thiazides, there is an increased incidence of thrombocytopaenia 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 e undertaken as appropriate (see section 4.4).

Phenytoin and digoxin - the patient should be carefully controlled as trimethoprim may increase the elimination half-life of phenytoin and digoxin.

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.

Ciclosporin may increase the nephrotoxicity of trimethoprim.

Trimethoprim may potentiate the anticoagulant effects of warfarin and other coumarins.

 

4.6 Fertility, pregnancy and lactation

Pregnancy

Trimethoprim should not be administered to pregnant women, premature infants or infants during the first few weeks of life.

Breast-feeding

Although trimethoprim is excreted in breast milk, it is not necessarily contraindicated for short-term therapy during lactation.

 

4.7 Effects on ability to drive and use machines

None known.

 

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, gastrointestinal disturbances including nausea, vomiting and glossitis. These effects are generally mild and quickly reversible on withdrawal of the drug.

The adverse affected are displayed by system organ class and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1,000), very rare (≥ 1/100,000 to <1/10,000), (and not known (cannot be estimated from the available data).

¹ 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.

²Close 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

³Aseptic 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.

⁴Cholestatic jaundice and hepatic necrosis may be fatal.

⁵Lyell's syndrome (toxic epidermal necrolysis) carries a high mortality.

⁶It is not known however, whether this represents inhibition of creatinine tubular secretion or genuine renal dysfunction.

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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

 

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

Mechanism of action:

Trimethoprim is a dihydrofolate reductase inhibitor which affects the nucleoprotein metabolism of micro-organisms by interference in the folic-folinic acid systems, 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 microorganisms than on the mammalian cells. Trimethoprim may be bactericidal or bacteriostatic depending on growth conditions.

Trimethoprim is effective in vitro against a wide range of Gram-positive and aerobic Gram-negative organisms, including enterobacteria Escherica coli, Proteus, Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus faecalis, Haemophilus influenzae and Staphylococcus aureus.

It is not effective against Anaerobes, Pseudomonas aeruginosa, Treponema pallidum, Mycobacteria, Nocardia species, Neisseria species and Brucella abortus.

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:

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

 

5.2 Pharmacokinetic properties

Trimethoprim is rapidly and almost completely absorbed from the gastrointestinal tract and peak concentrations in the circulation occur about 1-4 hours after an oral dose. Peak plasma concentrations of about 1µg/ml have been reported after a single dose of 100mg. Approximately 40-70% 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. The half life is approximately 8-10 hours. About 40-60% of a dose is excreted unchanged in the urine within 24 hours, together with metabolites; hence, patients with impairment of renal function such as the elderly may require a reduction in dosage due to accumulation. Urinary concentrations are generally well above the MIC of common pathogens for more than 24 hours after the last dose. It appears in breast milk.

 

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber additional to that included in other sections of SmPC.

 

6. Pharmaceutical particulars

6.1 List of excipients

• Lactose monohydrate

• Povidone K-25

• Crospovidone

• Sodium starch glycolate (Type A)

• Magnesium stearate

 

6.2 Incompatibilities

None known

 

6.3 Shelf life

36 months

 

6.4 Special precautions for storage

Do not store above 25°C. Store in the original container.

 

6.5 Nature and contents of container

High density polystyrene with polythene lids and/or polypropylene containers with polythene lids and polyurethane or polythene inserts.

Blister pack - 25 micron PVC glass-clear/bluish rigid PVC (pharmaceutical grade) 20 micron hard tempered aluminium foil coated on the pull side with 6-7 gsm heat seal lacquer and printed on the bright side.

Pack sizes: 50, 100, 500, 1000, 5000 (Bulk pack), 6, 14 & 28 (blister pack)

 

6.6 Special precautions for disposal and other handling

No special instruction

 

7. Marketing authorisation holder

Accord Healthcare Limited

Sage house, 319 Pinner Road

North Harrow, Middlesex , HA1 4HF

United Kingdom

 

8. Marketing authorisation number

PL 20075/0291

 

9. Date of first authorisation/renewal of the authorisation

02/03/09

 

10. Date of revision of the text

25/07/2020