This information is intended for use by health professionals

1. Name of the medicinal product

Trimogal® 200mg Tablets

Trimethoprim 200mg Tablets

2. Qualitative and quantitative composition

Each tablet contains trimethoprim 200mg.

Excipients with known effect

Lactose

Sodium

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet.

White, round, biconvex, tablets with an approximate diameter of 9.0 mm, embossed with 'T & 3' separated by a score line on one side and plain on other side.

The score line is not intended for breaking the tablet.

4. Clinical particulars
4.1 Therapeutic indications

Treatment of urinary tract infections and long term prophylaxis of recurrent urinary tract infections.

Respiratory tract infections, in particular acute and chronic bronchopneumonia and pneumonia caused by organisms sensitive to trimethoprim.

Trimogal® is particularly useful for patients known to be sensitive to sulphonamides.

4.2 Posology and method of administration

Posology

Acute infections:

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

Adults: 200mg twice daily.

Paediatric population:

Children over 12 years: Same as adult dose.

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:

eGFR (ml/min)

Dosage advised

Over 30

Normal

15 – 30

Normal for 3 days, then half dose

Under 15

Half the normal dose

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.

Long-term treatment and prevention therapy:

Adults: 100mg at night

Paediatric population:

Children over 12 years: Same as adult dose

Children 6 – 12 years: 50mg at night. Where a single 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.

Method of administration

For oral administration.

4.3 Contraindications

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

Severe hepatic insufficiency. 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

Patients with marked impairment of renal function: Care should be taken to avoid accumulation and resulting adverse haematological effect.

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 pancytopenia. 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 haematological 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 of hyperkalaemia (see section 4.8). Elevation in serum potassium have been observed in some patients treated with trimethoprim. Patients at risk of developing 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 (e.g. ACE inhibitors or 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).

Caution should be used in patients with acute porphyria.

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

This medicine contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially 'sodium-free'.

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.

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 (e.g. ACE inhibitors or angiotensin-receptor blockers) and other potassium increasing substances (e.g. heparin). Monitoring of potassium should be undertaken as appropriate (see section 4.4).

Ciclosporin: 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 potentiate 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 contraindicated in 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.

This should be kept in mind when considering administration to breast-feeding women.

4.7 Effects on ability to drive and use machines

There are no reported effects on the ability to drive or operate machines.

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.

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.

Adverse reactions are listed below according to the MedDRA system organ classification. Frequency categories are defined according to the following MedDRA frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

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.

Not known: Megaloblastic anaemia, methaemoglobinaemia, hyperkalaemia (particularly in the elderly and in HIV patients). Trimogal therapy may affect haematopoiesis.

Fatalities have been reported (especially in the elderly, or those with impairment of renal or hepatic function in whom careful monitoring is advised (see section 4.3)), however the majority of haematological changes are mild and reversible when treatment is stopped.

Immune system disorders

Very rare: Hypersensitivity, anaphylaxis, anaphylactoid reaction, 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 Trimogal 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 Trimogal 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.

Not known: Sore mouth.

Hepatobiliary disorders

Very rare: Disturbance in liver enzymes, 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, angioedema.

Not known: Pruritus.

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

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia.

Renal and urinary disorders

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

Not known: 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.

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 administration 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 microorganisms 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.

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 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 per ml have been reported after a single dose of 100mg. About 40 to 70% is bound to plasma proteins. Tissue concentrations are reported to be higher than serum concentrations in the cerebrospinal fluid are about one half of those in the blood. About 40 to 60% of a dose is excreted in the urine within 24 hours (mainly as unchanged drug) 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. The half-life is approximately 8 – 10 hours. It appears in breast milk.

5.3 Preclinical safety data

No data held for this section.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose, Povidone, Microcrystalline cellulose, Sodium starch glycollate and Magnesium stearate.

6.2 Incompatibilities

Not known.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Polypropylene securitainers with polyethylene caps.

PVC Blisters with 20µm Aluminium Foil

Pack size: 14.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Ennogen Pharma Limited

Unit G4 Riverside Industrial Estate

Riverside Way

Dartford

Kent

DA1 5BS

8. Marketing authorisation number(s)

PL 40147/0083

9. Date of first authorisation/renewal of the authorisation

05/09/2006

10. Date of revision of the text

24/06/2020