Document: spc-doc_PL 40147-0082 change

• spc-doc_PL 00289-0196
• spc-doc_PL 12762-0429
• spc-doc_PL 40147-0082

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Trimogal® (Trimethoprim) Tablets 100mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Trimethoprim BP 100mg

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of acute urinary tract injections 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

Dosage and administration:

Urinary tract infections:

Treatment:

adults:    300mg

children over 12 years:    as for adults

6 - 12 years:    150 mg once daily

under 6 years:    formulation inapplicable

This dosage approximates to 6 mg/kg body weight/day

Prophylaxis:

adults:    100 mg once    daily

children over 12 years:    as for adults

6 - 12 years:    50 mg once daily

under 6 years:    formulation inapplicable

This dosage approximates to 2 mg/kg body weight/day.

To ensure maximal urinary concentrations it may be advantageous to take all the doses at bedtime.

Respiratory infections:

adults:    200mg once daily

children over 12 years:    as for adults

6 - 12 years:    100mg twice daily

6 months - 6 years:    50 mg twice daily

In acute infections, trimethoprim should be given for at least five days or until the patient has been symptom-free for two days. Long-term administration may be continued for three to 12 months or more as appropriate

Dosage recommendations in renal impairment:

When creatinine clearance is below 15 - 20ml/minute, trimethoprim levels should be monitored after approximately 3 days' treatment to provide guidance on the appropriate dosage reduction. When the clearance is below 10ml/minute trimethoprim should not be administered unless plasma concentrations can be estimated regularly and haemodialysis facilities are available.

Use in the elderly: no specific studies have been carried out in the elderly, although trimethoprim has been widely used in older people. However care is advised when treating the elderly because, as a group, they are more susceptible to adverse reactions.

4.3 Contraindications

Hypersensitivity to trimethoprim or any of the excipients.

Severe hepatic insufficiency. Severe renal insufficiency unless blood trimethoprim concentrations can be monitored regularly. Megoblastic 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. Use half the normal dose after 3 days if the creatinine clearance is 15 - 30 mL/minute; use half the normal dose if creatinine clearance less than 15 - 30 mL/ minute; (monitor plasma-trimethoprim concentration if creatinine clearance is less than 10mL/minute).

In patients with renal impairment, care should be taken to avoid accumulation.

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 megoblastic 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).

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

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

4.5 Interactions with other Medicaments 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

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.

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 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, 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 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

Nausea, vomiting, abdominal pain, dizziness and confusion are likely symptoms of overdosage. Gastric lavage may be useful although absorption of trimethoprim from the gastro-intestinal tract is normally complete in approx 2 hours. This may not be the case in gross overdosage. Calcium folinate (3 -6mg/day) given orally or intra-muscularly for five to seven days should counteract any effect of the bone marrow. Acidification of the urine will increase the elimination of trimethoprim. General supportive measures are recommended.

Trimethoprim is dialysable by renal dialysis.

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. type population is categorized as intermediate.		Hence the wild

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 1pg per ml have been reported after a single dose of 100mg. About 40 to 70% is bound to plasma proteins. Trimethoprim is widely distributed to various tissues and fluids including kidneys, liver, bronchial secretions, saliva, prostatic tissue and fluid, and vaginal secretions; tissue concentrations in the kidneys and lungs are reported to be higher than serum concentrations, but concentrations in the cerebrospinal fluid are half of those in the blood.

Trimethoprim readily crosses the placenta and it appears in breast milk.

The half life is about 8 to 10 hours, but is prolonged in severe renal failure. Trimethoprim is excreted primarily by the kidneys through glomerular filtration and tubular secretion. About 40 to 60% of a dose is excreted in the urine within 24 hours, predominantly as unchanged drug. About 10 to 20% of trimethoprim is metabolised primarily in the liver and small amounts are excreted in the faeces. Trimethoprim is removed from the blood by haemodialysis to some extent.

5.3 Preclinical safety data

No data held for this section

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Magnesium Stearate Sodium starch glycollate Microcrystalline cellulose Povidone Lactose

Ethyl alcohol

6.2 Incompatibilities

None known

6.3 Shelf life

3 years

6.4 Special precautions for storage

Protect from light.

Store in a cool, dry place

6.5 Nature and contents of container

Securitainer