SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Trimogal® (Trimethoprim) Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains trimethoprim BP 200mg.

3    PHARMACEUTICAL FORM

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

Adults and children over 12 years of age:

Treatment of acute urinary tract infections: 2 x 100mg tablets or one 200mg tablet twice daily.

Long term prophylaxis of recurrent urinary tract infections: one 100mg tablet each night before retiring.

Respiratory tract infections: 200mg twice daily.

Children:

Treatment of acute urinary tract infections in children aged 4 months to 12 years: 6mg/kg body weight daily subdivided into two equal doses.

Long-term prophylaxis of recurrent urinary tract infections in children aged 4 months to 12 years: 2.5mg/kg body weight daily given as a single dose before retiring.

Treatment of respiratory tract infections in children aged 6 months to 6 years:

50mg twice daily.

Treatment of respiratory tract infections in children aged 6 to 12 years:

100mg twice daily.

For oral administration.

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

Not 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, 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

Treatment of overdosage: Symptomatic treatment, gastric lavage and forced diuresis can be used. Depression of haematopoiesis by trimethoprim can be counteracted by intramuscular administration of calcium folinate.

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

The following pharmacokinetic parameters were obtained with Trimogal® 200mg tablets (n=8)

t^a:	9.8335 hours
t^3:	0.311 hours
Tmax:	1.60 hours
Cmax:	2.250 pg/ml
AUC:	35.734 pg/ml/hours
AUC24:	28.932 pg/ml/hours

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, povidone, microcrystalline cellulose, sodium starch glycollate, magnesium stearate and ethyl alcohol.

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. Pack size: 100.

6.6 Special precautions for disposal

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

01/05/2015