1    NAME OF THE MEDICINAL PRODUCT

Trimethoprim 50mg/5ml Suspension

Actavis Trimethoprim 50mg/5ml Oral Suspension

Almus Trimethoprim 50mg/5ml Oral Suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 50mg of Trimethoprim

Excipients:

Also contains:

Sodium methyl parahydroxybenzoate (E219) 8.6mg/5ml Sodium propyl parahydroxybenzoate (E217).2.3mg/5ml Maltitol Liquid 2g/5ml See section 4.4

For a full list of Excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Oral Suspension

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Treatment of susceptible infections caused by trimethoprim-sensitive organisms including urinary and respiratory tract infections and for prophylaxis of recurrent urinary tract infections.

4.2. Posology and method of administration

For oral administration

Acute infections:

Adults and children over 12 years: Children 6years to 12 years: Children 6 months to 5 years: Children 6 weeks to 5 months:

The approximate dosage in children is 8 mg trimethoprim per kg body weight per day.

Elderly: Depending on kidney function, see special dosage schedule.

Treatment should continue for at least one week but not last longer than two weeks. The first dose can be doubled.

Long-term treatment and prophylactic therapy:

Adults and children over 12 years:    100 mg (10 ml) at night

Children 6 years to 12 years:    50 mg (5 ml) at night

Children 6 months to 5 years:    25 mg (2.5 ml) at night

The approximate dosage in children is 2 mg trimethoprim per kg body weight per day.

Elderly: Depending on kidney function, see special dosage schedule.

Advised dosage in patients with reduced kidney function

Creatinine clearance (ml/sec)	Plasma creatinine (micromol/l)	Dosage advised
Over 0.45	men < 250	normal
	women < 175
0.25 - 0.45	men 250 - 600 women 175 - 400	normal for 3 days then half dose
under 0.25	men> 600	half normal dose
	women> 400

Trimethoprim is removed by dialysis. However, it should not be administered to dialysis patients unless plasma concentrations can be estimated regularly.

4.3 Contraindications

Trimethoprim 50mg/5ml oral suspension is contraindicated in patients who are hypersensitive to trimethoprim or to any of the suspension ingredients.

Trimethoprim is contraindicated in pregnancy, megaloblastic anaemia and other blood dyscrasias, severe hepatic insufficiency, and severe renal insufficiency where blood levels cannot be monitored.

4.4 Special warnings and precautions for use

Patients with marked impairment of renal function: In patients with marked impairment of renal function, care should be taken to avoid accumulation and resulting adverse haematological effects.

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.

Close monitoring of serum electrolytes is advised in patients at risk for hyperkalaemia (see section 4.8). Monitoring of blood glucose is advised if coadministered with repaglinide (see section 4.5).

Acute porphyria.

In neonates, trimethoprim should be used under careful medical supervision. Particular care should be exercised in the haematological monitoring of children on long term therapy.

The usual caution in prescribing any drug for women of child bearing age should be exercised with trimethoprim.

Trimethoprim Oral Suspension contains sodium methyl parahydroxybenzoate (E219) and sodium propyl parahydroxybenzoate (E217). These may cause allergic reactions (possibly delayed).

It also contains maltitol liquid. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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 anti-folate effect when trimethoprim is given with pyrimethamine.

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.

Cyclosporin: Increased risk of nephrotoxicity.

Diuretics: In elderly patients taking diuretics, particularly thiazides, there is an increased incidence of thrombocytopenia with purpura.

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

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

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.

Procainamide: Trimethoprim increases plasma concentrations of procainamide.

Repaglinide: Trimethoprim may enhance the hypoglycemic effects of repaglinide.

4.6 Fertility, pregnancy and lactation

Trimethoprim is contraindicated in pregnancy.

Trimethoprim is excreted in breast milk. Effects on the suckling child are likely if the therapeutic doses are administered to breastfeeding 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 known

4.8 Undesirable effects

The following list of undesirable effects has 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 following convention has been used for the classification of adverse events in terms of frequency:- Very common >1/10, common >1/100 and <1/10, uncommon >1/1000 and <1/100, rare >1/10,000 and <1/1000, very rare <1/10,000.

Infections and Infestations Common: Monilial overgrowth.

Very rare: Leucopenia, neutropenia, thrombocytopenia, pancytopaenia, bone marrow depression, agranulocytosis, aplastic anaemia, haemolytic anaemia, eosinophilia, purpura, haemolysis. Trimethoprim 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- refer to Section 4.3 Contraindications), however the majority of haematological changes are mild and reversible when treatment is stopped.

Cases of megaloblastic anaemia during prolonged therapy with trimethoprim in doses higher than those recommended rarely occur but are reversible with discontinuation of therapy and administration of folinic acid.

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 Trimethoprim is used in elderly patients or in patients taking high doses as these patients may be more susceptible to hyperkalaemia and hyponatraemia.

Very rare: Depression, hallucinations, confusional states, agitation, anxiety, abnormal behaviour, 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 Trimethoprim alone.

Eve 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, and hepatic necrosis. Cholestatic jaundice and hepatic necrosis may be fatal.

Skin and subcutaneous tissue disorders Common: Skin rashes, urticaria.

Very rare: Exfoliative dermatitis more severe skin sensitivity or allergic reactions such as photosensitivity, angioedema, erythema multiforme, fixed drug eruption, erythema nodusum, Stevens Johnson syndrome and toxic epidermal necrolysis, bullous dermatitis have been reported rarely.

Unknown: Pruritus.

Lyell’s syndrome (Toxic epidermal necrolysis) carrieds high mortality.

Musculoskeletal and connective tissue disorders Very rare: Arthralgia, myalgia and uveitis.

Renal and urinary disorders

Very rare: 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. 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.

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: SULFONAMIDES and TRIMETHOPRIM ATC code: J01EA01

Mechanism 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. It affects the nucleoprotein metabolism of micro-organisms by interference in the folic-folinic acid systems.

Trimethoprim is effective in-vitro against most Gram-positive and Gram- negative aerobic organisms, including enterobacteria - E. coli, Proteus, Klebsiella pneumoniae, Streptococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Trimethoprim has a considerably greater effect on the cells of microorganisms than on the mammalian cells. It may be bactericidal or bacteriostatic depending on the growth conditions.

It is not active 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:

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

Absorption and half-life:

Trimethoprim is absorbed rapidly and almost completely following oral administration and maximal plasma concentrations are reached after 1-4 hours. Peak plasma concentrations of about 1 pg per ml have been reported after a single dose of 100 mg.

The half-life is about 10 hours in patients with normal renal function but up to 20-50 hours in anuric patients.

Distribution:

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 the lungs but concentrations in the cerebrospinal fluid are about one half of those in the blood.

Biotransformation and elimination:

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. It appears in breast milk.

Trimethoprim may cause an apparent rise in serum creatinine levels due to competition in the tubular secretory mechanisms.

5.3. Preclinical safety data

There are no preclinical 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

Xanthan Gum Maltitol Liquid

Polysorbate 80 Microcrystalline cellulose Sodium Carboxymethylcellulose Saccharin Sodium Citric Acid Monohydrate Sodium Methylhydroxybenzoate Sodium Propylhydroxybenzoate Aniseed Flavour Purified Water.

6.2.    Incompatibilities

None known.

6.3.    Shelf life

2 years

6.4.    Special precautions for storage

Do not store above 25°C.

6.2. Nature and contents of containers

Amber Type III Glass

10 DATE OF REVISION OF THE TEXT

25/06/2015