Trimethoprim Tablets BP 200mg

Summary of Product Characteristics Updated 12-Sep-2018 | Accord-UK Ltd

1. Name of the medicinal product

TRIMETHOPRIM TABLETS BP 200mg

2. Qualitative and quantitative composition

Each tablet contains 200mg Trimethoprim.

3. Pharmaceutical form

White uncoated tablets.

4. Clinical particulars
4.1 Therapeutic indications

BLACK DIAMOND SUIT (9830) Treatment of susceptible infections caused by trimethoprim-sensitive organisms including urinary infections and respiratory tract infections.

BLACK DIAMOND SUIT (9830) Long-term prophylaxis of recurrent urinary tract infections

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: note contraindication for patients with severe renal; impairment (section 4.3).

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.

Trimethoprim should not be administered to dialysis patients (see section 4.3).

Route of administration

For oral administration.

4.3 Contraindications

Hypersensitivity to trimethoprim or any of the excipients.

Pregnancy.

Blood dyscrasias.

Severe renal insufficiency

Severe hepatic insufficiency.

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.

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).

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

Concomitant use of spironolactone known to cause hyperkalaemia with trimethoprim may result in severe hyperkalaemia.

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.

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

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.

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

Ciclosporin may increase the nephrotoxicity of trimethoprim.

In addition to other medicinal products known to cause hyperkalaemia concomitant use of trimethoprim with spironolactone may result in clinically relevant hyperkalaemia.

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.

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).

System organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to <1/10)

Very rare

(≥ 1/100,000 to <1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations

Monilial overgrowth

Blood and lymphatic system disorders1

Leucopenia, thrombocytopenia, agranulocyctosis, neutropenia, pancytopaenia, bone marrow depression, aplastic anaemia, haemolytic anaemia, eosinophilia, purpura, haemolysis

Megaloblastic anaemia, methaemoglobinaemia. Trimethoprim therapy may affect haematopoiesis

Immune system disorders

Hypersensitivity, anaphylaxis, anaphylactoid reaction, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus

Metabolism and nutrition disorders

Hyperkalaemia (particularly in the eldery and in HIV patients),

Hypoglycaemia, hyponatraemia2, anorexia

Psychiatric disorders

Depression, hallucinations, confusional states, agitation, anxiety, abnormal behavior, insomnia and nightmares

Nervous system disorders

Headache.

Dyskinesias, aseptic meningitis3, tremor, ataxia, dizziness, lethargy, syncope, paraesthesiae, convulsions, peripheral neuritis, vertigo, tinnitus

Eye disorders

Uveitis

Respiratory, thoracic and mediastinal disorder

Cough, shortness of breath, wheeze, epistaxis

Gastrointestinal disorder

Nausea, vomiting,

Diarrhoea,

Glossitis, constipation, stomatitis, pseudomembranous colitis, pancreatitis

Gastrointestinal disturbances, sore mouth

Hepatobiliary disorder

Disturbances in liver enzyme values, elevation of serum transaminases, elevation of bilirubin levels, cholestatic jaundice, hepatic necrosis4

Skin and subcutaneous disorder

Skin rashes, urticaria

Exfoliative dermatitis, photosensitivity, angioedema, erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis5, fixed drug eruption, erythema nodusum, bullous dermatitis, purpura

Pruritus

Musculoskeletal and connective tissue disorders

Myalgia. arthralgia

Renal and urinary disorders

Impaired renal function (sometimes reported as renal failure), haematuria

Raised serum creatinine and blood urea nitrogen levels6

1Fatalities 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

Symptomatic treatment, gastric lavage and forced alkaline diuresis may be used. Depression of haematopoiesis by trimethoprim may be countered with intramuscular 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:

EUCAST Species-related breakpoints (Susceptible -

Enterobacteriac

Staphylococ

Enterococc

- 2/>4

- 2/>4

- 0.032/>1 *

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

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

Not applicable.

6. Pharmaceutical particulars
6.1 List of excipients

Also contains: colloidal silicon dioxide, lactose, macrogol, magnesium stearate, povidone, sodium starch glycollate, stearic acid, E460.

6.2 Incompatibilities

None known.

6.3 Shelf life

Four years from the date of manufacture (PVC/Al blister packs).

Three years from the date of manufacture (all other containers).

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special precautions for storage

Store below 25°C in a dry place.

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad or polythene ullage filler and snap-on polythene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 6, 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500, 1000.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material.

Maximum size of bulk packs: 50,000.

6.6 Special precautions for disposal and other handling

Not applicable.

Administrative Data

7. Marketing authorisation holder

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing authorisation number(s)

PL 0142/0225

9. Date of first authorisation/renewal of the authorisation

26 May 1987

May 1992, June 1997

10. Date of revision of the text

21/08/2018

Company Contact Details
Accord-UK Ltd
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