Trimethoprim Tablets 200mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Trimethoprim 200mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Trimethoprim 200.00mg For full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of susceptible infections caused by trimethoprim sensitive organisms including urinary and respiratory tract infections and for the prophylaxis of recurrent urinary tract infections.
It is effective against most Gram-positive and Gram-negative aerobic organisms, including Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumonia, Staphylococcus aureus, Escherichia coli, Enterobacter, Proteus and Streptococcus faecalis.
Exceptions include anaerobic bacteria. Mycobacterium tuberculosis, Neisseria gonorrhoeae, Pseudomonas aeruginosa and Treponema pallidum.
4.2 Posology and method of administration
Posology Acute infections:
Treatment should continue for a period of between 3 days (eg, uncomplicated bacterial cystitis in women) to 2 weeks depending on the nature and severity of the infection. The first dose may be doubled.
Adults and children over 12 years: treatment of urinary tract infections and all other susceptible infections: 200mg twice daily.
Long-term prophylaxis of recurrent urinary tract infections: 100mg at night before bed-time.
Children: 6 to 12 years of age:- treatment of urinary tract infections and all other susceptible infections: 6mg/kg bodyweight daily, sub-divided into 2 equal doses.
Long-term prophylaxis of recurrent urinary tract infections: 2.5mg/kg body weight daily given as a single dose before bedtime.
Children under 6 years: This dosage form is not suitable for use in children younger than 6 years.
Older people
Dosage is dependent on renal function. See special dosage schedule below. Advised dosage schedule where there is reduced kidney function:
|
Creatinine Clearance (ml/sec) |
Plasma creatinine (micromol/l) |
Dosage advised |
|
Over 0.45 |
Men <250 Women <175 |
Normal |
|
0.25 - 0.45 |
Men 250-600 Women 175-400 |
Normal for 3 days then half dose |
|
Under 0.25 |
Men >600 Women >400 |
Half the normal dose |
Trimethoprim is removed by dialysis. However, it should not be administered to dialysis patients unless plasma concentrations can be estimated regularly.
Method of administration:
For oral administration
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipient listed in section 6.1.
• Severe hepatic insufficiency.
• Severe renal insufficiency, unless plasma levels can be monitored regularly.
• Megaloblastic anaemia and other blood dyscrasias.
• Trimethoprim should not be administered to premature infants or children
under 4 months of age.
• Trimethoprim should not be administered to pregnant women.
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 hepatological effects.
Trimethoprim may cause depression of haemopoiesis . Regular haematological tests should be undertaken in patients receiving long-term treatment and those pre-disposed 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 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.
Special care is necessary in patients receiving pyrimethamine therapy in addition to trimethoprim.
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.
Rifampicin may increase the elimination and shorten the elimination half-life of trimethoprim.
Phenytoin and digoxin - the patient should be carefully monitored as trimethoprim may increase plasma concentration of these agents by increasing^ the elimination half-life of phenytoin and digoxin.
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.
Anticoagulants: Trimethoprim may potentiate the anticoagulant effect of warfarin and other coumarins.
Cyclosporin may increase the nephrotoxicity of trimethoprim.
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.
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.
Breastfeeding:
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
None.
4.8 Undesirable effects
The following list of undesirable effects have been reported by healthcare professionals. It may be difficult to distinguish reactions caused by condition being treated from adverse reactions, which means that not all the listed reactions were caused by drug administration. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (>1/10), common (< 1/10), uncommon (<1/100), rare (<1/1,000) very rare (<1/10,000), not known
(cannot be estimated from the available data).
Infections and Infestations Common: Monilial overgrowth
Blood and lymphatic system disorders
Very rare: Leucopenia, neutropenia, pancytopenia, thrombocytopenia, agranulocyctosis, aplastic anemia, bone marrow depression, hemolytic anemia, eosinophilia, purpura, haemolysis. Trimethoprim therapy may affect haematopoiesis.
Unknown: Megaloblastic anaemia, methaemoglobinaemia.
Fatalities have been reported (especially in elderly or those with impairment of renal or hepatic function in whom careful monitoring is adviced-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
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 Trimethoprim 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
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: 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) carried high mortality.
Musculoskeletal and connective tissue disorders Very rare: Arthralgia, Myalgia
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. Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Treat symptomatically, gastric lavage and forced diuresis can be used. Depression of haematopoiesis by trimethoprim can be counteracted by intramuscular injections 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, 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 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.
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 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</ |
Resistant>) Units: mg/L | |
|
Enterob acteri aceae |
Staphylococcus |
Enterococcus |
|
<2/>4 |
<2/>4 |
<0.032/>11 |
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/ml have been reported after a single dose of 100mg.
Distribution:
Approximately 40-70% is bound to plasma proteins. After dose, 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. Trimethroprim may cause an apparent rise in serum creatinine levels due to competition in the tubular secretory mechanisms.
5.3 Preclinical safety data
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose
Povidone 25cps Crospovidone Sodium starch glycollate Magnesium stearate Industrial methylated spirit Purified water
6.2 Incompatibilities
None known
6.3 Shelf life
36 months for all
6.4 Special precautions for storage
Store in a well closed container. Store in a dry place below 25°C
6.5 Nature and contents of container
High density polystyrene with polythene lids and/or polypropylene containers with polythene lids and polyurethane or polythene inserts Blister pack - 25 micron PVC glass-clear/bluish rigid PVC (pharmaceutical grade) 20 micron hard-tempered aluminium foil coated on the pull side with 6-7gsm heat seal lacquer and printed on the bright side.
Pack sizes: 50,100, 500, 1000, 5000, 28 (blister pack)
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd Capital House,
85 King William Street,
London EC4N 7BL UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 12762/0430
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
9 January 2008
08/02/2015
The activity of trimethoprim is uncertain against enterococci. Hence the wild type population is categorized as intermediate.
5.2 Pharmacokinetic properties
Absorption: