Co-Trimoxazole 80/400mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-Trimoxazole 80/400mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Trimethoprim 80.00mg Sulphamethoxazole 400.00mg
3. PHARMACEUTICAL FORM
Tablets for oral administration.
White round flat bevel edged tablets marked “COT 480” on one side and a cross break line on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Co-trimoxazole is an antibacterial agent. Co-trimoxazole is effective in vitro against a wide range of gram-positive and gram-negative organisms. It is not active against mycobacterium tuberculosis, mycoplasma or treponema pallidum, pseudomonas aeruginosa is usually insensitive.
Co-trimoxazole is indicated for the following:
• Treatment and prophylaxis (primary and secondary) of Pneumocytosis carinii (Pneumocytosis jiroveci) pneumonitis in adults and children.
• Treatment and prophylaxis of toxoplasmosis, treatment of nocardia.
• Treatment of urinary tract infections and acute exacerbations of chronic bronchitis, where there is bacterial evidence of sensitivity to co-trimoxazole and good reason to prefer this combination to a single antibiotic.
• Treatment of acute ototis media in children, where there is good reason to prefer co-trimoxazole to a single antibiotic.
Co-trimoxazole should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent.
4.2 Posology and method of administration
Adults
Standard dosage: 2 tablets twice daily For severe infections: 3 tablets twice daily
Children
A more appropriate dosage formulation should be used.
Over 12 years:
6-12 years:
6 weeks - 5 months: 6 months - 5 years:
As for adults 1 Tablet twice daily 120mg twice daily 240mg twice daily
Co-trimoxazole may be taken with some food to minimise the possibility of GI disturbances.
Special Dosage Recommendations:
Unless stated, standard dosage applies.
In acute infections, Co-trimoxazole should be given for at least five days or until patient has been symptom-free for two days. If clinical improvement is not evident after seven days therapy, the patient should be reassessed. As an alternative to standard therapy for acute uncomplicated lower urinary tract infections, short-term therapy of one to three days duration has been shown to be effective.
Impaired Renal Function:
If Co-trimoxazole is given to patients with renal impairment then the following dosage scheme is suggested (no information is available for children with renal failure).
Creatinine Serum creatinine Dosage Clearance (umol/I)
(ml/min)
Above 25 Men <265 Standard dosage
Women <175
|
15-25 |
Men |
265-620 |
Standard dosage for a maximum |
|
Women |
175-400 |
of three days followed by half the | |
|
Standard dosage | |||
|
Below 15 |
Men |
>620 |
Not to be administered unless |
|
Women |
>400 |
Haemodialysis facilities are |
available. Under this condition half the standard dosage may be given.
Measurements of plasma concentrations of sulphamethoxazole at intervals of two to three days are recommended in samples obtained 12 hours after administration of Co-trimoxazole. If the concentration of total sulphaamethoxazole exceeds 150mcg/ml, then treatment should be interrupted until the value falls below 120 mcg/ml.
Long-term prophylaxis of recurrent or suppression of chronic infection following sterilisation of the urine:
Adults and children over 12 years:
1 tablet nightly
Children under 12 years
A single nightly dose of 2mg trimethoprim and 10mg sulphamethoxazole per kg body weight.
Treatment may be continued for 3 to 12 months or more as appropriate. Chronic Prostatitis:
It may be advisable to use a higher than standard dose initially. The course of treatment should last for three months to reduce the risk of relapse.
Pneumocystis Carinii (Pneumocytosis jiroveci) Pneumonitis :
Treatment: 20mg trimethoprim and 100mg sulphamethoxazole per kg body weight per day in two or more divided doses for two weeks. The steady state of serum level of trimethoprim should be maintained at 5 mcg/ml or higher for maximum efficacy.
Prevention: Standard dosage for the duration of the period at risk. The following regimen have been used:
Two tablets daily for seven days or
Two tablets daily three times a week on alternate days or
Two tablets twice a day three times a week on alternate days
Treatment of Nocardiosis: Six to eight tablets daily for up to 3 months. Treatment and prophylaxis of toxoplasmosis: as prophylaxis of Pneumocytosis jiroveci (P. carinii).
Gonorrhoea
In uncomplicated cases 4 tablets every 12 hours for two days or 5 tablets followed by a further dose of 5 tablets eight hours later.
Acute Brucellosis:
It may be advisable to use a higher than standard dose initially. Treatment should continue for a period of at least four weeks and repeated courses may be beneficial.
Typhoid and Paratyphoid Carriage:
Treatment should be continued for at least 1-3 months.
Use in the Elderly:
No specific studies have been carried out in the elderly, although Co-trimoxazole 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 and more likely to suffer effects as a result particularly when complicating conditions exist e.g. impaired kidney and/or liver function and/or concomitant use of other drugs.
Route of administration
Oral.
4.3 Contraindications
Co-trimoxazole should not be given to patients with a history of sulphonamide, trimethoprim or Co-trimoxazole hypersensitivity or to any other ingredients in the tablet.
Contra-indicated in patients showing Severe hepatic failure or marked liver parenchymal damage, jaundice.
Except in certain circumstances it should not be given to patients with serious haematological disorders and porphyria. The combination has been administered to patients receiving cytotoxic agents without evidence of an adverse effect on the bone marrow or peripheral blood.
Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.
Co-trimoxazole should not be given to premature babies, infants under six weeks, except for the treatment/prophylaxis (primary or secondary) of
Pneumocystosis carinii (Pneumocystosis jiroveci) when treatment can be given in infants of four weeks of age or greater.
Pregnancy - especially in the period prior to birth (see section 4.6)
4.4 Special warnings and precautions for use
Co-trimoxazole should be discontinued if a skin rash appears.
Fatalities may occur with Stevens Johnson syndrome, Lyell syndrome/TEN, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias, hypersensitivity of respiratory tract.
In cases with renal impairment a modified dosage schedule as described above is indicated. In such patients, measurements of the plasma concentration of the drug is advisable.
An adequate urinary output should be maintained at all times, the risk of crystalluria is increased in patients suffering from malnutrition.
A folate supplement should be considered when treating potentially folate deficient patients such as the elderly or with prolonged high dosage of Co-trimoxazole. These patients will require special care. Megaloblastic changes have been reported with long-term treatment, but have been reversed with folic acid therapy.
Special care should be taken when treating elderly patients, especially with renal/hepatic dysfunction and patients taking other drugs.
Patients with glucose-6-phosphatase dehydrogenase deficiency may be at risk of haemolytic reactions.
Care is generally advisable in patients with a history of allergy or asthma.
Do not use in Group A beta-haemolytic streptococci.
Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction . Co-trimoxazole can be used in phenylketonuria patients on diet.
There is a small risk of kericterus in jaundiced infants and haemolysis in G6PD-deficient infants (due to sulphamethoxazole).
If Co-trimoxazole treatment is prolonged, especially in patients with suspected impairment of folate metabolism, it is suggested that complete blood counts including thrombocytes be performed at monthly intervals. Any changes in haematological laboratory indices due to lack of available folate may be reversed by administration of 5 to 10mg folinic acid per day without interfering with the antibacterial activity.
Serum potassium levels should be monitored closely in those patients at risk of hyperkalaemia.
4.5 Interaction with other medicinal products and other forms of interaction
Co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulphamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Co-trimoxazole is advisable. The effect of acencoumarol may also be enhanced.
Co-trimoxazole prolongs the half life of phenytoin, digoxin, procainamide and amantadine and if co-administered the prescriber should be alert for excessive effect of these drugs. Close monitoring of the patient’s condition and serum levels are advisable.
Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.
The antifolate effect of methotrexate is increased by Co-trimoxazole. If Co-trimoxazole is considered to be appropriate therapy in patients receiving this or other antifolate drugs, a folate supplement should be considered (see Precautions). There is an increased risk of haematological toxicity with azathioprine and mercaptopurine.
Concurrent use of rifampicin and Co-trimoxazole results in increased rifampicin serum levels and a shortening of the plasma half life of Trimethoprim after a period of about one week. This is not thought to be of clinical significance.
Reversible deterioration in renal function has been observed in patients treated with Co-trimoxazole and cyclosporine following renal transplantation.
Occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25mg weekly may develop megaloblastic anaemia should Co-trimoxazole be prescribed concurrently.
In elderly patients concurrently receiving diuretics thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.
Care should be exercised when giving Co-trimoxazole to patients receiving:
• ACE Inhbitors: risk of severe hyperkalaemia.
• Anaesthetics: increased risk of methaemoglobinaemia when sulphonamides given with prilocaine.
• Antiarrhythmics: increased risk of ventricular arrhythmias with amiodarone. Plasma levels of dofetilide increased markedly by co-administration with Co-trimoxazole resulting in the increase dofetilide-induced QT prolongation and the risk of arrhythmias.
• Antibacterials: serum levels of dapsone and Co-trimoxazole are possibly raised by the presence of the other. Be alert for dapsone toxicity causing methaemoglobinaemia. Increased risk of crystalluria when sulphonamides given with methenamine.
• Antivirals: plasma concentrations of lamivudine increased-avoid concomitant high dose co-trimoxazole. Concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to Co-trimoxazole. Zalcitabine plasma concentrations possibly increased by co-trimoxazole.
• Clozapine: avoid concomitant use; increased risk of fatal agranulocytosis.
• Cytotoxics: increased risk of haematological toxicity with mercaptopurine and azathioprine.
• Potassium aminobenzoate: effects of sulphonamides inhibited.
• Laboratory tests- trimethoprim and sulphonamides have been reported to interfere with diagnostic tests, including serum-methotrexate and serum-plasma creatinine levels, also urea, urinary glucose and urobilinogen tests.
4.6 Pregnancy and lactation
The safety of Co-trimoxazole in human pregnancy has not been established. The drug should not be given during pregnancy. Co-trimoxazole interferes with folate metabolism and can cause teratogenic effects if given in the first trimester. Animal studies have shown teratogenic effects typical of a folate antagonist in rats but not in rabbits at high doses; these were prevented by administration of dietary folates. Sulphonamide-containing products should not be administered in late pregnancy because of the risk of kernicterus. Co-trimoxazole can cause neonatal haemoylosis and methaemoglobinaemia when used in the third trimester, if given close to delivery kernicterus may occur due to displacement of bilirubin. Other toxicities that may be observed in the new born include jaundice and haemalytic anaemia. The risk of kernicterus is higher in infants at increased risk of hyperbilirubinaemia, such as if the infant is ill, stressed or premature or has glucose-6-phosphate dehydrogenase deficiency.
The usual caution is prescribing any drug for women of child-bearing age should be exercised with Co-trimoxazole.
Both sulphamethoxazole and trimethoprim may be found in breast milk but the administered of Co-trimoxazole of lactating women represents a negligible risk to the suckling infant. However, there is a risk of kernicterus if the infant is at increased risk of hyperbilirubinaemia
4.7 Effects on ability to drive and use machines
As Co-trimoxazole can cause dizziness, drowsiness, tinnitus, insomnia and hallucinations patients should make sure they are not affected before driving or operating machines
4.8 Undesirable effects
As Co-trimoxazole contains trimethoprim and a sulphonamide, the type and frequency of adverse effects associated with such compounds may be expected.
• Immune system disorders- Hypersensitivity reactions may also precipitate serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, peri-arteritis nodosa and systemic lupus erythematosus (SLE). Severe skin sensitivity reactions such which have a high mortality as erythema multiforme bullosa (Stevens-Johnson Syndrome), and toxic epidermal necrolysis (Lyell Syndrome) have occurred infrequently Treatment should be discontinued if these occur
• Skin and subcutaneous tissue disorders - photosensitivity and skin rashes can occur. Exfoliative dermatitis, fixed drug eruptions and Henoch-Schonlein purpura have also been reported.
• Blood and the lymphatic system disorders - The haematological changes reported with Co-trimoxazole mainly consist of thrombocytopenia, purpura, leucopenia, eosinophilia, neutropenia and very rarely agranulocytosis and bone marrow depression, especially in the elderly. They have usually proved to be reversible on withdrawal of the drug. Less commonly megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, and methaemoglobinaemia. Fatalities resulting from haematological changes may occur. Elderly patients are more susceptible to these blood changes. The changes may be worse in hepatic and renal failure and in poor folate status. Co-trimoxazole may include haemolysis in certain susceptible glucose-6-phosphate dehydrogenase deficient patients.
• Gastrointestinal disorders - Nausea, vomiting, diarrhoea, glossitis, sore mouth, anorexia and stomatitis. Pseudomembranous colitis has been reported rarely.
Hepato-biliary disorders - Jaundice and, very rarely, hepatic necrosis have been reported as well as elevated transaminases and bilirubin and rarely, cholestatic jaundice; stomatitits and anorexia and, rarely, pancreatitis.
• Ear and labyrinth disorders - vertigo, tinnitus.
• Nervous system disorders - There have been a few reports of subjective experiences such as headache, depression, dizziness and hallucinations but their relationship to therapy remains unproven. There have been reports of aseptic meningitis - reversible on withdrawal. Other neurological adverse effects include convulsions, peripheral neuritis, ataxia, drowsiness, fatigue, and insomnia.
• Renal and urinary disorders - Impaired renal function and rarely, interstitial nephritis and crystalluria which can be avoided by adequate fluid intake.
During long-term therapy, isolated cases of megaloblastic changes in the bone marrow have been reported; these are reversible by folinic acid therapy.
• Respiratory, thoracic and mediastinal disorders - Cough, dyspnoea and pulmonary infiltration, suggesting hypersensitivity, which may be fatal, have occurred.
• Other - At the high dosages used for the therapy of pneumocystis carinii pneumonitis in patients with acquired immune deficiency syndrome, rash, fever, hyperkalaemia/hyponatraemia, bone marrow depression requiring folate supplements, neutropenia, thrombocytopenia and raised liver enzymes have been reported, necessitating cessation of therapy. On re-exposure to the drug severe hypersensitivity may occur.
• Metabolism and nutrition disorders - electrolyte disturbances, metabolic acidosis, Hyperkalaemia and hyponatraemia, especially in the elderly and at high doses, may occur.
• Musculoskeletal disorders - Arthralagia, myalgia
• Infections and infestations: monilial over growth have been reported.
4.9 Overdose
Symptoms of acute overdosage are likely to be nausea, vomiting, abdominal pain, dizziness, rashes, headache, ataxia, drowsiness, dysuria, swelling of the face, weakness and confusion. Symptoms of bone marrow depression may develop. Peritoneal dialysis is of no use. Treatment should consist of gastric lavage if within an hour of ingestion. Absorption of trimethoprim from the gastrointestinal tract is normally complete in approximately 2 hours, but this may not be the case in gross overdosage. Increased fluid intake will increase the elimination of sulphamethoxazole. Alkalinisation of the urine will also increase the elimination of sulphamethoxazole but decrease that of the trimethoprim. Calcium Leucovirin 510mg daily will counteract any adverse effects of trimethoprim on bone marrow or Calcium folinate (3-6mg/day) given orally or intramuscularly for five to seven days should reverse any folate deficiency effect of trimethoprim. Generally supportive measures are recommended. Observe the patient for at least four hours and monitor
U&Es and full blood count in symptomatic cases.
Both trimethoprim and sulphamethoxazole are dialysable by renal dialysis.
PHARMACOLOGICAL PROPERTIES
5.
5.1. Pharmacodynamic Properties
Both sulphamethoxazole and trimethoprim are dihydrofolate reductase inhibitors which affect the nucleoprotein metabolism of micro-organisms by interference in the folic-folinic acid systems. Both substances are employed in the treatment of bacterial infections.
5.2. Pharmacokinetic Properties
Trimethoprim is readily absorbed from the gastro-intestinal tract and peak concentrations in the circulation occur about 3 hours after a dose is taken. Above 45% 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 cerebro-spinal fluid are about one-half of those in the blood. The half-life is about 10 to 16 hours. About 40 - 50% of a dose is excreted unchanged in the urine within 24 hours, together with metabolites. Trimethoprim appears in breast milk.
Sulphamethoxazole is readily absorbed from the gastro-intestinal tract and peak plasma concentrations are reached within 4 hours. Doses of 1g twice daily should produce blood concentrations of unconjugated sulphamethoxazole in excess of 50pg per ml. About 65% is bound to plasma albumin and the plasma half-life is about 10 hours. About 15% of sulphamethoxazole in the blood is present as the acetyl derivative. Elimination in the urine is dependent on pH. About 25% of a single 2g dose of sulphamethoxazole has been reported to be excreted in the urine within 8 hours, about 60% being in the form of the acetyl derivative.
When Co-trimoxazole is administered, plasma concentrations of trimethoprim and sulphamethoxazole are generally in the ratio of 1:20; in urine this ratio may vary from 1:1 to
1:5. About 50% of administered trimethoprim and 50% of sulphamethoxazole is excreted in the urine in 24 hours; a larger proportion of sulphamethoxazole appears as inactive metabolite.
5.3. Pre-clinical Safety Data
None available
6.1. List of excipients
Microcrystalline Cellulose USNF Starch Pregelatinised USNF Maize Starch BP Nipastat HSE
Hydrogenated Castor Oil NF Magnesium Stearate BP Sodium Starch Glycollate (Primojel) BP Purified Water BP
6.2. Incompatibilities
None known.
6.3. Shelf-Life
3 years
6.4. Special Precautions for Storage
Store in a dry place below 25°C. Protect from heat, light and moisture.
6.5 Nature and contents of container
PVC/Aluminium blister pack
HDPE round, tear strip tamper evident container containing white absorbent cotton BP and an HDPE pilfer proof lock ring cap.
Pack sizes: 4, 8, 12, 16, 20, 28, 50, 100, 250, 500 or 1000 tablets per blister pack/container.
Not all pack sizes may be marketed
6.6. Instruction for Use/Handling
None
7. MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited
3 Howard Road
Eaton Socon
St Neots
Cambridgeshire
PE198ET
UK
8. MARKETING AUTHORISATION NUMBER(S)
PL 11311/0352
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/06/2003
10 DATE OF REVISION OF THE TEXT
30/01/2013