Co-Trimoxazole Forte 160mg/800mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-trimoxazole Forte 160mg/800mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Trimethoprim 160mg Sulphamethoxazole 800.00mg
3. PHARMACEUTICAL FORM
Tablets for oral administration.
White oblong shaped tablets marked "COT 960"on one side and a break line on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
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 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 otitis media in children, where there is good reason to prefer co-trimoxazole to a single antibiotic.
4.2 Posology and method of administration Adults
|
Standard dosage: |
1 tablet twice daily |
|
For severe infections: |
1/ tablets twice daily |
Children
|
Over 12 years: |
As for adults |
|
Under 12 years: |
Not recommended |
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 the 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(pmol/l) Dosage
clearance
|
(ml/min) | |||
|
Above 25 |
Men |
<265 |
Standard dosage |
|
Women |
<175 | ||
|
15-25 |
Men |
265-620 |
Standard dosage for a maximum of three |
|
Women |
175-400 |
days followed by half the standard dosage | |
|
Below 15 |
Men |
>620 |
Not to be administered unless haemodialysis |
|
Women |
>400 |
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 sulphamethoxazole 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 or 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.
Gonorrhoea:
In uncomplicated cases 2 tablets every 12 hours for two days or 2% tablets followed by a further dose of 2% 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.
Nocardis:
There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used.
Toxoplasmosis:
There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of PCP may be appropriate.
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.
Contraindicated in patients with severe hepatic impairment, particularly those showing marked liver parenchymal damage, jaundice.
Co-trimoxazole should be avoided in porphyria risk patients.
Except in certain circumstances it should not be given to patients with serious haematological disorders. The combination has been administered to patients receiving cytotoxic agents without evidence of an adverse effect on the bone marrow or peripheral blood.
Contraindicated 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 from four weeks of age.
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 or blood disorder develops.
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. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased.
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.
Co-trimoxazole should not be used in treatment of infections due to Group A beta-haemolytic streptococci such as streptococcal pharyngitis. Eradication of these organisms from the oropharynx is less effective than with penicillin.
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 possibly 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. The antifolate effect of phenytoin may be increased. Close monitoring of the patient's condition and serum levels are advisable. Co-trimoxazole increases the risk of ventricular arrhythmias with amiodarone. Concomitant use should be avoided. 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.
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. The plasma concentration of dapsone and trimethoprim may be increased when they are used concomitantly. Be alert for dapsone toxicity causing methaemoglobinaemia.
Reversible deterioration in renal function has been observed in patients treated with Co-trimoxazole and cyclosporin 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. There is an increased risk of antifolate effect with pyrimethamine.
In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.
In some situations, concomitant treatment with zidovudine may increase the risk of haematological reactions to Co-trimoxazole. If concomitant treatment is necessary consideration should be given to monitoring of haematological parameters.
The plasma concentration of lamivudine and possibly zalcitabine is increased when they are administered with Co-trimoxazole. Avoid high dose Co-trimoxazole with lamivudine.
The effect of thiopental is enhanced and there is an increased risk of methaemoglobinaemia when prilocaine is administered concomitantly with Co-trimoxazole.
Potassium aminobenzoate inhibits the effects of sulphonamides.
• ACE Inhbitors: risk of severe hyperkalaemia.
• Clozapine: avoid concomitatnt use; increased risk of fatal agranulocytosis.
• 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 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 in 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 administration of Co-trimoxazole to 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.. Discontinue immediately if these occur. 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 induce haemolysis in certain susceptible glucose-6-phosphate dehydrogenase deficient patients.
• Gastrointestinal disorders - Nausea, vomiting, diarrhoea, glossitis Pseudomembranous colitis has been reported rarely. Sore mouth
Hepato-biliary disorders - Jaundice and, very rarely, hepatic necrosis have been reported as well as elevated transaminases and bilirubin and rarely, cholestatic jaundice; stomatitis and anorexia and, rarely, pancreatitis, antibiotic-induced colitis
• 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, convulsions, peripheral neuritis, ataxia, drowsiness, fatigue, and insomnia.
• Ear and labyrinth disorders- vertigo, tinnitus.
• Renal and urinary disorders - Impaired renal function and rarely, interstitial nephritis, 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 overgrowth
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 5-10mg 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. General 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.
5 PHARMACOLOGICAL PROPERTIES
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. Sulphamethoxazole competitively inhibits the utilisation of para-aminobenzoid acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme that converts dihydrofolate to tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Sulphamethoxazole and trimethoprim block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents. Both substances are employed in the treatment of bacterial infections.
Trimethoprim binds to plasmodial DHFR but less tightly than to the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.
Most common pathogenic bacteria are sensitive in vitro to trimethoprim and sulphamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must not be noted that satisfactory sensitivity testing is achieved only with the recommended media free from inhibitory substances especially thymidine and thymine.
5.2 Pharmacokinetic properties
After oral administration trimethoprim and sulphamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption.
Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose.
Trimethoprim is a weak base with pKa of 7.4. It is lopophilic. 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 concentration in the cerebro-spinal fluid are about one-half of those in the blood. The half-life is about 10 to 16 hours when renal function is normal. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10ml/minute. About 40 - 50% of a dose is excreted unchanged in the urine within 24 hours, together with metabolites. There appears to be no significant difference in the elderly compared with young patients. Trimethoprim appears in breast milk.
Sulphamethoxazole is a weak acid with pKa of 6.0. 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 50 pg 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. The concentration of active sulphamethoxazole in a variety of body fluids is of order of 20 to 50% of the plasma concentration. 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. There is no change in the half-life of active sulphamethoxazole with a reduction in renal function but the half-life of the major acetylated metabolite is increased when creatinine clearance is below 25ml/minute. In elderly patients, there clearance of sulphamethoxazole is reduced.
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 Preclinical safety data
None available
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Microcrystalline Cellulose BP Sta-Rx 1500 HSE (Pregelatinised Starch)
Starch BP Nipastat HSE
Hydrogenated Vegetable Oil HSE
Magnesium Stearate BP
Sodium Starch Glycollate (Primojel) BP
6.2 Incompatibilities
None known
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in a cool dry place.
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: 2, 4, 6, 8, 10, 14, 100, 250, 500 or 1000 tablets per blister pack/container. Not all pack sizes may be marketed
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited
3 Howard Road
Eaton Socon
St. Neots
Cambridgeshire
PE198ET
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0354
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/12/2008
10 DATE OF REVISION OF THE TEXT
30/01/2013