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MEDITRIM T TABLETS
MEDITRIM S SUSPENSION

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

MEDITRIM T TABLETS
MEDITRIM S SUSPENSION

COMPOSITION:

Each tablet contains:	Trimethoprim	80 mg
	Sulphamethoxazole	400 mg
	Nipastat (as preservative)	0,025% m/m
Each 5 mL of suspension contains:	Trimethoprim	40 mg
	Sulphamethoxazole	200 mg
	Nipastat (as preservative)	0,3% m/m
	(Contains alcohol 1,5% m/v)

PHARMACOLOGICAL CLASSIFICATION:
A 20.2 Antimicrobial (Chemotherapeutic) agents other than antibiotics.

PHARMACOLOGICAL ACTION:
MEDITRIM is a combination of trimethoprim and sulphamethoxazole and results in synergistic effects causing a bactericidal action. The action of co-trimoxazole is achieved by the sequential blocking of two enzymes essential in folinic acid synthesis in the organism.

INDICATIONS:
Infections caused by sensitive organisms of the upper and lower respiratory tract, the urinary tract and alimentary and genital tract in both sexes, and skin infections.

CONTRA-INDICATIONS:
Patients with known sulphonamide or trimethoprim hypersensitivity or who are suffering from porphyria. It should not be used in patients suffering from liver parenchymal damage, or a severe renal insufficiency. Co-trimoxazole should not be used during pregnancy or by lactating woman. Use of the substance in premature or new-born infants as well as during the first two months of life, is contra-indicated.
Contra-indicated in the presence of vitamin B12 and folic acid deficiency states. Should not be given to patients with megaloblastic anaemia or blood dyscrasia or in patients receiving anticonvulsant medicines.
Trimethoprim should not usually be given to patients with serious haematological disorders and particularly not in megaloblastic anaemia secondary to folate depletion.

WARNINGS:
Erythema multiforme, toxic dermal necrolysis or allergic vasculitis may occur. Treatment should be discontinued immediately when a rash appears because of the danger of severe allergic reactions.
A high incidence of side-effects occurs in immunocompromised patients such as those suffering from AIDS or patients receiving immunosuppressive therapy. The adverse effects include skin rash, recurrent fever, neutropenia, thrombocytopenia and raised liver enzyme values.

DOSAGE AND DIRECTIONS FOR USE:
Adults and children under 12 years:        two tablets every 12 hours.

Infants:	8 weeks to 5 months.	Half medicine measureful (2,5 mL) every 12 hours.
Children:	6 months to 5 years.	1 medicine measureful (5 mL) every 12 hours.
	6 years to 12 years.	2 medicine measureful (10 mL) every 12 hours

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Gastro-intestinal disturbances (nausea & vomiting mainly, as well as anorexia, diarrhoea and sore mouth) and skin reactions are the most common adverse effects. Reactions involving the skin may include rashes, pruritus, photosensitivity reactions, exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome), and erythema nodosum. A severe, potentially fatal, form of erythema multiforme, associated with widespread lesions of the skin and mucus membranes, termed the Stevens-Johnson syndrome has occurred. Dermatitis may occur on contact of sulphonamides with the skin. Systemic lupus erythematosus, particularly exacerbations of pre-existing disease, has also been reported.
Fever is relatively common but occasionally hypersensitivity reactions may be severe and manifest as anaphylaxis.
There have been occasional deaths especially in elderly patients, mainly due to blood dyscrasias or severe skin reactions. A high incidence of adverse effects has been reported in AIDS patients, desensitisation may sometimes be considered.
Trimethoprim: Disturbances of liver enzyme values and cholestatic jaundice have been associated with trimethoprim. Rises in serum creatinine and blood-urea nitrogen have been reported although it is unclear whether this represents genuine renal dysfunction or inhibition of tubular secretion of creatinine.
Cases of aseptic meningitis have also been reported.
Trimethoprim may cause a depression of haemopoiesis due to interference of the medicine in the metabolism of folic acid, particularly when given over a prolonged period or in high doses. This may manifest as megaloblastic anaemia, or as thrombocytopenia and leucopenia; methaemoglobinaemia has also been seen. Calcium folinate 5 to 15 mg daily by mouth may be given to counter this effect. Trimethoprim is teratogenic in animals.
Sulphamethoxazole: Nephrotoxic reactions including interstitial nephritis and tubular necrosis, which may result in renal failure, have been attributed to hypersensitivity to sulphamethoxazole. Lumbar pain, haematuria, oliguria, and anuria may also occur due to crystallisation in the urine of sulphamethoxazole or its less soluble acetylated metabolite. The risk of crystalluria can be reduced by the administration of fluids to maintain a high urine output. If necessary, alkalinisation of the urine by administration of sodium bicarbonate may increase solubility and aid the elimination of sulphonamides.
Blood disorders have occurred during treatment with the sulphonamides including sulphamethoxazole, and include agranulocytosis, aplastic anaemia, thrombocytopenia, leucopenia, hypoprothombinaemia, and eosinophilia. Many of these effects on the blood may result from hypersensitivity reactions. Acute haemolytic anaemia is a rare complication which may be associated with glucose-6-phosphate dehydrogenase deficiency.
Other adverse effects which may be manifestations of a generalised hypersensitivity reaction to sulphonamides include a syndrome resembling serum sickness, liver necrosis, hepatomegaly and jaundice, myocarditis, pulmonary eosinophilia and fibrosing alveolitis, and vasculitis including polyarteritis nodosa.
Sulphonamides may rarely cause cyanosis due to methaemoglobinaemia.
Other adverse effects which may be manifestations of a generalised hypersensitivity reaction to sulphonamides include a syndrome resembling serum sickness, liver necrosis, hepatomegaly and jaundice, myocarditis, pulmonary eosinophilia and fibrosing alveolitis, and vasculitis including polyarteritis nodosa.
Other adverse reactions that has been reported after the administration of sulphamethoxazole or other sulphonamides include hypoglycaemia, hypothyroidism, neurological reactions including aseptic meningitis, ataxia, benign intracranial hypertension, convulsions, dizziness, drowsiness, fatigue, headache, insomnia, mental depression, peripheral or optic neuropathies, psychoses, and vertigo, and pancreatitis. Sulphonamides may displace serum bound bilirubin resulting in jaundice and kernicterus in premature neonates.
Sulphamethoxazole may cause alterations of the bacterial flora in the gastro-intestinal tract. There is, therefore, the possibility, although it appears to be small that pseudomembranous colitis may occur. Slower acetylators of sulphamethoxazole may be at greater risk of adverse reactions than fast acetylators.
Precautions:
See Contra-indications and Warnings. MEDITRIM should be used with caution in patients with hepatic impairment. MEDITRIM should be used with caution in impaired renal function, and dosage adjustment may be necessary. An adequate fluid intake should be maintained to reduce the risk of crystalluria, but alkalinisation of the urine, although it increases urinary excretion of the sulphamethoxazole component, decreases urinary trimethoprim excretion. Regular blood counts and urinalysis and renal function tests should be carried out in patients receiving prolonged treatment with MEDITRIM. Elderly patients may be more susceptible to adverse effects. Folate supplementation may be necessary in patients predisposed to folate deficiency, such as elderly patients and when high doses of MEDITRIM are given for a prolonged period.
Treatment with MEDITRIM should be discontinued immediately a rash appears because of the danger of severe allergic reactions such as the Stevens-Johnson syndrome. Elderly patients may be more susceptible to adverse effects and a lower dosage may be advisable.
Trimethoprim may increase serum concentrations and potentiate the effect of a number of medicines, including phenytoin, digoxin, and procainamide. The effect may be due to competitive inhibition of renal excretion, decreased metabolism, or both. It has been suggested that trimethoprim may potentiate the effects of warfarin by stereoselective inhibition of warfarin metabolism. Trimethoprim has been reported to reduce the renal excretion of zidovudine. Trimethoprim and dapsone increase each others serum concentrations when given concomitantly, whereas rifampicin may decreased trimethoprim concentrations.
An increased risk of nephrotoxicity has been reported with the use of trimethoprim or co-trimoxazole and cyclosporin. Intravenous administration of trimethoprim and sulphonamides may reduce cyclosporin concentrations in blood. In patients given trimethoprim who were also receiving diuretics hypernatraemia has been reported (an increased risk of thrombocytopenia has been seen in elderly patients given co-trimoxazole with diuretics, although it is unclear which component is responsible).
Administration of trimethoprim with other depressants of bone marrow function may increase the likelihood of myelosuppression and there may be a particular risk of megaloblastic anaemia if it is given with other folate inhibitors such as pyrimethamine or methotrexate.
Trimethoprim may interfere with some diagnostic tests including serum methotrexate assay where dihydrofolate reductase is used, and the Jaffé reaction for creatinine.
Sulphamethoxazole The administration of components which render the urine acid may increase the risk of crystalluria as may the concomitant administration of paraldehyde or hexamine: the risk may be reduced with alkaline urine.
Care is generally advised in patients with the history of allergy or asthma.
Sulphamethoxazole should not be given to patients with acute porphyria (see Contra-indications) it may cause exacerbations of the disease and some authorities considered it contra indicated in lupus erythematosus for similar reasons. Patients with glucose-6-phosphate dehydrogenase deficiency may be at risk of haemolytic reactions.
Sulphamethoxazole should not be given to infants within 1 to 2 months of birth because of the risk of producing kernicterus; for the same reason, it is contradicted in woman prior to delivery or in nursing mothers. (see Contra-indications)
Sulphamethoxazole and other sulphonamides may potentiate the effects of some medicines, such as oral anticoagulants, methotrexate, and phenytoin: this may be due to displacement of the medicine from plasma protein binding sites or to inhibition of metabolism. However, the clinical significance of these interactions appears to depend on the particular sulphonamide involved. The possibility of interactions with other highly protein-bound medicines such as nonsteroidal anti-inflammatory agents should be considered.
High doses of sulphonamides have been reported to have a hypoglycaemic effect: the antidiabetic effect of the sulphonylurea compounds may be enhanced by the concomitant administration of sulphonamides.
The action of sulphonamides may be antagonised by p-aminobenzoic acid and compounds derived from it, particularly the procaine group of local anaesthetics.
Sulphonamides have been reported to interfere with some diagnostic tests including those for urea, creatinine and urinary glucose and urobilinogen.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Nausea, vomiting, cyanosis, haematuria, oliguria or anuria and allergic skin reactions (skin rashes, anaphylaxis, etc.) If megaloblastic changes occur, folinic acid must be given.
Treatment is supportive and symptomatic.

IDENTIFICATION:

Tablets:	White, round flat, bisected tablets 12,8 mm in diameter.
Suspension:	White suspension, with an aniseed odour and sweet tasting with a slightly better after taste.

Please note the suspension does contain a small quantity of alcohol.

PRESENTATION:

Tablets:	In white polypropylene containers of 1000 tablets.
Suspension:	PVC Bottles of 50 mL, 100 mL and 500 mL.

STORAGE INSTRUCTIONS:
Store in a cool, dry place, below 25°C. Protect from heat and light. Keep well closed.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:

Tablets:	33/20.2/0039
Suspension:	33/20.2/0040

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
IMPILO DRUGS (PTY) LTD
9 Green Street
ISITHEBE

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
June 2003

        PME 0261/06-03
        Pro-Print

New addition to this site: March 2004
Source: Pharmaceutical Industry
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