Fatalities, although rare, have occurred due to severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocystosis, aplastic anaemia and other blood dyscrasias. Sulfamethoxazole/trimethoprim should be discontinued if a skin rash appears. Clinical signs such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions.
Adverse reactions have been reported in approximately 5 to 7% of patients treated in the published literature. In general, the adverse reactions correspond to those of a sulfonamide of moderately low toxicity.
Nausea and vomiting are the most frequent gastrointestinal reactions to sulfamethoxazole/trimethoprim, but glossitis, stomatitis, abdominal pain, pancreatitis, pseudomembranous colitis and diarrhoea have also been reported.
Haematological changes have been observed in some patients, particularly the elderly. The majority of these changes were mild, asymptomatic and proved reversible on withdrawal of the drug. The reported changes consist primarily of neutropenia and thrombocytopenia. Leucopenia, eosinophilia, megaloblastic anaemia, methaemoglobinaemia, hypothrombinaemia, aplastic and haemolytic anaemia, purpura, agranulocytosis and bone marrow depression have been observed less frequently. Haematological toxicity may occur with increased frequency in folate depleted patients including geriatric, malnourished, alcoholic, pregnant or debilitated patients; in patients receiving anti-folates (e.g. phenytoin or methotrexate) or diuretics; in patients with haemolysis or impaired renal function; and in patients receiving sulfamethoxazole/trimethoprim in high dosages and/or for prolonged periods (e.g. longer than 6 months). In geriatric patients receiving some diuretics (principally thiazides) and sulfamethoxazole/trimethoprim concomitantly, an increased incidence of thrombocytopenia with purpura has been reported. The risk of leucopenia, neutropenia and thrombocytopenia also appear to be increased in patients with AIDS.
Several cases of Stevens-Johnson syndrome (erythema multiforme bullosa) and Lyell's syndrome (toxic epidermal necrolysis) have been reported. Together with exfoliative dermatitis, serum sickness and allergic myocarditis, these are the most severe allergic reactions reported with sulfonamides alone, or in combination with trimethoprim. Other reported allergic and anaphylactoid reactions include anaphylaxis, arthralgia, erythema multiforme, Schonlein-Henoch purpura, pruritus, urticaria, periorbital oedema, corneal ring infiltrates, conjunctival and scleral redness and oedema, and photosensitivity. Mild to moderate rashes, when they occur, usually appear within 7 to 14 days after initiation of sulfamethoxazole/trimethoprim. Rashes are generally erythematous, maculopapular, morbilliform, and/or pruritic. Generalised pustular dermatosis and fixed drug eruption have also been reported. Patients with AIDS appear to be at particular risk of developing rash (usually diffuse, erythematous and maculopapular) during sulfamethoxazole/trimethoprim therapy.
Hepatic changes (as indicated by abnormal elevations in alkaline phosphatase and serum transaminase levels) including hepatic necrosis have been reported rarely and may be fatal. Jaundice rarely occurs and has usually been mild and transient, frequently occurring in patients with a past history of infectious hepatitis. Elevation of bilirubin levels has also been reported.
Dysuria, oliguria, anuria, haematuria, urgency and functional kidney changes (as indicated by abnormal elevations in serum urea, serum creatinine and urine protein concentrations) have been reported occasionally. Renal failure, interstitial nephritis and toxic nephrosis have been reported. Crystalluria and stone formation have occurred in patients receiving sulfamethoxazole/trimethoprim. Diuresis has occurred rarely in patients receiving sulfonamides.
Central nervous system:
Adverse nervous system effects of sulfamethoxazole/trimethoprim include headache, insomnia, fatigue, apathy, nervousness, muscle weakness, ataxia, vertigo, tinnitus, peripheral neuritis, mental depression, aseptic meningitis, seizures and hallucinations. Tremor and other neurologic manifestations (e.g. ataxia, ankle clonus, apathy) developed during sulfamethoxazole/trimethoprim therapy in several patients with AIDS; although such manifestations have also been associated with the underlying disease process, they resolved in these patients within 2 to 3 days after discontinuing the drug.
Pain, local irritation, inflammation, and thrombophlebitis may occasionally occur with intravenous sulfamethoxazole/trimethoprim, especially if extravasation of the drug occurs.
Other adverse effects reported with sulfamethoxazole/ trimethoprim include drug fever, chills, myalgia, pulmonary infiltrates, cough, shortness of breath, hypotension, periarteritis nodosa and a positive lupus erythematous phenomenon. Vision problems, alopecia and epistaxis have been reported rarely.