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Hypersensitivity and allergic reactions: DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low; such sensitivity appears to occur more frequently in asthmatic than in non-asthmatic individuals.
Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. Pulmonary infiltrates reported in the context of eosinophilic or allergic alveolitis may manifest through symptoms such as cough or shortness of breath. Should such symptoms appear or unexpectedly worsen, the patient should be re-evaluated and discontinuation of sulfamethoxazole/trimethoprim therapy considered.
Severe cutaneous adverse reactions: Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP) and drug reaction with eosinophilia with systemic symptoms (DRESS) have been reported with the use of sulfamethoxazole/trimethoprim.
Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.
If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or mucosal lesions), AGEP or DRESS (e.g. fever, eosinophilia) are present, DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg treatment should be discontinued immediately (see Adverse Reactions) and an alternative treatment should be considered.
The best results in managing SJS, TEN or DRESS come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
If the patient has developed SJS, TEN or DRESS with the use of DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg, DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg must not be re-started in this patient at any time.
At the start of treatment, the occurrence of a generalised febrile erythema associated with pustules, should raise the suspicion of AGEP (see Adverse Reactions); it requires cessation of treatment and contraindicates any new administration of DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg alone or in combination with other drugs.
Haemophagocytic lymphohistiocytosis (HLH): Cases of HLH have been reported very rarely in patients treated with sulfamethoxazole/trimethoprim. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, sulfamethoxazole/trimethoprim treatment should be discontinued.
Respiratory tract: Cough, shortness of breath, and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract have been reported in association with trimethoprim sulfamethoxazole treatment.
Other severe pulmonary adverse reactions occurring within days to week of trimethoprim sulfamethoxazole initiation and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), lung transplantation or death have also been reported in patients and otherwise healthy individuals treated with trimethoprim-sulfamethoxazole products.
Respiratory toxicity: Very rare, severe cases of respiratory toxicity, sometimes progressing to Acute Respiratory Distress Syndrome (ARDS), have been reported during co-trimoxazole treatment. The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function may be preliminary signs of ARDS. In such circumstances, cotrimoxazole should be discontinued and appropriate treatment given.
Circulatory shock: Circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with trimethoprim-sulfamethoxazole in patients with history of recent (days to weeks) exposure to sulfamethoxazole-trimethoprim.
Acute respiratory failure including acute eosinophilic pneumonia has been reported in healthy adolescents with sulfamethoxazole/trimethoprim treatment.
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.
Thrombocytopenia: Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim.
Streptococcal infections and rheumatic fever: The sulfonamides should not be used for the treatment of group A beta-haemolytic streptococcal infections (see Contraindications). In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.
Use in treatment of "Pneumocystis carinii" pneumonitis in patients with Acquired Immunodeficiency Syndrome (AIDS): Because of their unique immune dysfunction, AIDS patients may not tolerate or respond to sulfamethoxazole/trimethoprim in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, neutropenia, thrombocytopenia, raised liver enzymes and leucopenia necessitating cessation of therapy, with sulfamethoxazole/trimethoprim therapy in AIDS patients who are being treated for Pneumocystis carinii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of sulfamethoxazole/trimethoprim in non-AIDS patients. Such adverse effects have occurred in up to 80% of AIDS patients receiving the drug, usually during the second week of therapy. The exact mechanism(s) of this increased risk of sulfamethoxazole/trimethoprim toxicity has not been determined, but may be immunologically based. These adverse effects usually recur following rechallenge with the drug, although cautious desensitisation has been performed successfully in some patients in whom continued sulfamethoxazole/trimethoprim therapy was considered necessary. Some evidence indicates that sulfamethoxazole/trimethoprim may be better tolerated in HIV infected children than adults. Adverse effects are usually less severe in patients receiving the drug for prophylaxis of Pneumocystis carinii pneumonia compared with those receiving sulfamethoxazole/trimethoprim for treatment of the disease.
Adjunctive treatment with leucovorin for Pneumocystis jirovecii pneumonia: Treatment failure and excess mortality were observed when sulfamethoxazole/trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia in a randomized placebo-controlled trial. Co-administration of sulfamethoxazole/trimethoprim and leucovorin during treatment of Pneumocystis jirovecii pneumonia should be avoided.
Use in glucose-6-phosphate dehydrogenase deficiency: In individuals with glucose-6-phosphate dehydrogenase deficiency, haemolysis may occur. This is frequently dose-related.
Clostridiodes difficile associated diarrhoea (CDAD): Clostridiodes difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy).
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement, antibiotic treatment of C. difficile, and surgical evaluation should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.
Hypoglycaemia: Cases of hypoglycaemia in non-diabetic patients treated with sulfamethoxazole/trimethoprim have been reported, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole/trimethoprim are particularly at risk.
Electrolyte abnormalities: Close monitoring of serum potassium and renal function is warranted in patients receiving high-dose sulfamethoxazole/trimethoprim, as used in patients with Pneumocystis jirovecii pneumonia, or in patients receiving standard-dose sulfamethoxazole/trimethoprim with underlying disorders of potassium metabolism or renal insufficiency, or who are receiving drugs which induce hyperkalaemia (see Interactions). Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole/trimethoprim, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.
Patients who are "slow acetylators" may be more prone to idiosyncratic reactions to sulfonamides.
Monitoring: Complete blood counts should be done frequently in patients receiving sulfamethoxazole/trimethoprim; if a significant reduction in the count of any formed blood element is noted, sulfamethoxazole/trimethoprim should be discontinued.
Folate deficiency: Because of the possible interference with folate metabolism, regular blood counts are advisable in patients on long term therapy, in those who are pre-disposed to folate deficiency (i.e. the elderly, chronic alcoholics and those with rheumatoid arthritis), in malabsorption syndromes, malnutrition states or during the treatment of epilepsy with anticonvulsant drugs such as phenytoin, primidone and barbiturates. Folic acid may be administered during sulfamethoxazole/trimethoprim therapy and will not interfere with the drugs' antibacterial effect. Megaloblastic anaemia and occasionally neutropenia and thrombocytopenia may be reversed by administration of calcium leucovorin (folinic acid). If signs of bone marrow suppression occur in patients receiving sulfamethoxazole/trimethoprim, leucovorin may be administered.
Phenylalanine metabolism: Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.
Porphyria and hypothyroidism: As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.
Use in renal impairment: In renal impairment, a reduced or less frequent dosage is recommended in order to avoid accumulation of trimethoprim in the blood. Non-ionic diffusion is the main factor in the renal handling of trimethoprim, and as renal failure advances, trimethoprim excretion decreases. For such patients, serum assays are necessary.
Patients with severe renal impairment who are receiving sulfamethoxazole/trimethoprim should be closely monitored for symptoms and signs of toxicity such as nausea, vomiting and hyperkalaemia. Sulfamethoxazole/trimethoprim should be given with caution to patients with impaired renal function and to those with underlying disorders such as: possible folate deficiency; hypoglycaemia; electrolyte abnormalities (hyperkalaemia).
Urinalysis with careful microscopic examination and renal function tests should be performed frequently, particularly for those patients with impaired renal function. Adequate fluid intake and urinary output must be maintained in order to prevent crystalluria and stone formation. In patients with renal impairment, a reduced or less frequent dosage is recommended to avoid accumulation of trimethoprim in the blood.
Effects on laboratory tests: Two laboratory procedures, namely the Lactobacillus casei serum folate assay and the L. leishmanii serum vitamin B12 assay are affected by sulfamethoxazole/trimethoprim.
Sulfamethoxazole/trimethoprim, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay.
The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% of the range of normal values.
Other: As with other sulfonamide preparations, critical appraisal of benefit versus risk should be made in patients with liver damage, renal damage, urinary obstruction, blood dyscrasias, allergies or bronchial asthma.
The possibility of superinfection with a non-sensitive organism should be borne in mind.
Effects on Ability to Drive and Use Machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in Children: See Dosage & Administration and Contraindications.
Use in the Elderly: The use of sulfamethoxazole/trimethoprim in elderly patients carries an increased risk of severe adverse reactions. In rare instances fatalities have occurred. The risk of severe adverse reactions is particularly greater when complicating conditions exist, e.g. impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, or generalised bone marrow suppression (see Adverse Reactions) or a specific decrease in platelets (with or without purpura), and hyperkalaemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant sulfamethoxazole/trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Haematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimise risks of undesired reactions (see Dosage & Administration). The trimethoprim component of DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg treatment is recommended to help lower potassium serum levels.
In view of the increased risk of severe adverse reactions in the elderly, consideration should be given to whether sulfamethoxazole/trimethoprim is the antibacterial of choice in this age group.
