DBL Sulfamethoxazole & Trimethoprim Drug Interactions

Methotrexate: Sulfonamides such as sulfamethoxazole may displace methotrexate from protein binding sites, thereby increasing free methotrexate levels. Cases of pancytopenia have been reported in patients taking the combination of sulfamethoxazole/trimethoprim and methotrexate.
Para-aminobenzoic acid (PABA) or its derivatives: May antagonise the antibacterial effects of sulfamethoxazole.
Warfarin/anticoagulants: Anticoagulant activity may be increased by concurrent treatment with sulfamethoxazole/trimethoprim. It has been reported that sulfamethoxazole/trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when sulfamethoxazole/trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.
Phenytoin: Increased effects and side effects of phenytoin (folate deficiencies) could occur when sulfamethoxazole/trimethoprim is given concurrently. Sulfamethoxazole/trimethoprim may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Oral sulfamethoxazole/trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
Sulphonylureas: Concomitant use may result in potentiation of hypoglycaemia in occasional patients.
Diuretics: An increased incidence of thrombocytopenia is reported when this combination is used in the elderly.
Cyclosporin: Deterioration in renal function in patients with renal transplants. There have been reports of marked but reversible nephrotoxicity with co-administration of sulfamethoxazole/trimethoprim and ciclosporin in renal transplant recipients.
Pyrimethamine: Occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia should sulfamethoxazole/trimethoprim be prescribed concurrently.
Digoxin: Concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients. Serum digoxin levels should be monitored.
Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing diuretics, prednisolone: Due to the potassium sparing effects of sulfamethoxazole/trimethoprim, caution should be used when other agents that increase serum potassium, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing diuretics and prednisolone, are co-administered (see Precautions). In the literature, two cases of hyperkalaemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.
Tricyclic antidepressants: The efficacy of tricyclic antidepressants can decrease when co-administered with sulfamethoxazole/trimethoprim.
Increased sulfamethoxazole blood levels: may occur in patients who are also receiving urinary acidifiers, oral anticoagulants, phenylbutazone, oxyphenbutazone and indomethacin.
Cross sensitisation: may exist between sulfamethoxazole/trimethoprim and some antithyroid agents, diuretics (acetazolamide and the thiazides) and oral hypoglycaemic drugs. Trimethoprim is an inhibitor of CYP2C8 as well as an OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP is co-administered with drugs that are substrates of CYP2C8 and 2C9 or OCT2. Sulfamethoxazole/trimethoprim potentiates the effect of oral hypoglycaemics that are metabolised by CYP2C8 (e.g. pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g. glipizide and glyburide) or eliminated renally via OCT2 (e.g. metformin). Additional monitoring of blood glucose may be warranted.
In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported.
Others: When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.