Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of sulfamethoxazole and trimethoprim injection with drugs that are substrates of CYP2C8 and 2C9 or OCT2.
Table 4: Drug Interactions with Sulfamethoxazole and trimethoprim injection
|Diuretics||Avoid concurrent use||In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.|
|Warfarin||Monitor prothrombin time and INR||It has been reported that sulfamethoxazole and trimethoprim injection 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 and trimethoprim injection is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.|
|Phenytoin||Monitor serum phenytoin levels||Sulfamethoxazole and trimethoprim injection may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Sulfamethoxazole and trimethoprim injection, 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.|
|Methotrexate||Avoid concurrent use||Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.|
|Cyclosporine||Avoid concurrent use||There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim injection and cyclosporine in renal transplant recipients.|
|Digoxin||Monitor serum digoxin levels||Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim injection therapy, especially in elderly patients|
|Indomethacin||Avoid concurrent use||Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin.|
|Pyrimethamine||Avoid concurrent use||Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim injection is prescribed.|
|Tricyclic Antidepressants (TCAs)||Monitor therapeutic response and adjust dose of TCA accordingly||The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim injection.|
|Oral hypoglycemics||Monitor blood glucose more frequently||Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim injection potentiates the effect of oral hypoglycemic that are metabolized 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.|
|Amantadine||Avoid concurrent use||In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole and trimethoprim injection and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported.|
|Angiotensin Converting Enzyme Inhibitors||Avoid concurrent use||In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole and trimethoprim injection and an angiotensin converting enzyme inhibitor.6,7|
|Zidovudine||Monitor for hematologic toxicity||Zidovudine and sulfamethoxazole and trimethoprim injection are known to induce hematological abnormalities. Hence, there is potential for an additive myelotoxicity when coadministered.8|
|Dofetilide||Concurrent administration is contraindicated||Elevated plasma concentrations of dofetilide have been reported following concurrent administration of trimethoprim and dofetilide. Increased plasma concentrations of dofetilide may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes.2,3|
|Procainamide||Closely monitor for clinical and ECG signs of procainamide toxicity and/or procainamide plasma concentration if available||Trimethoprim increases the plasma concentrations of procainamide and its active N-acetyl metabolite (NAPA) when trimethoprim and procainamide are coadministered. The increased procainamide and NAPA plasma concentrations that resulted from the pharmacokinetic interaction with trimethoprim are associated with further prolongation of the QTc interval.9|
Sulfamethoxazole and trimethoprim injection, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).
The presence of sulfamethoxazole and trimethoprim injection may also interfere with the Jaff¡SR alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.
Sulfamethoxazole and trimethoprim injection may cause fetal harm if administered to a pregnant woman. Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim injection during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot (see Human Data).
One of 3 rat studies showed cleft palate at doses approximately 5 times the recommended human dose on a body surface area basis; the other 2 studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately 6 times the human dose on a body surface area basis (see Animal Data).
The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Advise pregnant women of the potential harm of sulfamethoxazole and trimethoprim injection to the fetus (see Clinical Considerations).
Disease-associated Maternal and/or Embryo/Fetal Risk
Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to the pregnant woman. P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman. Sulfamethoxazole and trimethoprim injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
While there are no large, prospective, well-controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole and trimethoprim injection with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons.
Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole and trimethoprim injection exposure and specific malformations. Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.
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