Drug Interactions between Bethaprim Pediatric and Cerebyx

MONITOR CLOSELY: Coadministration with trimethoprim may increase the serum concentrations of phenytoin. The proposed mechanism is inhibition by trimethoprim of the CYP450 2C9-mediated metabolism of phenytoin. Although trimethoprim is primarily a CYP450 2C8 inhibitor, it may demonstrate some CYP450 2C9 inhibition at higher concentrations. Moreover, trimethoprim is frequently given in combination with sulfamethoxazole, which can also inhibit CYP450 2C9 as well as displace phenytoin from protein binding sites resulting in increased free concentrations of phenytoin. In one study, administration of a single intravenous dose of phenytoin to healthy volunteers receiving trimethoprim 320 mg/day for 7 days resulted in a 30% decrease in metabolic clearance and a 51% increase in the half-life of phenytoin. However, administration with sulfamethoxazole-trimethoprim (SMX-TMP) did not result in an increased magnitude of interaction, with phenytoin metabolic clearance decreasing by 27% and half-life increasing by 39%. Sulfamethoxazole alone produced a small but significant increase in phenytoin half-life without a corresponding fall in metabolic clearance. There have been isolated case reports describing symptoms of phenytoin toxicity following the concomitant use of SMX-TMP. In a population-based, case-control study of a cohort of Ontario (Canada) residents aged 66 years of age or older treated with phenytoin over a 17-year period, investigators reported a greater than twofold increase in the risk of phenytoin toxicity following a prescription of SMX-TMP among 796 case patients who had been hospitalized for phenytoin toxicity. No such risk was observed with amoxicillin. Concomitant use of phenytoin and SMX-TMP may also be associated with an increased risk of Stevens-Johnson syndrome (SJS). In a retrospective longitudinal study using SJS-related mortality cases between 1999 and 2008 from the National Health Insurance database in Taiwan, investigators reported that phenytoin and SMX-TMP were among various drug combinations that were administered one month before the patients' deaths. Finally, a case of acute fulminant hepatic failure resulting in death was reported in a 60-year-old woman who was treated with phenytoin and SMX-TMP. The patient was also receiving cimetidine, which may have contributed to increased phenytoin levels.

MANAGEMENT: Caution is advised when phenytoin is prescribed with trimethoprim or sulfamethoxazole-trimethoprim. Pharmacologic response and serum phenytoin levels should be monitored more closely whenever trimethoprim or SMX-TMP is added to or withdrawn from therapy, and the phenytoin dosage adjusted as necessary. Patients should be advised to notify their physician if they experience signs and symptoms of phenytoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, and changes in mental status. Alternative antibiotics should be considered in elderly patients treated with phenytoin when possible.

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MONITOR: Some sulfonamides may inhibit the hepatic metabolism of hydantoins. Serum hydantoin levels and risk of toxicity may be increased. Data are available for sulfadiazine, sulfaphenazole, and sulfamethizole.

MANAGEMENT: Monitoring for clinical and laboratory evidence of altered efficacy and safety is recommended. Hydantoin dosage adjustments or an alternate antimicrobial may be required if an interaction is suspected. Patients should be advised to notify their physician if they experience symptoms of hydantoin toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia).

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