Drug Interactions between mephenytoin and mipomersen

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of mipomersen. Mipomersen can cause elevations in serum transaminases and hepatic steatosis. In a premarketing clinical trial, 12% (4/34) of patients treated with mipomersen had at least one elevation in alanine aminotransferase (ALT) 3 times the upper limit of normal (ULN) or greater, and 9% (3/34) had at least one elevation in ALT 5 times ULN or greater, compared to 0% of the 17 patients treated with placebo. There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or partial thromboplastin time (PTT). Mipomersen also increases hepatic fat, with or without concomitant increases in transaminases. In clinical trials of patients with heterozygous familial hypercholesterolemia and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, from 0% at baseline, measured by magnetic resonance imaging. The long-term consequences of hepatic steatosis associated with mipomersen therapy are unknown. Hepatic steatosis may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.

MANAGEMENT: Since alcohol may increase levels of hepatic fat and induce or exacerbate liver injury, the manufacturer recommends that patients taking mipomersen not consume more than one alcoholic drink per day.

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ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

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