Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of buprenorphine, which is partially metabolized (approximately 30%) by the isoenzyme. The interaction appears to be dependent, in part, on the route of administration of buprenorphine. When administered transdermally, buprenorphine peak plasma concentration (Cmax) and systemic exposure (AUC) were not significantly affected by ketoconazole, a potent CYP450 3A4 inhibitor. However, it was reported in another study that ketoconazole increased the Cmax and AUC of buprenorphine (route unspecified) by approximately 70% and 50%, respectively, and to a lesser extent, of the metabolite norbuprenorphine. The interaction has also been reported with atazanavir/ritonavir. A case series describes three patients who experienced excessive opiate effects of buprenorphine during concomitant antiretroviral therapy with atazanavir, ritonavir, and various nucleoside reverse transcriptase inhibitors. Two of the patients had been on their antiretroviral regimen for several months and reported doped-up feeling, dizziness, and feeling high following initiation of buprenorphine 8 mg/day. The dosage was reduced to 8 mg every other day. One was maintained on this dosage while the other had dosage increased up to 12 mg/day, whereupon he developed hypersomnolence but managed to maintain that dosage. The third patient had been inducted with buprenorphine and titrated to a stable dose of 14 mg/day for two days prior to beginning antiretroviral therapy. The next day, the patient complained of daytime somnolence and decreased mental functioning. His buprenorphine dosage was decreased to 8 mg/day, and he developed tolerance to the sedative effects within 7 days.

MANAGEMENT: Caution is advised if buprenorphine is prescribed with CYP450 3A4 inhibitors. Induction with buprenorphine should begin at a reduced dosage, and dosage escalation should occur more slowly to allow for assessment of opiate effects and development of patient tolerance. In patients who are already stabilized on buprenorphine, pharmacologic response and vital signs should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the buprenorphine dosage adjusted as necessary. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities. Patients should seek medical attention if potential signs and symptoms of toxicity occur such as dizziness, confusion, fainting, extreme sedation, bradycardia, slow or difficult breathing, and shortness of breath.

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including buprenorphine. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

MANAGEMENT: Patients taking buprenorphine should not consume alcohol or use medications that contain alcohol on days of buprenorphine dosing. In general, potent narcotics such as buprenorphine should not be combined with alcohol.

ADJUST DOSING INTERVAL: Administration of lomitapide with food may increase the risk of common gastrointestinal adverse reactions such as diarrhea, nausea, vomiting, dyspepsia, abdominal pain or discomfort, abdominal distension, constipation, and flatulence. Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lomitapide. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Weak CYP450 3A4 inhibitors can increase lomitapide exposure (AUC) by approximately 2-fold according to the product labeling. Ketoconazole, a potent CYP450 3A4 inhibitor, has been shown to increase lomitapide AUC by 27-fold .

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of lomitapide. In a premarketing clinical trial, 34% (10/29) of patients treated with lomitapide had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times the upper limit of normal (ULN) or greater, and 14% (4/29) had at least one elevation in ALT or AST 5 times ULN or greater. There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase. Lomitapide also increases hepatic fat, with or without concomitant increases in transaminases. In the same study, the median absolute increase in hepatic fat was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy. Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with lomitapide, although the long-term consequences are unknown.

MANAGEMENT: Lomitapide should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal. Strict adherence to a low-fat diet (<20% of total calories from fat) and gradual dosage titration may also help to reduce gastrointestinal intolerance. Patients should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract during treatment with lomitapide. Since alcohol may increase levels of hepatic fat and induce or exacerbate liver injury, the manufacturer recommends that patients taking lomitapide not consume more than one alcoholic drink per day.