Drug Interactions between lomitapide and thioguanine

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.

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MONITOR: The concomitant or sequential use of other agents known to induce hepatotoxicity may potentiate the risk of liver injury associated with thioguanine. A high risk of liver toxicity characterized by vascular endothelial damage has been reported with long-term continuous use of thioguanine, particularly in children receiving the drug as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Histopathological features include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.

MANAGEMENT: The risk of hepatic injury should be considered when thioguanine is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Baseline and regular monitoring of hepatic function is recommended. Thioguanine therapy should be discontinued if there is evidence of toxic hepatitis or biliary stasis, as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal. Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported, but do not always occur.

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