Drug Interactions between lomitapide and ruxolitinib topical

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.

MONITOR CLOSELY: Smoking during treatment with topical ruxolitinib may increase the risk of major adverse cardiovascular events (MACE) and the risk of developing malignancies, including lymphomas. During clinical trials, patients who were current or past smokers and received oral Janus Kinase (JAK) inhibitors to treat inflammatory conditions had an additional increased risk of overall malignancies. Additionally, oral JAK inhibitors reportedly increase patients' risk of MACE, including cardiovascular death, myocardial infarction, and stroke, particularly in patients who are current or past smokers or patients with other cardiovascular risk factors.

MANAGEMENT: The potential risks and benefits of topical ruxolitinib should be carefully weighed prior to initiating therapy, particularly in patients with cardiovascular risk factors, as well as those with a history of malignancy, those who develop a malignancy while on treatment, and/or patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. The manufacturer recommends discontinuing topical ruxolitinib in patients who have experienced a myocardial infarction or stroke.