Drug Interactions between IsonaRif and lomitapide

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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GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

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GENERALLY AVOID: Concurrent use of isoniazid (INH) in patients who ingest alcohol daily may result in an increased incidence of both hepatotoxicity and peripheral neuropathy. The increase in hepatotoxicity may be due to an additive risk as both alcohol and INH are individually associated with this adverse reaction. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of acetylation is genetically determined and generally classified as slow or rapid. Slow acetylators have been identified by some studies as having a higher risk of hepatotoxicity; therefore, this interaction may be more significant for patients who fall into this category. Other studies have postulated that alcohol-mediated CYP450 2E1 induction may play a role, as this isoenzyme is involved in INH metabolism and may be responsible for producing hepatotoxic metabolites. However, available literature is conflicting. The labeling for some INH products lists daily alcohol use or chronic alcoholism as a risk factor for hepatitis, but not all studies have found a significant association between alcohol use and INH-induced hepatotoxicity. Additionally, INH and alcohol are both associated with pyridoxine (B6) deficiency, which may increase the risk of peripheral neuropathy.

GENERALLY AVOID: Concomitant administration of isoniazid (INH) with foods containing tyramine and/or histamine may increase the risk of symptoms relating to tyramine- and/or histamine toxicity (e.g., headache, diaphoresis, flushing, palpitations, and hypotension). The proposed mechanism is INH-mediated inhibition of monoamine oxidase (MAO) and diamine oxidase (DAO), enzymes responsible for the metabolism of tyramine and histamine, respectively. Some authors have suggested that the reactions observed are mainly due to INH's effects on DAO instead of MAO or the amounts of histamine instead of tyramine present in the food. A Japanese case report recorded an example in 8 out of 25 patients on the tuberculosis ward who developed an accidental histamine poisoning after ingesting a fish paste (saury). Patients developed allergy-like symptoms, which started between 20 minutes and 2 hours after ingesting the food. A high-level of histamine (32 mg/100 g of fish) was confirmed in the saury paste and all 8 patients were both on INH and had reduced MAO concentrations. The 17 remaining patients were not on INH (n=5) or reported not eating the saury paste (n=12).

ADJUST DOSING INTERVAL: Administration with food significantly reduces oral isoniazid (INH) absorption, increasing the risk of therapeutic failure or resistance. The mechanism is unknown. Pharmacokinetic studies completed in both healthy volunteers (n=14) and tuberculosis patients (n=20 treatment-naive patients during days 1 to 3 of treatment) have resulted in almost doubling the time to reach INH's maximum concentration (tmax) and a reduction in isoniazid's maximum concentration (Cmax) of 42%-51% in patients who consumed high-fat or high-carbohydrate meals prior to INH treatment.

MANAGEMENT: The manufacturer of oral forms of isoniazid (INH) recommends administration on an empty stomach (i.e., 30 minutes before or 2 hours after meals). Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and INH concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with INH. Concomitant pyridoxine (B6) administration is also recommended to reduce the risk of peripheral neuropathy, with some authorities suggesting a dose of at least 10 mg/day. Patients should be advised to avoid foods containing tyramine (e.g., aged cheese, cured meats such as sausages and salami, fava beans, sauerkraut, soy sauce, beer, or red wine) or histamine (e.g., skipjack, tuna, mackerel, salmon) during treatment with isoniazid. Consultation of product labeling for combination products containing isoniazid and/or relevant guidelines may be helpful for more specific recommendations.

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