Drug Interaction Report

MONITOR: Coadministration with an inhibitor of both CYP450 1A2 and 3A4 such as ciprofloxacin may significantly increase the plasma concentrations of erlotinib, which is a substrate of both isoenzymes. According to the product labeling, coadministration with ciprofloxacin increased erlotinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 17% and 39%, respectively, compared to administration of erlotinib alone.

MANAGEMENT: Caution is advised if erlotinib must be used with inhibitors of both CYP450 1A2 and 3A4. A dosage reduction or temporary interruption of therapy should be considered in patients who experience undue adverse effects of erlotinib such as severe diarrhea (i.e., that which is unresponsive to loperamide or results in dehydration), severe skin reactions, or severe liver function test abnormalities.

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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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GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of erlotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor that increased erlotinib systemic exposure (AUC) by 67%. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

GENERALLY AVOID: Cigarette smoking reduces erlotinib exposure due to induction of hepatic CYP450 1A2, one of the isoenzymes responsible for the metabolic clearance of erlotinib. Induction of CYP450 1A1 in the lungs may also contribute. In one pharmacokinetic study of healthy subjects given a single 150 mg dose of erlotinib, mean erlotinib peak plasma concentration (Cmax), systemic exposure (AUC) and plasma concentration at 24 hours were decreased by 35%, 64% and 88%, respectively, in current smokers compared to former/never smokers. Likewise, in a phase 3 non-small cell lung cancer (NSCLC) trial, the steady-state trough plasma concentrations of erlotinib in current smokers were approximately 2-fold less than in former/never smokers, accompanied by a 24% increase in apparent erlotinib plasma clearance. In a phase 1 dose-escalation study that analyzed the steady-state pharmacokinetics of erlotinib in current smokers with NSCLC, there was a dose-proportional increase in erlotinib exposure when the dose was increased from 150 mg to 300 mg, the maximum tolerated dose in the study population. Median steady-state trough plasma concentration at the 300 mg dose was approximately 3-fold higher than at the 150 mg dose. The clinical impact of smoking on erlotinib efficacy has not been studied.

ADJUST DOSING INTERVAL: Food enhances the oral absorption of erlotinib. According to the product labeling, administration with food increased the oral bioavailability of erlotinib from approximately 60% to almost 100% compared to administration in the fasting state.

MANAGEMENT: Consumption of grapefruit and grapefruit juice should be avoided or limited during treatment with erlotinib. Patients who currently smoke cigarettes are advised to stop smoking as soon as possible. If cigarette smoking is continued while taking erlotinib, the manufacturer recommends increasing the dosage of erlotinib by 50 mg increments at 2-week intervals up to a maximum of 300 mg as tolerated. However, the efficacy and long-term safety of dosages higher than 150 mg daily have not been established. Data from a double-blind, randomized phase 3 study (MO22162, CURRENTS) demonstrated no benefit in progression free survival or overall survival with an erlotinib dosage of 300 mg daily relative to the recommended dosage of 150 mg daily in active smokers (average of 38 pack years) with locally advanced or metastatic NSCLC who have failed chemotherapy, although patients in the study were not selected based on epidermal growth factor receptor (EGFR) mutation status. Safety data were comparable between the two dosages, but a numerical increase in the incidence of rash, interstitial lung disease and diarrhea was observed with the higher dosage. Patients who have received a dosage increase should immediately revert to the recommended dosage of 150 mg or 100 mg once daily (depending on indication) upon cessation of smoking. Erlotinib should be administered on an empty stomach at least one hour before or two hours after the ingestion of food.

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