Drug Interaction Report

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (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; other HIV 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. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

GENERALLY AVOID: Patients exposed to photosensitizing agents at the same time as or in the 30 to 90 days following treatment with porfimer may be at an increased risk of a photosensitivity reaction (e.g., erythema, swelling, pruritus, burning sensations, feeling hot, and/or blisters). These agents have each been individually associated with photosensitivity reactions and may have additive effects if used together. Medicinal products with known phototoxic or photoallergic potential include, but are not limited to, hypericin-containing products (e.g., St. John's Wort), griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides, quinolones, and tetracyclines. Photosensitivity with porfimer is due to residual drug being present in the skin. Porfimer is cleared from a variety of tissues over 40 to 72 hours after treatment, but organs of the reticuloendothelial system (e.g., liver, spleen), skin and the tumor itself retain the drug for a longer period. Patients treated with porfimer will be photosensitive for at least 30 days and possibly up to 90 days or more for patients with hepatic or severe renal dysfunction. In clinical studies of porfimer, photosensitivity reactions occurred in approximately 20% of cancer patients and 69% of high-grade dysplasia in Barrett's esophagus patients.

MANAGEMENT: Use of photosensitizing agents should be avoided for at least 30 days and maybe up to 90 days or longer after porfimer treatment depending on the patient's hepatic function, renal function, and/or ability to tolerate exposure to sunlight. Following treatment with porfimer, patients should follow measures outlined in the product labeling for light and sun exposure. It is important to counsel patients to expose their skin to ambient indoor light as it is not only safe but will help eliminate porfimer through the skin by a process called "photobleaching." Before exposing skin or eyes to direct sunlight or bright indoor light (e.g., examination lamps, dental lamps, operating room lamps, floodlights, halogen lamps, unshaded light bulbs at close proximity, etc.), patients should test for residual photosensitivity as described in porfimer's product labeling.

GENERALLY AVOID: Patients exposed to photosensitizing agents at the same time as or in the 30 to 90 days following treatment with porfimer may be at an increased risk of a photosensitivity reaction (e.g., erythema, swelling, pruritus, burning sensations, feeling hot, and/or blisters). These agents have each been individually associated with photosensitivity reactions and may have additive effects if used together. Medicinal products with known phototoxic or photoallergic potential include, but are not limited to, hypericin-containing products (e.g., St. John's Wort), griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides, quinolones, and tetracyclines. Photosensitivity with porfimer is due to residual drug being present in the skin. Porfimer is cleared from a variety of tissues over 40 to 72 hours after treatment, but organs of the reticuloendothelial system (e.g., liver, spleen), skin and the tumor itself retain the drug for a longer period. Patients treated with porfimer will be photosensitive for at least 30 days and possibly up to 90 days or more for patients with hepatic or severe renal dysfunction. In clinical studies of porfimer, photosensitivity reactions occurred in approximately 20% of cancer patients and 69% of high-grade dysplasia in Barrett's esophagus patients.

MANAGEMENT: Use of photosensitizing agents should be avoided for at least 30 days and maybe up to 90 days or longer after porfimer treatment depending on the patient's hepatic function, renal function, and/or ability to tolerate exposure to sunlight. Following treatment with porfimer, patients should follow measures outlined in the product labeling for light and sun exposure. It is important to counsel patients to expose their skin to ambient indoor light as it is not only safe but will help eliminate porfimer through the skin by a process called "photobleaching." Before exposing skin or eyes to direct sunlight or bright indoor light (e.g., examination lamps, dental lamps, operating room lamps, floodlights, halogen lamps, unshaded light bulbs at close proximity, etc.), patients should test for residual photosensitivity as described in porfimer's product labeling.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (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; other HIV 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. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

ADJUST DOSING INTERVAL: Administration with food increases the plasma concentrations of efavirenz and may increase the frequency of adverse reactions. According to the product labeling, administration of efavirenz capsules (600 mg single dose) with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with mean increases of 39% and 51% in efavirenz peak plasma concentration (Cmax) and 22% and 17% in systemic exposure (AUC), respectively, compared to administration under fasted conditions. For efavirenz tablets, administration of a single 600 mg dose with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) resulted in a 79% increase in mean Cmax and a 28% increase in mean AUC of efavirenz relative to administration under fasted conditions.

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of efavirenz. 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: Efavirenz should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms such as dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations, although they often resolve on their own after the first 2 to 4 weeks of therapy . Patients should be advised of the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs, and to avoid driving or operating hazardous machinery until they know how the medication affects them.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.