Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may decrease the plasma concentrations of voclosporin, which is primarily metabolized by the isoenzyme. Drug interaction studies showed that coadministration with potent CYP450 3A4 inducer rifampin (600 mg once daily for 10 days) reduced the peak plasma concentration (Cmax) and systemic exposure (AUC) by 68% and 87%, respectively. In addition, coadministration with moderate CYP450 3A4 inducer efavirenz is predicted to reduce the Cmax and the AUC 0-12h by 61% and 70%, respectively.

MONITOR CLOSELY: Voclosporin may cause dose-related prolongation of the QT interval in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. A randomized, placebo- and active-controlled (moxifloxacin 400 mg), single dose, parallel study reported that a single dose of voclosporin (given in a dose range from 0.5 mg/kg to 4.5 mg/kg) led to a dose-dependent QTcF prolongation, with maximum mean placebo-adjusted changes from baseline ranging from 6.4 msec (0.5 mg/kg) to 34.6 msec (4.5 mg/kg). A randomized, placebo-controlled, crossover study in healthy subjects (n=31) taking voclosporin 0.3 mg/kg, 0.5 mg/kg, and 1.5 mg/kg twice daily for 7 days did not detect QT prolongation greater than 20 msec. In addition, in phase 2 and 3 clinical trials (n= 355), investigators observed no prolongation of the QT interval in the placebo group, 2 patients in the voclosporin 23.7 mg twice daily group, and one patient in the voclosporin 39.5 mg twice daily group. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concomitant use of voclosporin with potent or moderate CYP450 3A4 inducers should generally be avoided.

GENERALLY AVOID: Coadministration of tenofovir with other nephrotoxic agents may increase the risk of renal impairment due to additive effects on the kidney. Additionally, renal impairment secondary to the use of these agents may reduce the clearance of tenofovir, which is primarily eliminated by a combination of glomerular filtration and active tubular secretion. The use of tenofovir has been associated with dose-related nephrotoxicity including acute renal failure and Fanconi syndrome characterized by renal tubular injury with severe hypophosphatemia, possibly as a result of mitochondrial toxicity. Cases of acute renal failure after initiation of high-dose or multiple nonsteroidal anti-inflammatory agents have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir therapy. Some patients required hospitalization and renal replacement therapy. Available clinical data seem to suggest a lower risk of nephrotoxicity with tenofovir alafenamide fumarate (TAF) than with tenofovir disoproxil fumarate (TDF), presumably due to lower tenofovir systemic exposure following administration of TAF relative to TDF. Whereas TDF is metabolized in plasma to tenofovir and phosphorylated intracellularly to the active moiety tenofovir diphosphate, TAF is largely metabolized and phosphorylated intracellularly, resulting in substantially higher intracellular concentrations of tenofovir diphosphate and lower plasma levels of tenofovir at the therapeutic dose of 25 mg compared to TDF 300 mg. It has been further reported that tenofovir is actively transported into the proximal renal tubular cell by organic anion transporters (OAT) 1 and 3, but that TAF is not a substrate for these transporters and thus less likely to cause tubular injury. There have been no cases of Fanconi syndrome or proximal renal tubulopathy in clinical trials of various TAF-containing products according to the manufacturers.

MANAGEMENT: The use of tenofovir in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral agents such as acyclovir, adefovir, cidofovir, foscarnet, and ganciclovir; antineoplastics such as aldesleukin, cisplatin, clofarabine, ifosfamide, streptozocin, and high intravenous dosages of methotrexate; chelating agents such as deferasirox, deferoxamine, edetate disodium, and edetate calcium disodium; immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus; intravenous bisphosphonates; intravenous pentamidine; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents; gallium nitrate; lithium; penicillamine) should be avoided if possible. Renal function tests including serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein should be performed prior to and during therapy with tenofovir. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

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.

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: Coadministration with grapefruit juice may increase the plasma concentrations of voclosporin. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because voclosporin prolongs the QT interval in a dose-dependent manner, high plasma levels of voclosporin may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In drug interaction studies, coadministration with multiple doses of moderate CYP450 3A4 inhibitors fluconazole or diltiazem is predicted to increase the peak plasma concentration (Cmax) and the area under the 12-hour plasma concentration-time curve (AUC 0-12) of voclosporin by approximately 2- and 3-fold respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In addition, moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using voclosporin, which has been reported with the use of voclosporin. Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

ADJUST DOSING INTERVAL: Consumption of food can decrease the rate and extent of gastrointestinal absorption of voclosporin. When administered with either low- or high-fat meals, the peak plasma concentration (Cmax) of voclosporin decreased by 29% to 53% and systemic exposure (AUC) decreased by 15% to 25%.

MANAGEMENT: Patients receiving voclosporin therapy should be advised to avoid consumption of grapefruit or grapefruit juice. Voclosporin therapy should be administered at least 1 hour before or 2 hours after meals. Patients should also receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their doctor. If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended. Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs.

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.