Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and levoketoconazole

GENERALLY AVOID: Coadministration with strong CYP450 3A4 inhibitors may increase systemic exposure (AUC) of levoketoconazole and increase the risk of possibly life-threatening adverse reactions such as hepatotoxicity and QT prolongation. The mechanism is inhibition of CYP450 3A4 metabolism. Levoketoconazole is a strong CYP450 3A4 inhibitor and a substrate of the isoenzyme, and may increase systemic exposure of other CYP450 3A4 substrates. There are no data about the interaction between strong CYP450 3A4 inhibitors and levoketoconazole. However, there is data for ketoconazole, of which levoketoconazole is an enantiomer. In 12 study subjects, administration of ketoconazole (200 mg orally daily for 7 days) with the strong CYP450 3A4 inhibitor ritonavir (500 mg orally twice a day for 10 days) increased mean ketoconazole peak plasma concentration (Cmax) by 55% and AUC by nearly 250% compared to ketoconazole administered alone. Ritonavir also increased the mean half-life of ketoconazole from 2.7 to 13.2 hours. Conversely, ritonavir Cmax and AUC increased by just 10% and 18%, respectively, in the presence of ketoconazole. A published study involving 12 HIV-infected subjects supported the modest effect of ketoconazole on plasma ritonavir levels. However, cerebrospinal fluid (CSF) ritonavir levels were increased by 178%, which is thought to be due primarily to ketoconazole inhibition of CSF-to-plasma active transport systems (e.g., P-glycoprotein) and secondarily to decreased systemic clearance of ritonavir.

MANAGEMENT: Coadministration of strong CYP450 3A4 inhibitors such as ritonavir, ritonavir-boosted darunavir, ritonavir boosted fosamprenavir, saquinavir, or mifepristone is not recommended. These drugs should be avoided from 2 weeks before and during treatment with levoketoconazole.

CONTRAINDICATED: Levoketoconazole can cause concentration-dependent, life-threatening prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death. According to cardiac electrophysiology data provided by the prescribing information, the largest mean increase in QTc was 24 msec following administration of levoketoconazole 150 mg to 600 mg twice daily in patients with endogenous Cushing's syndrome, and the increase was dose-related. During two premarketing levoketoconazole clinical studies, 4 (2.4%) patients experienced QTcF greater than 500 msec, and 23 (14.7%) patients presented a change in QTcF greater than 60 msec from baseline. The clinical studies did not include patients with baseline QTcF interval greater than 470 msec. 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: Coadministration of levoketoconazole with other drugs that can prolong the QT interval is considered contraindicated.

GENERALLY AVOID: Use of hepatotoxic drugs together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole and hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no risk factors for liver disease. During clinical studies, drug-induced liver injury (peak ALT or AST greater than 3 times the upper limit of normal) occurred in 13% of patients using levoketoconazole.

MANAGEMENT: The use of ketoconazole or levoketoconazole with other potentially hepatotoxic agents should be avoided. Patients treated with levoketoconazole or ketoconazole should have liver tests performed prior to and during treatment. Levoketoconazole manufacturer recommends interrupting treatment immediately if signs of hepatotoxicity occur. Refer to levoketoconazole labeling for specific instructions on management of hepatotoxicity. 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.

GENERALLY AVOID: Use of hepatotoxic drugs together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole and hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no risk factors for liver disease. During clinical studies, drug-induced liver injury (peak ALT or AST greater than 3 times the upper limit of normal) occurred in 13% of patients using levoketoconazole.

MANAGEMENT: The use of ketoconazole or levoketoconazole with other potentially hepatotoxic agents should be avoided. Patients treated with levoketoconazole or ketoconazole should have liver tests performed prior to and during treatment. Levoketoconazole manufacturer recommends interrupting treatment immediately if signs of hepatotoxicity occur. Refer to levoketoconazole labeling for specific instructions on management of hepatotoxicity. 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.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.