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

GENERALLY AVOID: Coadministration with rifampin may decrease the plasma concentrations of ritonavir. The mechanism is rifampin induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of ritonavir. In seven study subjects, rifampin (300 or 600 mg daily for 10 days) decreased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ritonavir (500 mg every 12 hours) by 25% and 35%, respectively, compared to data from nine control subjects. The clinical significance of this interaction is unknown but may be minor. In a small pilot study, protease inhibitor-naive, advanced HIV-infected patients received antituberculosis therapy with isoniazid, pyrazinamide, and rifampin (600 mg/day) for 2 months before starting concomitant antiretroviral treatment with ritonavir (600 mg twice a day) and two nucleoside reverse transcriptase inhibitors (NRTIs). The patients tolerated and responded well to both therapy during follow-up of up to 40 weeks, and drug levels were generally within normal limits relative to historical data and deemed therapeutically adequate. No additive hepatotoxic effects were apparent, with only mild elevations in serum transaminase levels reported (less than a 3-fold increase of normal values).

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, ritonavir labeling recommends that alternative antimycobacterial agents such as rifabutin be considered in HIV patients treated with ritonavir. However, some experts, as well as CDC guidelines, suggest that usual antituberculous dosages of rifampin may be used with ritonavir 400 to 600 mg twice daily in combination with one or more NRTIs. Rifampin should not be used with low-dose ritonavir (i.e. 100 mg twice daily given as a pharmacokinetic booster of other protease inhibitors), since low-dose ritonavir does not prevent rifampin-induced decreases in the concentrations of lopinavir and presumably other protease inhibitors. In general, treatment of tuberculosis (TB) in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related TB should be consulted, and TB and HIV care providers should work in close coordination throughout treatment.

Switch to consumer interaction data

CONTRAINDICATED: Coadministration with rifampin may significantly decrease the plasma concentrations of lopinavir even in the presence of low-dose ritonavir as a pharmacokinetic booster. Rifampin is a potent inducer of CYP450 3A4 and may override some of the inhibiting effects of ritonavir, resulting in accelerated clearance of both lopinavir and ritonavir. In a study of 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg capsule twice a day for 20 days) in combination with rifampin (600 mg once a day for 10 days) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively, compared to administration of lopinavir-ritonavir alone. In another study, the same dosage of rifampin reduced the AUC and Cmin of lopinavir by 16% and 57%, respectively, in 10 healthy subjects when coadministered with lopinavir-ritonavir at a dosage of 800 mg-200 mg twice a day compared to lopinavir-ritonavir alone at 400 mg-100 mg twice a day. No significant changes in lopinavir pharmacokinetics were observed when lopinavir-ritonavir was administered at 400 mg-400 mg (400 mg-100 mg capsule + ritonavir 300 mg) twice a day with rifampin compared to lopinavir-ritonavir alone at 400 mg-100 mg twice a day. However, higher dosages of lopinavir-ritonavir coadministered with rifampin may be associated with an increased risk of liver and gastrointestinal toxicity. In the study, 28% of the subjects experienced a grade 2 or greater increase in ALT and AST, of which 21% prematurely discontinued study per protocol. It was not possible to determine whether the frequency or magnitude of the liver enzyme elevations observed is higher than what would be seen with rifampin alone.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, alternative antimycobacterial agents should be considered in patients already receiving effective antiretroviral therapy with lopinavir-ritonavir. For treatment of latent tuberculosis (TB) infection, a nine-month regimen of isoniazid may be considered if feasible. For treatment of HIV-related TB, a regimen that includes rifabutin is generally preferred, as rifabutin appears to be as effective as rifampin but is a much less potent inducer of CYP450 3A4. Nonrifamycin-containing regimens may be suboptimal (higher mortality rates; higher rates of treatment failure and relapse; increased adverse effects; longer treatment duration) and are usually not recommended for HIV-related TB except in patients who are intolerant of rifamycins or infected with a rifamycin-resistant isolate. In patients who have not begun antiretroviral therapy at the time TB treatment is initiated, clinicians may also consider using rifampin and postponing antiretroviral therapy. With early HIV disease, it may be reasonable to monitor CD4 cell count and postpone antiretroviral therapy until TB treatment is complete, since there is low risk of HIV disease progression or death during this period. However, the optimal time for starting antiretroviral therapy should be individualized based on initial response to TB treatment and occurrence of side effects. In patients with low CD4 cell counts, clinicians may consider delaying antiretroviral therapy until after the first one or two months of TB therapy, as side effects are common during this multi-drug phase of TB treatment and may overlap with those of antiretroviral medications. Moreover, delaying antiretroviral therapy may ameliorate adherence issues and decrease the frequency and severity of paradoxical reactions (i.e., immune restoration syndromes resembling exacerbation of TB that sometimes occur after initiation of antituberculosis treatment in patients receiving potent antiretroviral therapy). Rifabutin can be substituted approximately 2 weeks before the planned initiation of antiretroviral therapy to allow time for rifampin's enzyme induction effects to wane. In general, treatment of TB in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related tuberculosis should be consulted, and TB and HIV care providers should work in close coordination throughout treatment.

Switch to consumer interaction data

GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

Switch to consumer interaction data

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.

Switch to consumer interaction data

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.

Switch to consumer interaction data

MONITOR: Coadministration of rifampin with agents known to induce hepatotoxicity may potentiate the risk of liver injury. There are various possible mechanisms related to rifampin-associated hepatotoxicity described in product labeling and medical literature, however no consensus has been made. These include increased mitochondrial oxidative stress, apoptotic liver cell injury (in rodent studies), the development of cholestasis, hepatic lipid accumulation, and elevated toxic metabolites caused by rifampin-mediated induction of cytochrome P450 enzymes. Cases of drug-induced liver injury (including fatal cases) have been reported within the first few days to months following rifampin treatment initiation. Additional data suggests that 1-2% of patients receiving rifampin monotherapy for tuberculosis prophylaxis experience hepatotoxicity. The severity of hepatotoxicity from rifampin ranges from asymptomatic elevations in liver enzymes, jaundice and/or hyperbilirubinemia, and symptomatic self-limiting hepatitis to fulminant liver failure and death. In most cases, liver function recovers upon on discontinuation of rifampin treatment, however, progression to acute liver failure requiring liver transplantation is possible. Known risk factors that may predispose the patient to rifampin related hepatotoxicity include: coadministration with other hepatotoxic agents, alcoholism, existing liver disease, malnutrition, extensive liver tuberculosis, liver adenocarcinoma and biliary tract neoplasm. Clinical data have been reported with concurrent use of rifampin with other antituberculosis agents (e.g. isoniazid, pyrazinamide), acetaminophen, antiretroviral agents (e.g., saquinavir/ritonavir) and halothane. Data with other hepatotoxic agents are limited.

MANAGEMENT: Caution and close clinical monitoring should be considered if rifampin is coadministered with other hepatotoxic medications. In addition, the manufacturer recommends patients with impaired liver function only be given rifampin in cases of necessity and then under strict medical supervision. Some authorities consider rifampin treatment in patients with existing liver injury contraindicated (Canada). In cases where coadministration of rifampin with hepatotoxic agents is required, careful monitoring of liver function, especially ALT and AST, should be done prior to therapy and then every 2 to 4 weeks during therapy. If hepatic damage is suspected, rifampin should be immediately discontinued. Furthermore, if hepatitis is attributed to rifampin in patients with tuberculosis, alternative agents should be considered. Patients should be instructed to contact their physician immediately if they experience symptoms such as itching, weakness, loss of appetite, nausea, vomiting, abdominal pain, yellowing of the eyes or skin or dark urine.

Switch to consumer interaction data