Efavirenzinteractions

Consult Full Prescribing Information prior to and during treatment for important potential drug interactions.

HIV-1 protease inhibitors: Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either atazanavir or atazanavir and ritonavir is not recommended.

7.1 Efavirenz

Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with EFV. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV, resulting in lowered plasma concentrations. There is limited information available on the potential for a pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV. Consider alternatives to efavirenz emtricitabine and tenofovir disoproxil fumarate when coadministered with a drug with a known risk of Torsade de Pointes.

7.2 Drugs Affecting

Renal Function FTC and tenofovir are primarily eliminated by the kidneys. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

7.3 Established and

Potentially Significant Interactions Other important drug interaction information for efavirenz, emtricitabine and tenofovir disoproxil fumarate is summarized in Table 3. The drug interactions described are based on trials conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate, the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate (EFV, FTC, or TDF) as individual agents, or are potential drug interactions. Table 3 Established and Potentially Significant a Drug Interactions Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: atazanavir ↓ atazanavir ­ ↑ tenofovir Coadministration of atazanavir with efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended. The combined effect of EFV plus TDF on atazanavir plasma concentrations is not known. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with efavirenz, emtricitabine and tenofovir disoproxil fumarate.

Protease inhibitor: fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and efavirenz, emtricitabine and tenofovir disoproxil fumarate with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir plus ritonavir twice daily.

Protease inhibitor: indinavir ↓ indinavir The optimal dose of indinavir, when given in combination with EFV, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to EFV.

Protease inhibitor: darunavir/ritonavir lopinavir/ritonavir ­ ↑ tenofovir ↓ lopinavir ­↑ tenofovir Monitor patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate concomitantly with ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions. Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with EFV. Refer to the Full Prescribing Information for lopinavir/ritonavir for guidance on coadministration with EFV- or tenofovir-containing regimens, such as efavirenz, emtricitabine and tenofovir disoproxil fumarate. Patients should be monitored for tenofovir-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions.

Protease inhibitor: ritonavir ­ ↑ ritonavir ­ ↑ efavirenz When ritonavir 500 mg every 12 hours was coadministered with EFV 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when efavirenz, emtricitabine and tenofovir disoproxil fumarate is used in combination with ritonavir.

Protease inhibitor: saquinavir ↓ saquinavir Appropriate doses of the combination of EFV and saquinavir/ritonavir with respect to safety and efficacy have not been established.

CCR5 co-receptor antagonist: maraviroc ↓ maraviroc Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz, emtricitabine and tenofovir disoproxil fumarate.

NRTI: didanosine ­ ↑ didanosine Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and didanosine should be monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine- associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving TDF with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with efavirenz, emtricitabine and tenofovir disoproxil fumarate. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. When coadministered, efavirenz, emtricitabine and tenofovir disoproxil fumarate and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).

NNRTI: Other NNRTIs ­↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. Efavirenz, emtricitabine and tenofovir disoproxil fumarate contains EFV and should not be coadministered with other NNRTIs.

Integrase strand transfer inhibitor: raltegravir ↓ raltegravir The clinical significance of this interaction has not been directly assessed. Hepatitis C antiviral agents boceprevir ↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with EFV, which may result in loss of therapeutic effect. The combination should be avoided. elbasvir/grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. glecaprevir/pibrentasvir ↓ glecaprevir ↓ pibrentasvir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended because it may lead to reduced therapeutic effect of glecaprevir/pibrentasvir. ledipasvir/sofosbuvir ­↑ tenofovir Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and HARVONI ® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with TDF. simeprevir ↓ simeprevir ↔ efavirenz Concomitant administration of simeprevir with EFV is not recommended because it may result in loss of therapeutic effect of simeprevir. sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ­ ↑ tenofovir ↓ velpatasvir ↓ voxilaprevir Coadministration of EFV-containing regimens and EPCLUSA ® (sofosbuvir/velpatasvir) or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) is not recommended.

Other agents Anticoagulant: warfarin ­ ↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by EFV.

Anticonvulsants: carbamazepine ↓ carbamazepine ↓ efavirenz There are insufficient data to make a dose recommendation for efavirenz, emtricitabine and tenofovir disoproxil fumarate. Alternative anticonvulsant treatment should be used. phenytoin phenobarbital ↓ anticonvulsant ↓ efavirenz Potential for reduction in anticonvulsant and/or EFV plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.

Antidepressants: bupropion ↓ bupropion The effect of EFV on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response.

Antifungals: itraconazole ↓ itraconazole ↓ hydroxy- itraconazole Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. ketoconazole ↓ ketoconazole Drug interaction trials with efavirenz, emtricitabine and tenofovir disoproxil fumarate and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks. voriconazole ↓ voriconazole ­ ↑ efavirenz Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with voriconazole is contraindicated because it may lead to reduced therapeutic effect of voriconazole and increased risk of EFV-associated adverse reactions Anti-infective: clarithromycin ↓ clarithromycin ↑ 14-OH metabolite Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.

Antimycobacterial: rifabutin ↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. rifampin ↓ efavirenz If efavirenz, emtricitabine and tenofovir disoproxil fumarate is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of EFV is recommended.

Antimalarials: artemether/ lumefantrine atovaquone/proguanil ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine ↓ atovaquone ↓ proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Concomitant administration of atovaquone/proguanil with efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended.

Calcium channel blockers: diltiazem ↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz, emtricitabine and tenofovir disoproxil fumarate is necessary when administered with diltiazem. Others e.g., felodipine nicardipine nifedipine verapamil ↓ calcium channel blocker No data are available on the potential interactions of EFV with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).

HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin ↓ atorvastatin ↓ pravastatin ↓ simvastatin Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with EFV. Consult the Full Prescribing Information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.

Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate Implant: etonogestrel ↓ active metabolites of norgestimate ↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on EFV plasma concentrations was observed. A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in EFV- exposed patients.

Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immuno- suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by EFV. These immunosuppressants are not anticipated to affect exposure of EFV. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate.

Narcotic analgesic: methadone ↓ methadone Coadministration of EFV in HIV-1 infected individuals with a history of injection drug use resulted in signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. a. This table is not all inclusive.

7.4 Efavirenz

Assay Interference Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving EFV. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.