Efavirenzinteractions

Efavirenz, lamivudine and tenofovir disoproxil fumarate should not be administered with other antiretroviral medications for the treatment of HIV-1 infection. Coadministration of efavirenz, lamivudine and tenofovir disoproxil fumarate can alter the concentrations of other drugs and other drugs may alter the concentration of efavirenz, lamivudine and tenofovir disoproxil fumarate. The potential for drug-drug interactions should be considered before and during therapy.

7.1 Not Recommended with

Other Antiretroviral Medications Efavirenz, lamivudine and tenofovir disoproxil fumarate is a complete regimen for the treatment of HIV-1 infection; therefore, it should not be administered with other antiretroviral medications for treatment of HIV-1 infection.

7.2 QT Prolonging

Drugs 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 EFV when coadministered with a drug with a known risk of Torsade de Pointes.

7.3 Drugs Affecting

Renal Function Tenofovir is primarily eliminated by the kidneys. Coadministration of EFV/3TC/TDF with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drugs. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs. Drugs that decrease renal function may increase concentrations of tenofovir.

7.4 Cannabinoid

Test Interaction EFV 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.

7.5 Established and

Other Potentially Significant Interactions EFV 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. No drug interaction studies have been conducted using efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. However, drug interaction studies have been conducted with the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 3TC, and TDF). Drug interactions with EFV are summarized in Table 5 [for pharmacokinetics data see Clinical Pharmacology (12.3, Tables 8 and 9) ]. This table includes potentially significant interactions, but is not all inclusive. Table 5. Established and Other Potentially Significant Drug Interactions with EFV: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction * The interaction between EFV and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive.

Concomitant Drug Class: Drug Name Effect Clinical Comment Anticoagulant: Warfarin ­↑ or ↓ warfarin Monitor INR and adjust warfarin dosage if necessary.

Anticonvulsants: Carbamazepine ↓carbamazepine* ↓EFV* There are insufficient data to make a dose recommendation for EFV. Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital ↓ anticonvulsant ↓ EFV Monitor anticonvulsant plasma levels periodically because of potential for reduction in anticonvulsant and/or EFV plasma levels.

Antidepressants: Bupropion Sertraline ↓ bupropion* ↓ sertraline* Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose. Increases in sertraline dosage should be guided by clinical response.

Antifungals: Itraconazole Ketoconazole Posaconazole Consider alternative antifungal treatment because no dose recommendation for itraconazole or ketoconazole can be made. Avoid concomitant use unless the benefit outweighs the risks. ↓ itraconazole* ↓ hydroxyitraconazole* ↓ ketoconazole ↓ posaconazole* Anti-infective: Clarithromycin ↓ clarithromycin* ­↑14-OH metabolite* Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.

Antimycobacterial: Rifabutin Rifampin ↓ rifabutin* ↓ EFV* Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. Increase EFV total daily dose to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more.

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 is not recommended.

Calcium channel blockers: Diltiazem Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓diltiazem* ↓ desacetyl diltiazem* ↓ N- monodesmethyldiltiazem* ↓ calcium channel blocker Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). When coadministered with EFV, dosage adjustment of calcium channel blocker may be needed and 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. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.

Hepatitis C antiviral agents: Boceprevir Elbasvir/Grazoprevir Pibrentasvir/Glecaprevir Simeprevir Velpatasvir/Sofosbuvir Velpatasvir/Sofosbuvir/ Voxilaprevir Ledipasvir/Sofosbuvir ↓ boceprevir* ↓ elbasvir ↓ grazoprevir ↓ pibrentasvir ↓ glecaprevir ↓ simeprevir* ↔ EFV ↓ velpatasvir ↓ velpatasvir ↓ voxilaprevir ­ ↑TDF Concomitant administration of boceprevir is not recommended. Coadministration of EFV with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. Coadministration of EFV is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Concomitant administration of simeprevir is not recommended. Coadministration of EFV and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir. Coadministration of EFV and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Monitor for adverse reactions associated with TDF. Hepatitis B antiviral agents Adefovir dipivoxil Concomitant administration of adefovir dipivoxil is not recommended.

Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate Implant Etonogestrel ↓ active metabolites of norgestimate* ↓ etonogestrel A reliable method of barrier contraception should be used in addition to hormonal contraceptives. A reliable method of barrier contraception should 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 ↓ immunosuppressant 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 EFV.

Narcotic analgesic: Methadone ↓ methadone* Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms.

7.6 Drugs without

Clinically Significant Interactions No dosage adjustment is recommended when efavirenz, lamivudine and tenofovir disoproxil fumarate is administered with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, and lorazepam.

7.7 Drugs Inhibiting

Organic Cation Transporters 3TC, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of 3TC.

7.8 Sorbitol

Coadministration of single doses of 3TC and sorbitol resulted in a sorbitol dose-dependent reduction in 3TC exposures. When possible, avoid use of sorbitol-containing medicines with 3TC.