Efavirenzinteractions

Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions should be considered before and during therapy.

7.1 Potential for efavirenz to

Affect other Drugs 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 efavirenz

7.2 Potential for

Other Drugs to Affect efavirenz Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

7.3 QT Prolonging

Drugs There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes.

7.4 Established and

Other Potentially Significant Drug Interactions Drug interactions with efavirenz are summarized in Table 5. For pharmacokinetics data, Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations 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 tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz tablets are administered with fosamprenavir plus ritonavir twice daily.

Protease inhibitor: Atazanavir ↓ atazanavir * Treatment –naïve patients: When co-administered with efavirenz tablets, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz tablets 600 mg ( once daily on an empty stomach, preferably at bedtime).

Treatment-experienced patients: Co-administration of efavirenz tablets and atazanavir is not recommended.

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

Protease inhibitor: Lopinavir/ritonavir ↓ lopinavir * Lopinavir/ritonavir once daily dosing is not recommended when co-administered with efavirenz. The dose of lopinavir/ritonavir must be increased when co-administered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when co-administered with efavirenz in adult and pediatric patients.

Protease inhibitor: Ritonavir ↑ ritonavir * ↑ efavirenz * Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is co-administered with ritonavir.

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

NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/ or NNRTI Combining two NNRTIs has not been shown to be beneficial. efavirenz should not be coadministered with other NNRTIs.

CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the full prescribing information for maraviroc for guidance on co-administration with efavirenz. Hepatitis C antiviral agents Boceprevir ↓ boceprevir* Concomitant administration of boceprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of boceprevir Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration o efavirenz with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir ↓ pibrentasvir Co-administration of efavirenz is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir Simeprevir ↓simeprevir* ↔efavirenz* Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss oftherapeutic effect of simeprevir. Velpatasvir/ Sofosbuvir ↓ velpatasvir Co-administration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir Velpatasvir /Sofosbuvir/Voxilaprevir ↓ velpatasvir ↓ voxilaprevir Co-administration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.

Other agents Anticoagulant: Warfarin ↑ or ↓ warfarin Monitor INR and adjust warfarin dosage if necessary.

Anticonvulsants: Carbamazepine ↓ carbamazepine * ↓ efavirenz * There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital ↓ anticonvulsant ↓ efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.

Antidepressant: 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: Voriconazole ↓ voriconazole * ↑ efavirenz * Efavirenz and voriconazole should not be co-administered at standard doses. When voriconazole is co-administered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz tablets must not be broken. Itraconazole ↓ itraconazole * ↓ hydroxyitraconazole * Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. Ketoconazole ↓ ketoconazole Drug interaction studies with efavirenz 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.

Anthelmintic: Praziquantel ↓ praziquantel Co-administration with efavirenz is not recommended due to significant decrease in plasma concentrations of praziquantel, with risk of treatment failure due to increased hepatic metabolism by efavirenz.

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 * Increase efavirenz to 800 mg once daily when co-administered with rifampin to patients weighing 50 kg or more.

Antimalarials: Artemether/ lumefantrine ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Atovaquone/ proguanil ↓ atovaquone ↓ proguanil Concomitant administration is not recommended.

Calcium channel blockers: Diltiazem ↓ diltiazem * ↓ desacetyl diltiazem * ↓ N-monodesmethyl diltiazem * Diltiazem dose adjustments should be guided by clinical response (refer to the complete prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker When co-administered with efavirenz, dosage adjustment of calcium channels 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 complete 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 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 post marketing reports of contraceptive failure with etonogestrel in efavirenz-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 metabolized by or stopping treatment with efavirenz.

Narcotic analgesic: Methadone ↓ methadone * Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms. * The interaction between efavirenz and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive.

7.5 Drugs Without

Clinically Significant Interactions with Efavirenz No dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), paroxetine, and raltegravir.

7.6 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 efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.