Efavirenz, lamivudine, and tenofovir disoproxil

7 DRUG INTERACTIONS • SYMFI should not be administered with other antiretroviral medications for the treatment of HIV-1 infection. ( 7.1 ) • Coadministration of SYMFI can alter the concentrations of other drugs and other drugs may alter the concentration of SYMFI. The potential for drug-drug interactions should be considered before and during therapy. ( 5.3 , 7 )

7.1 Not Recommended with Other Antiretroviral Medications SYMFI 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 [see Clinical Pharmacology (12.2) ] . 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 [see Clinical Pharmacology (12.3) ] . Coadministration of EFV/3TC/TDF with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4) ] . 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 SYMFI. However, drug interaction studies have been conducted with the individual components of SYMFI (EFV, 3TC, and TDF) [see Clinical Pharmacology (12.3) ] .

Drug interactions with EFV are summarized in Table 3 [for pharmacokinetics data see Clinical Pharmacology (12.3 , Tables 6 and 7) ]. This table includes potentially significant interactions, but is not all inclusive. Table 3. 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 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 The interaction between EFV and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ 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 ↓ bupropion Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose.

Sertraline ↓ sertraline Increases in sertraline dosage should be guided by clinical response. Antifungals: Itraconazole Ketoconazole ↓ itraconazole ↓ hydroxyitraconazole ↓ ketoconazole Consider alternative antifungal treatment because no dose recommendation for itraconazole or ketoconazole can be made. Posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks. 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 ↓ EFV Increase EFV total daily dose to 800 mg once daily when coadministered 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 [see Warnings and Precautions (5.16) ] . Atovaquone/ proguanil ↓ atovaquone ↓ proguanil Concomitant administration is not recommended.

Calcium channel blockers: Diltiazem ↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodesmethyldiltiazem Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker 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 ↓ boceprevir Concomitant administration of boceprevir is not recommended. Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of EFV with elbasvir/grazoprevir is contraindicated [see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir.

Pibrentasvir/Glecaprevir ↓ pibrentasvir ↓ glecaprevir Coadministration of EFV is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Simeprevir ↓ simeprevir ↔ EFV Concomitant administration of simeprevir is not recommended. Velpatasvir/Sofosbuvir ↓ velpatasvir Coadministration of EFV and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir. Velpatasvir/Sofosbuvir/ Voxilaprevir ↓ velpatasvir ↓ voxilaprevir Coadministration of EFV and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.

Ledipasvir/Sofosbuvir ↑ TDF 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 ↓ active metabolites of norgestimate A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Implant Etonogestrel ↓ etonogestrel 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 SYMFI 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 SYMFI, 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) [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ]…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SYMFI during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to EFV-containing regimens in the first trimester of pregnancy.

Although a causal relationship has not been established between exposure to EFV in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at a dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, EFV should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Prospective pregnancy data from the APR are not sufficient to adequately assess this risk of birth defects or miscarriage.

EFV and 3TC have been evaluated in a limited number of women as reported to the APR. Available data from the APR show no difference in the risk of major birth defects for EFV and 3TC compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Available data from the APR also show no increase in the overall risk of major birth defects with first trimester exposure for TDF (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the MACDP (see Data ) .

3TC produced embryonic toxicity in rabbits at a dose that produced similar human exposures as the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population.

The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. Human Data Efavirenz There are retrospective postmarketing reports of findings consistent with neural tube…