Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is a three-drug combination of efavirenz (EFV), a nonnucleoside reverse transcriptase inhibitor, and emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg.
( 1 )
Contraindications
Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet. [see Warnings and Precautions ( 5.2 )].
Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is contraindicated to be coadministered with voriconazole or elbasvir/grazoprevir [see Drug Interactions ( 7.3 ) and Clinical Pharmacology ( 12.3 )].
Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. ( 4 )
Coadministration with voriconazole. ( 4 )
Coadministration with elbasvir/grazoprevir. ( 4 )
Warnings and precautions
Rash: Discontinue if severe rash develops. ( 5.2 , 6.1 )
Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. ( 5.3 , 6.2 , 8.7 )
Risk of adverse reactions or loss of virologic response due to drug interactions: Consult full prescribing information prior to and during treatment for important potential drug interactions. Consider alternatives to Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. ( 5.4 )
Serious psychiatric symptoms: Immediate medical evaluation is recommended. ( 5.5 , 6.1 )
Nervous system symptoms (NSS): NSS are frequent, usually begin 1−2 days after initiating therapy, and resolve in 2−4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 2.2 , 5.6 )
New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Avoid administering efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.7 )
Embryo fetal toxicity: Fetal harm may occur when administered to a pregnant woman during the first trimester. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and for 12 weeks after discontinuation. ( 5.8 , 8.1 )
Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathological fracture or other risk factors for osteoporosis or bone loss. ( 5.9 )
Convulsions: Use caution in patients with a history of seizures. ( 5.10 )
Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.11 )
Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.12 )
Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.13 )
5.1Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
All patients should be tested for the presence of chronic HBV before or when initiating antiretroviral therapy [see Dosage and Administration ( 2.1 )]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, two of the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets.
Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
5.2Rash
In controlled clinical trials, 26% (266/1,008) of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of subjects treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with EFV in all trials and expanded access was 0.1%.
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with EFV (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008). Efavirenz, emtricitabine and tenofovir disoproxil fumarate can be reinitiated in patients interrupting therapy because of rash.
Efavirenz, emtricitabine and tenofovir disoproxil fumarate should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered [ See Contraindications ( 4 ) ].
Experience with EFV in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with EFV . Nine of these subjects developed mild-to-moderate rash while receiving therapy with EFV , and two of these subjects discontinued because of rash. Rash was reported in 59 of 182 pediatric subjects (32%) treated with EFV [ See Adverse Reactions ( 6.1 ) ].
Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3−1,642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz, emtricitabine and tenofovir disoproxil fumarate in pediatric patients should be considered.
5.3Hepatotoxicity
Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with EFV, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors [see Warnings and Precautions ( 5.1 )].
Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Adverse Reactions ( 6.2 ) and Use in Specific Populations ( 8.7 )]. Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration ( 2.1 )].
Consider discontinuing efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation [see Adverse Reactions ( 6.1 )].
5.4Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
The concomitant use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and other drugs may result in potentially significant drug interactions [see Contraindications ( 4 ) and Drug Interactions ( 7.3 )], some of which may lead to:
Loss of therapeutic effect of concomitant drug or efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and possible development of resistance.
Possible clinicall
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Interactions
Consult Full Prescribing Information prior to and during treatment for important potential drug interactions. ( 4 , 5.4 , 7 )
HIV-1 protease inhibitors: Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets with either atazanavir or atazanavir and ritonavir is not recommended. ( 7.3 )
7.1Efavirenz
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 [See Dosage and Administration ( 2.2 )]. 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes.
7.2Drugs Affecting Renal Function FTC
and tenofovir are primarily eliminated by the kidneys [see Clinical Pharmacology ( 12.3 )]. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 [see Warnings and Precautions ( 5.7 )].
Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.
7.3Established 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 [see Clinical Pharmacology ( 12.3 ) 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 tablets 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 tablets. 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 forthe increased indinavir metabolism due to EFV. Protease inhibitor: darunavir/ritonavir lopinavir/ritonavir ↑ tenofovir ↓ lopinavir ↑ tenofovir Monitor patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets concomitantly with ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 efavirenz-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 tablets 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 tablets.
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 didanosineassociated 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 tablets. 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 tablets 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 tablets with elbasvir/grazoprevir is contraindicated [see Contraindications ( 4 )] because it may lead to loss of virologic response to elbasvir/grazoprevir. glecaprevir/pibrentasvir ↓ glecaprevir ↓ pibrentasvir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate ta
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Pregnancy and breastfeeding
8.1Pregnancy Antiretroviral Pregnancy Registry:
There is a pregnancy exposure registry that monitors pregnancy outcomes in adults and adolescents exposed to efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at (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.
Prospective pregnancy data from the APR are not sufficient to adequately assess this risk. 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 (see Data). In addition, fetal and embryonic toxicities occurred in rats at a dose 10 times less than the human exposure at the recommended clinical human dose (RHD) of EFV.
Because of the potential risk of neural tube defects, EFV is not recommended for use in the first trimester of pregnancy. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and for 12 weeks after discontinuation. Advise pregnant patients of the potential risk to a fetus. Available data from the APR show no increase in the overall risk of major birth defects for EFV, FTC, or TDF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data).
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- 20%. The background risk of 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 mothers and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks' gestation.
In animal reproduction studies, no adverse developmental effects were observed when FTC and TDF were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF) and 2.7 (tenofovir) times those at the RHD of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (see Data). Data Human Data Efavirenz: There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to EFV-containing regimens in the first trimester.
Based on prospective reports to the APR of 1,217 exposures to EFV-containing regimens during pregnancy resulting in live births (including over 1,023 live births exposed in the first trimester and 194 exposed in the second/third trimester), there was no increase in overall birth defects with EFV compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.5% to 3.5%) with first trimester exposure to EFV -containing regimens, and 1.5% (95% CI: 0.3% to 4.5%) with the second/third trimester exposure to EFV -containing regimens.
One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to EFV has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia. Emtricitabine: Based on prospective reports from the APR of 4,005 exposures to FTC- containing regimens during pregnancy resulting in live births (including 2,785 exposed in the first trimester and 1,220 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC -containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC -containing regimens. Tenofovir DF: Based on prospective reports from the APR of 5,105 exposures to TDF containing regimens during pregnancy resulting in live births (including 3,535 exposed in the first trimester and 1,570 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF -containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF -containing regimens. Animal Data Efavirenz: Effects of EFV on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, EFV 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation Days 20 through 150).
The maternal systemic drug exposures (AUC) were 1.3 times the exposures at the RHD, with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third.
There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, EFV was administered either during organogenesis (gestation Days 7 to 18) or from gestation Day 7 through lactation Day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with an increase in the incidence of early resorptions, and doses 100 mg/kg/day and greater were associated with early neonatal mortality.
The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the RHD. Drug concentrations in the milk on lactation Day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, EFV was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation Days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the RHD.
Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the RHD.
In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD. Tenofovir DF: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively).
No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the RHD based on body surface area comparisons and in rabbits at doses up to 19 times the RHD ba
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Adverse reactions
The following adverse reactions are discussed in other sections of the labeling:
Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions ( 5.1 )].
Rash [See Warnings and Precautions ( 5.2 )].
Hepatotoxicity [See Warnings and Precautions ( 5.3 )].
Psychiatric Symptoms [See Warnings and Precautions ( 5.5 )].
Nervous System Symptoms [See Warnings and Precautions ( 5.6 )].
New Onset or Worsening Renal Impairment [See Warnings and Precautions ( 5.7 )].
Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.8 )].
Bone Loss and Mineralization Defects [see Warnings and Precautions ( 5.9 )].
Convulsions [see Warnings and Precautions ( 5.10 )].
Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions ( 5.11 )].
Immune Reconstitution Syndrome [See Warnings and Precautions ( 5.12 )].
Fat Redistribution [See Warnings and Precautions ( 5.13 )]. Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of EFV, FTC, and TDF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Subjects Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naïve subjects received either FTC + TDF administered in combination with EFV (N=257) or zidovudine (AZT)/lamivudine (3TC) administered in combination with EFV (N=254).
The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1). Table 1 Selected Adverse Reactions a (Grades 2-4) Reported in ≥5% in Either Treatment Group in Study 934 (0-144 Weeks) FTC + TDF + EFV b AZT/3TC + EFV N=257 N=254 Fatigue Depression Nausea Diarrhea Dizziness Upper respiratory tract infections Sinusitis Rash Event c Headache Insomnia Anxiety Nasopharyngitis Vomiting 9% 9% 9% 9% 8% 8% 8% 7% 6% 5% 5% 5% 2% 8% 7% 7% 5% 7% 5% 4% 9% 5% 7% 4% 3% 5% a.
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive efavirenz, emtricitabine and tenofovir disoproxil fumarate for to stay on their baseline regimen.
The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of efavirenz, emtricitabine and tenofovir disoproxil fumarate when each was administered in combination with other antiretroviral agents. Efavirenz, Emtricitabine, or TDF In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of EFV, FTC, or TDF in combination with other antiretroviral agents.
Efavirenz: The most significant adverse reactions observed in subjects treated with EFV were nervous system symptoms [see Warnings and Precautions ( 5.6 )], psychiatric symptoms [see Warnings and Precautions ( 5.5 )], and rash [see Warnings and Precautions ( 5.2 )]. Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of EFV-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.
Pancreatitis has also been reported, although a causal relationship with EFV has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with EFV 600 mg than in control subjects. Skin discoloration has been reported with higher frequency among FTC -treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic.
The mechanism and clinical significance are unknown. Clinical Trials in Pediatric Subjects Efavirenz: Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects who received EFV in combination with other antiretroviral agents for a median of 123 weeks. The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults [See Warnings and Precautions ( 5.2 )].
Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). Tenofovir DF: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF (N=81) were consistent with those observed in clinical trials of TDF in adults [See Warnings and Precautions ( 5.9 )].
Laboratory Abnormalities Efavirenz, Emtricitabine and Tenofovir DF: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 2). Table 2 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Either Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV a AZT/3TC + EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a.
From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934. Hepatic Events: In Study 934, 19 subjects treated with EFV, FTC, and TDF and 20 subjects treated with EFV and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive.
Among these coinfected subjects, one subject (1/19) in the EFV, FTC, and TDF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders [See Warnings and Precautions ( 5.3 )].
6.2Postmarketing Experience
The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF.
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At a glance
Brand name
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate
Active substance
efavirenz
Pharmacologic class
Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor, Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor
