Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate
Tablet, Film Coated · Oral
• Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and human immunodeficiency virus (HIV-1) and have discontinued lamivudine and tenofovir disoproxil fumarate. Monitor hepatic function closely in these…
Uses
Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors and are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. ( 1 )
Dosage and administration
Testing: Prior to initiation and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. ( 2.1 ) Recommended dose: One tablet taken orally once daily on an empty stomach, preferably at bedtime. ( 2.2 ) Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis. ( 2.3 ) Hepatic Impairment: Not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. ( 2.4 ) 2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Tablets Prior to initiation of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating efavirenz, lamivudine and tenofovir disoproxil fumarate tablets and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.4) ]. Monitor hepatic function prior to and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.9) ] . 2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 35 kg Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a three-drug fixed-dose combination product containing 400 mg of efavirenz (EFV), 300 mg of lamivudine (3TC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets in HIV-1-infected adults and pediatric patients weighing at least 35 kg is one tablet taken orally once daily. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)]. 2.3 Not Recommended in Renal Impairment Because efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination tablet and cannot be dose adjusted, they are not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis [see Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Moderate to Severe Hepatic Impairment Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.7)] .
Dosage forms and strengths
Tablets: 400 mg of efavirenz, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil). The 400 mg/300 mg/300 mg tablets are white to off-white, film-coated, oval, biconvex tablets debossed with “L40” on one side and plain on other side. Tablets: 400 mg efavirenz, 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil). ( 3 )
Contraindications
Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are contraindicated: in patients with a previous hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components contained in the formulation [see Warnings and Precautions (5.8) ] . when coadministered with elbasvir and grazoprevir [see Warnings and Precautions (5.3) and Drug Interactions (7.5)]. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are contraindicated in patients with previous hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. ( 4 ) Coadministration with elbasvir/grazoprevir. ( 4 )
Warnings and precautions
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.2 ) New Onset or Worsening Renal Impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering efavirenz, lamivudine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.4 ) Serious Psychiatric Symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. ( 5.5 ) Nervous System Symptoms (NSS): NSS are frequent, usually begin 1 to 2 days after initiating therapy and resolve in 2 to 4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 5.6 ) Rash: Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops. ( 5.8 ) 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. ( 5.9 , 8.7 ) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate as clinically appropriate. ( 5.10 ) Convulsions: Use caution in patients with a history of seizures. ( 5.11 ) Lipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. ( 5.12 ) Decreases in Bone Mineral Density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.13 ) Immune Reconstitution Syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. ( 5.14 ) Redistribution/Accumulation of Body Fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. ( 5.15 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Posttreatment Exacerbations of Hepatitis: All patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy therapy [see Dosage and Administration (2.1) ] . Discontinuation of anti-HBV therapy, including 3TC and TDF, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. Important Differences Among Lamivudine-Containing Products: Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets contain a higher dose of the same active ingredient, 3TC, than EPIVIR-HBV ® tablets. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of 3TC in EPIVIR- HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of 3TC have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with EPIVIR-HBV, TDF, or a tenofovir alafenamide (TAF)-containing product is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations . 5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of efavirenz, lamivudine and tenofovir disoproxil fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7.5)]:
• Loss of therapeutic effect of efavirenz, lamivudine and tenofovir disoproxil fumarate and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with efavirenz, lamivudine and tenofovir disoproxil fumarate; review concomitant medications during therapy with efavirenz, lamivudine and tenofovir disoproxil fumarate; and monitor for the adverse reactions associated with the concomitant drugs. 5.4 New Onset or Worsening Renal Impairment TDF, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2) ] .
Side effects
The following adverse reactions are discussed in other sections of the labeling: Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.1) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ] . Psychiatric Symptoms [see Warnings and Precautions (5.5) ] . Nervous System Symptoms [see Warnings and Precautions (5.6) ] . Skin and Systemic Hypersensitivity Reaction [see Warnings and Precautions (5.8) ] . Hepatotoxicity [see Warnings and Precautions (5.9) ]. Pancreatitis [see Warnings and Precautions (5.10) ] . Bone Loss and Mineralization Effects [see Warnings and Precautions (5.13) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.14) ] . Fat Redistribution [see Warnings and Precautions (5.15) ] . Most common adverse reactions (>5% with efavirenz, lamivudine and tenofovir disoproxil fumarate) are rash and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in 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. Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) administered in combination with 3TC and EFV for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 1 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 1. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d Peripheral neuropathy includes peripheral neuritis and neuropathy. TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophy c 1% 8% Peripheral neuropathy d 1% 5% ENCORE1 Study - Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 630 treatment-naïve subjects received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) in combination with fixed-dose emtricitabine (FTC)/TDF for 48 weeks were mild to moderate gastrointestinal events, dizziness, abnormal dreams, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including EFV 400 mg and EFV 600 mg are presented in Table 2. Table 2. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48 a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria. EFV 400 mg + FTC/TDF EFV 600 mg + FTC/TDF N = 321 N = 309 Rash event b 9% 13% Dizziness 6% 9% Insomnia 3% 4% Abnormal dreams 2% 2% Headache 1% 3% Diarrhea 2% 3% Vomiting 1% 2% Pyrexia 2% 1% Upper respiratory tract infection 3% 1% Nasopharyngitis 3% 2% Herpes zoster 3% 1% Gastroenteritis 2% 2% Laboratory Abnormalities: Table 3 provides a list of laboratory abnormalities (Grades 3 to 4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the TDF group (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the TDF and d4T treatment arms. Table 3. Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0 to 144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (> 240 mg/dL) 19% 40% Creatine Kinase (M: > 990 U/L; F: > 845 U/L) 12% 12% Serum Amylase (> 175 U/L) 9% 8% AST (M: > 180 U/L; F: > 170 U/L) 5% 7% ALT (M: > 215 U/L; F: > 170 U/L) 4% 5% Hematuria (> 100 RBC/HPF) 7% 7% Neutrophils (< 750/mm 3 ) 3% 1% Fasting Triglycerides (> 750 mg/dL) 1% 9% In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided in Table 4. Table 4.
Drug interactions
Efavirenz, lamivudine and tenofovir disoproxil fumarate should not be administered with other antiretroviral medications for the treatment of HIV-1 infection. ( 7.1 ) 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. ( 5.3 , 7 ) 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 [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 drugs. 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 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) [see Clinical Pharmacology (12.3) ] . 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 [see Warnings and Precautions (5.16) ] . 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.
Use in specific populations
Pregnancy: Women should avoid pregnancy during EFV therapy, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, and for 12 weeks after discontinuation. ( 5.7 , 8.1 , 8.3 ) Lactation: Breastfeeding not recommended due to potential for HIV transmission. ( 8.2 ) Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. ( 8.3 ) 8.1 Pregnancy Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz, lamivudine and tenofovir disoproxil fumarate 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 defects, including meningomyelocele, all in infants of mothers exposed to EFV- containing regimens in the first trimester [see Warnings and Precautions (5.7) ] . Based on prospective reports from the APR of approximately 1,000 live births following exposure to EFV-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between EFV and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4% to 3.6%). 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. Lamivudine: Based on prospective reports from the APR of over 11,000 exposures to 3TC during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between 3TC and overall risk of birth defects for 3TC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to 3TC-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to 3TC-containing regimens. 3TC pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks' gestation using 150 mg 3TC twice daily with zidovudine, 10 women at 38 weeks' gestation using 150 mg 3TC twice daily with zidovudine, and 10 women at 38 weeks' gestation using 3TC 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 3TC concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that 3TC crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of 3TC were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n = 8). Tenofovir Disoproxil Fumarate: Based on prospective reports from the APR exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 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 a U.S. reference population of the MACDP.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz, lamivudine and tenofovir disoproxil fumarate 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 defects, including meningomyelocele, all in infants of mothers exposed to EFV- containing regimens in the first trimester [see Warnings and Precautions (5.7) ] . Based on prospective reports from the APR of approximately 1,000 live births following exposure to EFV-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between EFV and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4% to 3.6%). 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. Lamivudine: Based on prospective reports from the APR of over 11,000 exposures to 3TC during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between 3TC and overall risk of birth defects for 3TC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to 3TC-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to 3TC-containing regimens. 3TC pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks' gestation using 150 mg 3TC twice daily with zidovudine, 10 women at 38 weeks' gestation using 150 mg 3TC twice daily with zidovudine, and 10 women at 38 weeks' gestation using 3TC 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 3TC concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that 3TC crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of 3TC were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n = 8). Tenofovir Disoproxil Fumarate: Based on prospective reports from the APR exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 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 a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF-containing regimens. Prospective reports from the APR of overall major birth defects in pregnancies exposed to TDF are compared with a U.S.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of efavirenz, lamivudine and tenofovir disoproxil fumarate as a fixed-dose tablet in pediatric patients infected with HIV-1 and weighing at least 35 kg have been established based on clinical studies using the individual components (efavirenz, lamivudine, and tenofovir disoproxil fumarate).
Geriatric use
8.5 Geriatric Use Clinical studies of efavirenz, lamivudine and tenofovir disoproxil fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of 3TC in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Overdosage
If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions. Treatment of overdose with EFV should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood. Lamivudine: There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event. Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of TDF 300 mg is available. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Description
Efavirenz, lamivudine and tenofovir disoproxil fumarate is a fixed-dose combination tablet for oral administration. Each film coated tablet contains efavirenz USP 400 mg, lamivudine USP 300 mg and tenofovir disoproxil fumarate 300 mg equivalent to tenofovir disoproxil 245 mg. Each tablet contains the following inactive ingredients: croscarmellose sodium, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc and titanium dioxide. Efavirenz: Efavirenz (EFV) is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as ( S )-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2 H -3,1-benzoxazin-2-one. Its molecular formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz USP is a white to off white powder with a molecular mass of 315.67. It is soluble in methanol and practically insoluble in water (< 10 microgram/mL). Lamivudine: Lamivudine (also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV.The chemical name of lamivudine is (-)-1-[(2 R ,5 S )-2-(Hydroxy methyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.26 g per mol. It has the following structural formula: Lamivudine USP is a white or almost white powder and is soluble in water. Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir , an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5' -monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase. The chemical name of tenofovir disoproxil fumarateis 9-[( R )-2- [[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P
• C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: Tenofovir disoproxil fumarate is a white to off white powder freely soluble in dimethyl formamide, soluble in methanol and slightly soluble in water at 25°C. It has a partition coefficient (log p) of 0.75. efavirenz-structure lamivudine-structure tenofovir-structure
Mechanism of action
12.1 Mechanism of Action Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of antiviral drugs EFV, 3TC, and TDF with antiviral activity against HIV-1 [see Microbiology (12.4) ].
How supplied
Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are supplied as fixed-dose combination tablets containing efavirenz USP 400 mg, lamivudine USP 300 mg and tenofovir disoproxil fumarate 300 mg equivalent to tenofovir disoproxil 245 mg. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are white to off-white, film-coated, oval, biconvex tablets debossed with “L40” on one side and plain on other side. They are supplied as follows: HDPE bottles with Molecular sieve desiccant Bottles of 30 NDC 42385-929-30 Bottles of 90 NDC 42385-929-90 Bottles of 180 NDC 42385-929-18 HDPE bottles with Silica gel canister desiccant Bottles of 30 NDC 42385-929-31 Bottles of 90 NDC 42385-929-91 Bottles of 180 NDC 42385-929-82 Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in original container.
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions: Efavirenz, lamivudine and tenofovir disoproxil fumarate may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort [see Contraindications (4) and Drug Interactions (7) ] . Post Treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection: Inform patients that severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued 3TC and TDF, components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Test patients with HIV-1 for hepatitis B virus (HBV) before initiating antiretroviral therapy. In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating 3TC and TDF, components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.1) ] . Lactic Acidosis and Severe Hepatomegaly: Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment: Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis to avoid efavirenz, lamivudine and tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) for patients [see Dosage and Administration (2.3) , Warnings and Precautions (5.4) ] . Psychiatric Symptoms: Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving EFV [see Warnings and Precautions (5.5)] . Advise patients to seek immediate medical evaluation if they experience severe psychiatric adverse experiences. Advise patients to inform their physician of any history of mental illness or substance abuse. Nervous System Symptoms: Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.6) ] . Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy. Alert patients to the potential for additive effects when used concomitantly with alcohol or psychoactive drugs. Instruct patients that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery. Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy, which may occur months to years after beginning efavirenz therapy [see Warnings and Precautions (5.6) ] . Embryo-Fetal Toxicity: Advise female patients that EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation of use. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate [see Warnings and Precautions (5.7), Use in Specific Populations (8.1 , 8.3) ] . Rash: Inform patients that rash is a common side effect of EFV [see Warnings and Precautions (5.8)] . Rashes usually go away without any change in treatment. However, since rash may be serious, patients should be advised to contact their physician promptly if rash occurs. Hepatotoxicity: Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces and to consult their healthcare provider promptly if such symptoms occur [see Warnings and Precautions (5.9) ]. Pancreatitis: Advise patients or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.10) ] . Convulsions: Advise patients that convulsions have been observed in patients receiving EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, generally in patients with known medical history of seizures [see Warnings and Precautions (5.11) ]. Lipid Elevations: Advise patients treatment with EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets has resulted in increases in the concentration of total cholesterol and triglycerides [see Warnings and Precautions (5.12)] . Bone Loss and Mineralization Effects: Inform patients that decreases in bone mineral density have been observed with the use of 3TC and TDF, components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, in patients with HIV [see Warnings and Precautions (5.13) ] .
Label text from the FDA structured product label by Laurus Labs Limited (revised May 7, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Efavirenz in 2 products
- Lamivudine in 2 products
- Tenofovir Disoproxil Fumarate in 2 products
Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 42385-928 | Efavirenz 600 mg/1; Lamivudine 300 mg/1; Tenofovir Disoproxil Fumarate 300 mg/1 Tablet, Film Coated | Laurus Labs Limited | ANDA |
| 42385-929 | Efavirenz 400 mg/1; Lamivudine 300 mg/1; Tenofovir Disoproxil Fumarate 300 mg/1 Tablet, Film Coated | Laurus Labs Limited | ANDA |
Frequently asked questions
What is Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate used for?
Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and…
What are the side effects of Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate?
The following adverse reactions are discussed in other sections of the labeling: Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.1) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ] . Psychiatric Symptoms [see Warnings and Precautions (5.5) ] .… See the full label for the complete list.
Who makes Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate?
Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate is listed by 1 labeler in the FDA NDC directory, including Laurus Labs Limited.