IMPORTANT SAFETY INFORMATION

Contraindications:  Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are 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 tablets. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are contraindicated to be coadministered with voriconazole or elbasvir/grazoprevir.

Severe 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. 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.

Rash

In controlled clinical trials, 26% of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% of those treated in control groups. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with EFV and, in most subjects continuing therapy with EFV, rash resolves within 1 month. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered.

Rash was reported in 32% of pediatric subjects treated with EFV. The median time to onset of rash in pediatric subjects was 28 days. Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in pediatric patients should be considered.

Hepatotoxicity

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.

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are 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.

Monitoring of liver enzymes before and during treatment is recommended for all patients. 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.

Risk 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, 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 clinically significant adverse reaction from greater exposures of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets or concomitant drug.

QTc prolongation has been observed with the use of EFV. Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets including severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, and manic reactions.

Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of EFV, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Nervous System Symptoms

Fifty-three percent of subjects receiving EFV in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% of subjects receiving control regimens. These symptoms included dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations. Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning EFV therapy. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to EFV use, and whether discontinuation of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is warranted.

Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be alerted to the potential for additive central nervous system effects when efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney; however, EFV is not. 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, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets.

Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min).

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Embryo-Fetal Toxicity

Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. Advise adults and adolescents of childbearing potential who are receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets to avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and for 12 weeks after discontinuation.

Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults, TDF (a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF.

Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis-B infected adolescent subjects aged 12 years to less than 18 years.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products.

Convulsions

Convulsions have been observed in adult and pediatric patients receiving EFV, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and FTC, components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals. Treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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).

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," has been observed in patients receiving antiretroviral therapy, including EFV.

Common Adverse Reactions: In clinical trials, the most common adverse reactions (incidence greater than or equal to 10%, any severity) in HIV-1 infected subjects included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

Please see full Prescribing Information including Boxed Warning.

APPROVED USES

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are 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.