efavirenz, emtricitabine and tenofovir disoproxil fumarate Dailymed

Warning: Posttreatment Acute Exacerbation Of Hepatitis B

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), which are components of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet.

Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B

See full prescribing information for complete boxed warning.

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients coinfected with HBV and HIV-1 who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet . Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.1)

• Testing: Consult Full Prescribing Information for important testing recommendations prior to initiation and during treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. (2.1)
• Recommended dosage in adults and pediatric patients weighing at least 40 kg: One tablet once daily taken orally on an empty stomach, preferably at bedtime. (2.2)
• Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL/min. (2.3)
• Hepatic impairment: Not recommended in patients with moderate to severe hepatic impairment. (2.4)
• Dosage adjustment with rifampin coadministration: An additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more. (2.5)

2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet

Prior to or when initiating Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation and during use of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet, 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 [see Warnings and Precautions (5.7)].

Monitor hepatic function prior to and during treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet [see Warnings and Precautions (5.3)].

Perform pregnancy testing before initiation of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet in adolescents and adults of childbearing potential [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Clinical Pharmacology (12.3)].

2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment

Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Warnings and Precautions (5.7), Use in Specific Populations (8.6)].

2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment

Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

2.5 Dosage Adjustment with Rifampin

If Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is co-administered with rifampin in patients weighing 50 kg or more, take one tablet of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet once daily followed by one additional 200 mg per day of efavirenz [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths

Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil). The tablets are pink coloured, capsule-shaped, biconvex film-coated tablet, debossed with 'C210'on one side and plain on other side.

Tablets: 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate. (3)

4 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 tablet. (4)
• Coadministration with voriconazole. (4)
• Coadministration with elbasvir/grazoprevir. (4)

5 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 tablet, 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 tablet 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 tablet 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)

5.1 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 [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 tablet. 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 tablet. If appropriate, initiation of anti-hepatitis 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.

5.2 Rash

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 bulering, 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 tablet can be reinitiated in patients interrupting therapy because of rash. Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet should be discontinued in patients developing severe rash associated with bulering, 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 tablet in pediatric patients should be considered.

5.3 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 tablet. 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 tablet 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 tablet [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 tablet 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 tablet if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation [see Adverse Reactions (6.1)].

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet 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 tablet and possible development of resistance.
• Possible clinically significant adverse reaction from greater exposures of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet or concomitant drug.

QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)]. Consider alternatives to Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate tablet 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.

See Table 3 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 Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet therapy and review concomitant medications during Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet therapy [see Dosage and Administration (2.5), Contraindications (4), and Drug Interactions (7)].

5.5 Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. In controlled trials of 1,008 subjects treated with regimens containing EFV for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received EFV or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006, NCT00002410), a Phase 3 randomized, open-label trial of EFV-containing regimens versus controls in 1,266 subjects (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with EFV + zidovudine + lamivudine, EFV + indinavir, and indinavir + zidovudine + lamivudine, respectively), treatment with EFV was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at trial entry; similar associations were observed in both the EFV and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the trial for both EFV-treated and control-treated subjects. One percent of EFV-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of EFV cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased EFV exposure. 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 [see Adverse Reactions (6)].

5.6 Nervous System Symptoms

Fifty-three percent (531/1,008) of subjects receiving EFV in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1,008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2‑4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing EFV and from 3% to 5% in subjects treated with a control regimen. 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 [see Warnings and Precautions (5.5)]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration (2.2)].

Analysis of long-term data from Study 006 showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among EFV‑treated subjects were generally similar to those in the indinavir-containing control arm.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning EFV therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased EFV levels despite standard dosing of EFV. 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 tablet is warranted.

Patients receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet should be alerted to the potential for additive central nervous system effects when Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is 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.

5.7 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 [see Adverse Reactions (6.2)].

Prior to initiation and during use of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet, 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 tablet is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min).

Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.2)]. 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. Some patients required hospitalization and renal replacement therapy. 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 tablet in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.8 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 tablet to avoid pregnancy while receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet and for 12 weeks after discontinuation [see Dosage and Administration (2.1), Use in Specific Populations (8.1, 8.3)].

5.9 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 tablet) 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.

Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. 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. In all pediatric trials, skeletal growth (height) appeared to be unaffected.

The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

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 [see Adverse Reactions (6.2)]. 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 [see Warnings and Precautions (5.7)].

5.10 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.

Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [see Drug Interactions (7.3)].

5.11 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 tablet, alone or in combination with other antiretrovirals. Treatment with Efavirenz, Emtricitabine and tenofovir disoproxil fumarate tablet 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).

5.12 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 tablet. 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-Barre 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.

5.13 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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6 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 Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical 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-naive 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+EFVb	AZT/3TC+EFV
	N=257	N=254
Fatigue	9%	8%
Depression	9%	7%
Nausea	9%	7%
Diarrhea	9%	5%
Dizziness	8%	7%
Upper respiratory tract infections	8%	5%
Sinusitis	8%	4%
Rash Eventc	7%	9%
Headache	6%	5%
Insomnia	5%	7%
Anxiety	5%	4%
Nasopharyngitis	5%	3%
Vomiting	2%	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 tablet or 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 tablet 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)

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.
	FTC + TDF + EFVa	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/mm3)	3%	5%
Fasting Triglycerides (>750 mg/dL)	4%	2%

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)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Efavirenz:

Cardiac Disorders

Palpitations

Ear and Labyrinth Disorders

Tinnitus, vertigo

Endocrine Disorders

Gynecomastia

Eye Disorders

Abnormal vision

Gastrointestinal Disorders

Constipation, malabsorption

General Disorders and Administration Site Conditions

Asthenia

Hepatobiliary Disorders

Hepatic enzyme increase, hepatic failure, hepatitis

Immune System Disorders

Allergic reactions

Metabolism and Nutrition Disorders

Redistribution/accumulation of body fat [see Warnings and Precautions (5.13)], hypercholesterolemia, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders

Arthralgia, myalgia, myopathy

Nervous System Disorders

Abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

Psychiatric Disorders

Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea

Skin and Subcutaneous Tissue Disorders

Flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome

Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir DF:

Immune System Disorders

Allergic reaction, including angioedema

Metabolism and Nutrition Disorders

Lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

Dyspnea

Gastrointestinal Disorders

Pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT)

Skin and Subcutaneous Tissue Disorders

Rash

Musculoskeletal and Connective Tissue Disorders

Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

Asthenia

The following adverse reactions, uled under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.