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warnings and cautions
5 WARNINGS AND PRECAUTIONS • 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 toefavirenz, lamivudine and tenofovir disoproxil fumarate tabletsin patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. ( 5.2 ) •New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tabletsand periodically during treatment. Avoid administering efavirenz, lamivudine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) • Serious psychiatric symptoms:Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation.( 5.4 , 17 ) • 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. ( 5.5 , 17 ) • Embryo-Fetal Toxicity: Avoid administration in the first trimester of pregnancy as fetal harm may occur. ( 5.6 , 8.1 ) • Rash:Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops. ( 5.7 , 17 ) • 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. ( 5.8 , 8.7 ) • Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.9 ) • Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment 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):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 ) • Lactic acidosis and severe hepatomegaly with steatosis:Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.15 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets. Discontinuation of anti-HBV therapy, including 3TC and TDF, two components of efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets 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. 5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of efavirenz, lamivudine, and tenofovir disoproxil fumarate tabletsand 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 tablets and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of concomitant drugs. QTc prolongation has been observed with the use of EFV [see Drug Interactions ( 7.2 , 7.5 ) and Clinical Pharmacology ( 12.2 )], a component of efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets. Consider alternatives to efavirenz, lamivudine, and tenofovir disoproxil fumarate tabletswhen 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 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 tablets; review concomitant medications during therapy with efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets therapy; and monitor for the adverse reactions associated with the concomitant drugs. 5.3 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 )]. Prior to initiation and during use of efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatine, estimated creatine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Avoid efavirenz, lamivudine and tenofovir disoproxil fumarate tablets with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions ( 7.7 )]. 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 at-risk patients. 5.4 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. In controlled trials of 1008 patients treated with regimens containing EFV for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients 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 a study using EFV 600 mg, 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 study entry; similar associations were observed in both the EFV and control treatment groups. In a study using EFV 600 mg, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of EFV-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. In the ENCORE1 (Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy) Trial, at Week 48 the frequency (regardless of causality) of the most common (occurring in > 1% patients) psychiatric events among patients who received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) regimens, respectively, were: abnormal dreams (8.7%, 11.3%), insomnia (6.2%, 6.5%), somnolence (3.1%, 3.9%), depression (3.1%, 1.6%), nightmare (1.9%, 2.6%), sleep disorder (2.2%, 1.3%), and anxiety (1.2%, 1.3%). 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 [see Adverse Reactions ( 6.2 )]. Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz 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. 5.5 Nervous System Symptoms Fifty-three percent (531/1008) of patients receiving EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 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 patients treated with regimens containing EFV and from 3% to 5% in patients treated with a control regimen. Inform patients 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 ( 5.4 )]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration ( 2.2 )]. In the ENCORE1 Trial, at Week 48, 40% of EFV 400 mg recipients and 48% of EFV 600 mg recipients reported central nervous system disorders. The most common symptoms (> 10%) were dizziness (27% vs. 35%) and headache (11% vs. 11%). 5.6 Embryo-Fetal Toxicity 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 who are receiving EFV to avoid pregnancy [seeUse in Specific Populations ( 8.1 , 8.3 )] 5.7 Skin and Systemic Hypersensitivity Reaction In controlled clinical trials, 26% (266/1008) of patients treated with EFV 600 mg experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in patients treated with EFV in all studies 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 patients continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). EFV can generally be reinitiated in patients interrupting therapy because of rash. EFV should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stephens-Johnson syndrome), alternate therapy should be considered [see Contraindications ( 4 )]. In the ENCORE1 Trial at Week 48, different types of rash (such as rash, rash papular, rash maculopapular and rash pruritic) occurred in 32% of EFV 600 mg recipients and 26% of EFV 400 mg recipients. Grade 3-4 rash was reported in 3% of EFV 600 mg recipients and 1% of EFV 400 mg recipients. The discontinuation rate for rash in the ENCORE1 Trail was 3% of EFV 600 mg recipients and 1% of EFV 400 mg recipients. 5.8 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. 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. EFV, a component of efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets, is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving EFV [see Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.7 )]. Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration ( 2.4 )]. Consider discontinuing efavirenz, lamivudine, 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, lamivudine, and tenofovir disoproxil fumarate tablets if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. 5.9 Risk of Hepatic Decompensation When Usedwith Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as 3TC, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with 3TC in HIV-1/HCV co-infected patients [see Clinical Pharmacology ( 12.3 )], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and 3TC should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6). See the complete prescribing information for interferon and ribavirin. 5.10 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, 3TC, a component ofefavirenz, lamivudine, and tenofovir disoproxil fumarate tablets, should be used with caution. Treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions ( 6.1 )]. 5.11 Convulsions Convulsions have been observed in patients receiving EFV, a component of efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets, generally in the presence of known medical history of seizures [see Nonclinical Toxicology ( 13.2 )]. 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 ( 7.5 )]. 5.12 Lipid Elevations 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. Cholesterol and triglyceride testing should be performed before initiating therapy with efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets and at periodic intervals during therapy. 5.13 Bone Loss and Mineralization Defects Bone Mineral Density In clinical trials in HIV-1 infected adults, TDF, a component of efavirenz, lamivudine, 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. Clinical trials evaluating TDF in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, 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 HBV-infected subjects 12 years to less than 18 years of age. In all pediatric trials, skeletal growth (height) appeared to be unaffected for the duration of the clinical trials. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown. 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. 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. If bone abnormalities are suspected, 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 the use of TD [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 products containing TDF [see Warnings and Precautions ( 5.3 )]. 5.14 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of efavirenz, lamivudine 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, and Guillain-Barre syndrome) 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. 5.15 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 analogues, including 3TC and TDF, two componentsof efavirenz, lamivudine, and tenofovir disoproxil fumarate tablets,alone or in combination with other antiretrovirals. Treatment with efavirenz, lamivudine, 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).