SYMFI

1 INDICATIONS AND USAGE SYMFI ® (efavirenz, lamivudine and tenofovir disoproxil fumarate) is 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 40 kg. SYMFI is a 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 is 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 40 kg. ( 1 )

2 DOSAGE AND ADMINISTRATION • Testing: Prior to initiation and during treatment with SYMFI, 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 SYMFI Prior to initiation of SYMFI, 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 SYMFI and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.4) ]. Monitor hepatic function prior to and during treatment with SYMFI [see Warnings and Precautions (5.9) ] . 2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 40 kg SYMFI is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 300 mg of lamivudine (3TC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of SYMFI in HIV-1-infected adults and pediatric patients who weigh at least 40 kg, and can swallow a solid tablet, is one tablet taken orally once daily. SYMFI 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 SYMFI is a fixed-dose combination tablet and cannot be dose adjusted, it is 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 SYMFI is 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) ] .

4 CONTRAINDICATIONS SYMFI is 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) ]. • SYMFI is 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 )

5 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 SYMFI 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 SYMFI 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 [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 SYMFI 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 SYMFI 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 SYMFI 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 SYMFI and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of concomitant drugs. 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 therapy with SYMFI; review concomitant medications during therapy with SYMFI; and monitor for the adverse reactions associated with the concomitant drugs. 5.4 New Onset or Worsening Renal Impairment TDF, a component of SYMFI 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 SYMFI, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patient s. Avoid SYMFI with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.3) ] . 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. 5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of SYMFI. 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 EFV-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. There have also been occasional postmarketing reports of death by suicide, delusions, 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. 5.6 Nervous System Symptoms Fifty-three percent (531/1008) of patients receiving EFV, a component of SYMFI, 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 (5.5) ] . Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration (2.2) ] . Late- onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz levels despite daily dosages of 600 mg of efavirenz. 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 efavirenz use, and whether discontinuation of SYMFI is warranted. 5.7 Embryo-Fetal Toxicity EFV, a component of SYMFI, 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 [see Use in Specific Populations (8.1 , 8.3) ]. 5.8 Skin and Systemic Hypersensitivity Reaction In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg EFV 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., Stevens-Johnson syndrome), alternate therapy should be considered [see Contraindications (4) ] . 5.9 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 SYMFI, 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 (2.1) ] . Consider discontinuing SYMFI in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue SYMFI if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. 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 of SYMFI, should be used with caution. Treatment with SYMFI 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, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2) ] . Caution should 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 has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating EFV therapy and at periodic intervals during therapy. 5.13 Bone Loss and Mineralization Effects Bone Mineral Density (BMD) In clinical trials in HIV-1-infected adults, TDF was associated with slightly greater decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions (6.1) ] . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. 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 exposuire in younger children is unknown. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. 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 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) ] . Arthralgia 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 (5.4) ]. 5.14 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including EFV, 3TC, and TDF. 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. 5.15 Fat Redistribution In HIV-infected patients, redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.16 QTc Prolongation QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.2 , 7.5) and Clinical Pharmacology (12.2) ] . Consider alternatives to products containing EFV 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.

7 DRUG INTERACTIONS • SYMFI should not be administered with other antiretroviral medications for the treatment of HIV-1 infection. ( 7.1 ) • Coadministration of SYMFI can alter the concentrations of other drugs and other drugs may alter the concentration of SYMFI. The potential for drug-drug interactions should be considered before and during therapy. ( 5.3 , 7 ) 7.1 Not Recommended with Other Antiretroviral Medications SYMFI 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 drug. 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 SYMFI. However, drug interaction studies have been conducted with the individual components of SYMFI (EFV, 3TC, and TDF) [see Clinical Pharmacology (12.3) ] . Drug interactions with EFV are summarized in Table 3 [for pharmacokinetics data see Clinical Pharmacology (12.3 , Tables 6 and 7) ]. This table includes potentially significant interactions, but is not all inclusive. Table 3. 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 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 The interaction between EFV and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ 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 ↓ bupropion Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose. Sertraline ↓ sertraline Increases in sertraline dosage should be guided by clinical response. Antifungals: Itraconazole Ketoconazole ↓ itraconazole ↓ hydroxyitraconazole ↓ ketoconazole Consider alternative antifungal treatment because no dose recommendation for itraconazole or ketoconazole can be made. Posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks. Anti-infective: Clarithromycin ↓ clarithromycin ↑ 14-OH metabolite Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterial: Rifabutin ↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. Rifampin ↓ EFV Increase EFV total daily dose to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more. Antimalarials: Artemether/lumefantrine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation [see Warnings and Precautions (5.16) ] . Atovaquone/ proguanil ↓ atovaquone ↓ proguanil Concomitant administration is not recommended. Calcium channel blockers: Diltiazem ↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodesmethyldiltiazem Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker 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. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. Hepatitis C antiviral agents: Boceprevir ↓ boceprevir Concomitant administration of boceprevir is not recommended. Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of EFV with elbasvir/grazoprevir is contraindicated [see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir ↓ pibrentasvir ↓ glecaprevir Coadministration of EFV is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Simeprevir ↓ simeprevir ↔ EFV Concomitant administration of simeprevir is not recommended. Velpatasvir/Sofosbuvir ↓ velpatasvir Coadministration of EFV and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir. Velpatasvir/Sofosbuvir/ Voxilaprevir ↓ velpatasvir ↓ voxilaprevir Coadministration of EFV and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Ledipasvir/Sofosbuvir ↑ TDF Monitor for adverse reactions associated with TDF. Hepatitis B antiviral agents Adefovir dipivoxil Concomitant administration of adefovir dipivoxil is not recommended. Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate ↓ active metabolites of norgestimate A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Implant Etonogestrel ↓ etonogestrel A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in EFV-exposed patients. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with EFV. Narcotic analgesic: Methadone ↓ methadone Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms. 7.6 Drugs without Clinically Significant Interactions No dosage adjustment is recommended when SYMFI is administered with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, and lorazepam. 7.7 Drugs Inhibiting Organic Cation Transporters 3TC, a component of SYMFI, is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim) [see Clinical Pharmacology (12.3) ] . No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of 3TC. 7.8 Sorbitol Coadministration of single doses of 3TC and sorbitol resulted in a sorbitol dose-dependent reduction in 3TC exposures. When possible, avoid use of sorbitol-containing medicines with 3TC [see Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS 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 are impaired concentration, abnormal dreams, headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, rash, dizziness, insomnia, pain, depression, asthenia, and cough. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 1. Selected Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0-144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 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 Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. 1% 8% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 1% 5% Laboratory Abnormalities Table 2 provides a list of laboratory abnormalities (Grades 3-4) 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 2. Grade 3-4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0-144 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% Pancreatitis Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.10) ]. Changes in Bone Mineral Density In HIV-1-infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.13) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use for each of the individual components of SYMFI (EFV, 3TC, and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EFV, 3TC, and TDF. Efavirenz Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.15) ]. Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo. Endocrine: gynecomastia. Gastrointestinal: constipation, malabsorption. Cardiovascular: flushing, palpitations. Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia. Musculoskeletal: arthralgia, myalgia, myopathy. Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia. Respiratory: dyspnea. Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome. Special Senses: abnormal vision, tinnitus. Lamivudine Body as a Whole: redistribution/accumulation of body fat [see Warnings and Precautions (5.15) ]. Endocrine and Metabolic: hyperglycemia. General: weakness. Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B [see Boxed Warning , Warnings and Precautions (5.1 , 5.2) ] . Hypersensitivity: anaphylaxis, urticaria. Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis. Skin: Alopecia, pruritus. Tenofovir Disoproxil Fumarate 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. Renal and Urinary Disorders: renal insufficiency, 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 [see Warnings and Precautions (5.4) ] . 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. General Disorders and Administration Site Conditions: asthenia. The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SYMFI 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 1000 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%-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. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. In published data from three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil fumarate from 28 to 32 weeks gestation through 1 to 2 months postpartum and followed for up to 12 months after delivery. There were no new safety findings in pregnant women compared with the known safety profile of tenofovir disoproxil fumarate in HBV-infected adults. An increased risk of adverse pregnancy-related outcomes was not observed; 2 stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in tenofovir disoproxil fumarate-exposed infants. Infants were followed for up to 12 months after delivery; there were no clinically relevant drug-related safety findings in infants exposed to tenofovir disoproxil fumarate during late gestation. Animal Data Efavirenz Effects of EFV on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, EFV 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microophthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, EFV was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, EFV was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose. Lamivudine 3TC was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to 3TC was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that 3TC is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, 3TC was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of 3TC. Tenofovir Disoproxil Fumarate TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of TDF.