FDA label 5b88be70-8056-442d-8fac-a374f029e06a

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD, which are components of COMPLERA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. 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. COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of COMPLERA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. ( 5.2 ) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with COMPLERA. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein before initiating treatment with COMPLERA and periodically during treatment. Avoid administering COMPLERA with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.4 ) Caution should be given to prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine. ( 5.5 ) Caution should be given to prescribing COMPLERA with drugs with a known risk of Torsade de Pointes. ( 5.5 ) Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.6 ) Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with COMPLERA in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. ( 5.7 ) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.8 ) Coadministration with other products: Do not use with drugs containing emtricitabine, tenofovir disoproxil fumarate, or tenofovir alafenamide, including ATRIPLA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, and VIREAD, or with drugs containing lamivudine. Do not administer in combination with HEPSERA. Do not coadminister in combination with rilpivirine (Edurant) unless required for dose adjustment when coadministered with rifabutin. ( 5.9 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.10 ) 5.1 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy. COMPLERA is not approved for the treatment of chronic HBV infection, and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of COMPLERA. In some patients infected with HBV and treated with EMTRIVA ® , the exacerbations of hepatitis B were associated with liver decompensation and liver failure. 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 COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. 5.2 Skin and Hypersensitivity Reactions Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects receiving rilpivirine plus emtricitabine/tenofovir DF. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [See Adverse Reactions (6.1 and 6.2) ] . Discontinue COMPLERA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated. 5.3 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF [See Adverse Reactions (6.2) ] . It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with COMPLERA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA ® , it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of COMPLERA and periodically during COMPLERA therapy. COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal 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 tenofovir DF. 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. Emtricitabine and tenofovir are principally eliminated by the kidney; however, rilpivirine is not. Since COMPLERA is a combination product and the dose of the individual components cannot be altered, patients with estimated creatinine clearance below 50 mL per minute should not receive COMPLERA. 5.4 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 tenofovir DF and emtricitabine, components of COMPLERA, alone or in combination with other antiretrovirals. Treatment with COMPLERA 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). 5.5 Drug Interactions Caution should be given to prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine [See Contraindications (4) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] . In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [See Drug Interactions (7) and Clinical Pharmacology (12.2) ] . COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes. 5.6 Depressive Disorders The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine whether the risks of continued therapy outweigh the benefits. During the Phase 3 trials in adults (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (n=686) or efavirenz (n=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the rilpivirine arm. During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving rilpivirine through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject. 5.7 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Patients with underlying hepatitis B or C, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in adult patients receiving a rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with COMPLERA is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. 5.8 Bone Effects of Tenofovir DF Bone Mineral Density In clinical trials in HIV-1-infected adults, tenofovir DF 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 tenofovir DF. For more information, please consult the VIREAD ® prescribing information. Clinical trials evaluating tenofovir DF 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 tenofovir DF-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. For more information, please consult the VIREAD prescribing information. The effects of tenofovir DF-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 the use of tenofovir DF [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 tenofovir DF [See Warnings and Precautions (5.3) ]. 5.9 Coadministration with Other Products COMPLERA is a fixed-dose combination of rilpivirine, emtricitabine, and tenofovir DF. Do not coadminister COMPLERA with other drugs containing emtricitabine, tenofovir DF, or tenofovir alafenamide, including ATRIPLA ® , DESCOVY ® , EMTRIVA, GENVOYA ® , ODEFSEY ® , STRIBILD ® , TRUVADA ® , VEMLIDY ® , or VIREAD; or with medicinal products containing lamivudine (Epivir ® , Epivir-HBV ® , Epzicom ® , Combivir ® , Triumeq ® , Trizivir ® ); or with adefovir dipivoxil (HEPSERA) . COMPLERA should not be administered with rilpivirine (Edurant) unless needed for dose adjustment (e.g., with rifabutin) [See Dosage and Administration (2) and Drug Interactions (7.5) ]. 5.10 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of COMPLERA. 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-Barré 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [See Boxed Warning , Warnings and Precautions (5.1) ] . Skin and Hypersensitivity Reactions [See Warnings and Precautions (5.2) ]. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions (5.4) ] . Drug Interactions [See Warnings and Precautions (5.5) ]. Depressive Disorders [See Warnings and Precautions (5.6) ]. Hepatotoxicity [See Warnings and Precautions (5.7) ] . Bone Effects of Tenofovir DF [See Warnings and Precautions (5.8) ] . Immune Reconstitution Syndrome [See Warnings and Precautions (5.10) ] . Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2–4) are depressive disorders, insomnia, and headache. ( 6.1 ) Most common adverse reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions from Clinical Trials Experience in Adult Subjects 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. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History Studies C209 and C215 Treatment-Emergent Adverse Drug Reactions: The safety assessment of rilpivirine, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 subjects in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1-infected adult subjects. A total of 686 subjects received rilpivirine in combination with other antiretroviral drugs as background regimen; most (N=550) received emtricitabine/tenofovir DF as background regimen. The number of subjects randomized to the control arm efavirenz was 682, of which 546 received emtricitabine/tenofovir DF as background regimen [See Clinical Studies (14) ] . The median duration of exposure for subjects in either treatment arm was 104 weeks. Adverse reactions observed at Week 96 in subjects who received rilpivirine or efavirenz + emtricitabine/tenofovir DF as background regimen are shown in Table 1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant). The proportion of subjects who discontinued treatment with rilpivirine or efavirenz + emtricitabine/tenofovir DF due to adverse reactions, regardless of severity, was 2% and 5%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the rilpivirine + emtricitabine/tenofovir DF arm and 12 (2.2%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Rash led to discontinuation in 1 (0.2%) subject in the rilpivirine + emtricitabine/tenofovir DF arm and 10 (1.8%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Common Adverse Reactions: Clinical adverse reactions to rilpivirine or efavirenz of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are shown in Table 1. Table 1 Selected Treatment-Emergent Adverse Reactions Frequencies of adverse reactions are based on all Grades 2–4 treatment-emergent adverse events assessed to be related to study drug. (Grades 2–4) Reported in ≥2% of Adult Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis) System Organ Class Preferred Term Rilpivirine + FTC/TDF Efavirenz + FTC/TDF N=550 N=546 Gastrointestinal Disorders Nausea 1% 2% Nervous System Disorders Headache 2% 2% Dizziness 1% 7% Psychiatric Disorders Depressive disorders Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 2% 2% Insomnia 2% 2% Abnormal dreams 1% 3% Skin and Subcutaneous Tissue Disorders Rash 1% 5% Rilpivirine: Treatment-emergent adverse reactions of at least moderate intensity (≥Grade 2) that occurred in less than 2% of subjects treated with rilpivirine plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis. In Virologically-Suppressed HIV-1-Infected Adult Subjects No new adverse reactions to COMPLERA were identified in stable, virologically-suppressed subjects switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% (Study 106) after switching to COMPLERA. Emtricitabine and Tenofovir DF: The most common adverse reactions that occurred in at least 10% of HIV-1-infected treatment-naïve adult subjects in a Phase 3 clinical trial of emtricitabine and tenofovir DF in combination with another antiretroviral agent were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials included abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-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. 6.2 Laboratory Abnormalities in Adult Subjects The percentage of subjects treated with rilpivirine + emtricitabine/tenofovir DF or efavirenz + emtricitabine/tenofovir DF in studies C209 and C215 with selected treatment-emergent laboratory abnormalities (Grades 1–4), representing worst-grade toxicity, is presented in Table 2. Table 2 Selected Laboratory Abnormalities (Grades 1–4) Reported in Adult Subjects Who Received Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis) Laboratory Parameter Abnormality DAIDS Toxicity Range Rilpivirine + FTC/TDF Efavirenz + FTC/TDF N=550 N=546 N=number of subjects per treatment group Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine + tenofovir DF as background regimen. BIOCHEMISTRY Increased Creatinine Grade 1 1.1–1.3 × ULN ULN=Upper limit of normal value. 6% 1% Grade 2 >1.3–1.8 × ULN 1% 1% Grade 3 >1.8–3.4 × ULN <1% 0 Grade 4 >3.4 × ULN 0 <1% Increased AST Grade 1 1.25–2.5 × ULN 16% 19% Grade 2 >2.5–5.0 × ULN 4% 7% Grade 3 >5.0–10.0 × ULN 2% 3% Grade 4 >10.0 × ULN 1% 1% Increased ALT Grade 1 1.25–2.5 × ULN 19% 22% Grade 2 >2.5–5.0 × ULN 5% 7% Grade 3 >5.0–10.0 × ULN 1% 2% Grade 4 >10.0 × ULN 1% 1% Increased Total Bilirubin Grade 1 1.1–1.5 × ULN 6% <1% Grade 2 >1.5–2.5 × ULN 3% 1% Grade 3 >2.5–5.0 × ULN 1% <1% Increased Total Cholesterol (fasted) Grade 1 200–239 mg/dL 14% 31% Grade 2 240–300 mg/dL 6% 18% Grade 3 >300 mg/dL <1% 2% Increased LDL Cholesterol (fasted) Grade 1 130–159 mg/dL 13% 28% Grade 2 160–190 mg/dL 5% 13% Grade 3 >190 mg/dL 1% 4% Increased Triglycerides (fasted) Grade 2 500–750 mg/dL 1% 2% Grade 3 751–1200 mg/dL 1% 2% Grade 4 >1200 mg/dL 0 1% Emtricitabine or Tenofovir DF: The following Grade 3 or 4 laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: increased pancreatic amylase (>2.0 × ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 × ULN), increased alkaline phosphatase (>550 U/L), increased or decreased serum glucose (<40 or >250 mg/dL), increased glycosuria (≥3+), increased creatine kinase (M: >990 U/L; F: >845 U/L), decreased neutrophils (<750/mm 3 ), and increased hematuria (>75 RBC/HPF). Adrenal Function: In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimens (N=686), at Week 96 there was an overall mean change from baseline in basal cortisol of –0.69 (−1.12, 0.27) micrograms/dL in the rilpivirine group, and of −0.02 (−0.48, 0.44) micrograms/dL in the efavirenz group. In the rilpivirine group, 43/588 (7.3%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the efavirenz group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the rilpivirine group and 9 subjects in the efavirenz group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known. Serum Creatinine: In the pooled Phase 3 trials of C209 and C215 in subjects treated with rilpivirine plus any of the allowed background regimens (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with rilpivirine. Most of this increase occurred within the first 4 weeks of treatment, with a mean change of 0.1 mg/dL (range –0.3 to 0.6 mg/dL) observed through Week 96. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant, and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs. Serum Lipids: Changes from baseline in total cholesterol, LDL-cholesterol, and triglycerides are presented in Table 3. Table 3 Lipid Values Reported in Adult Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 Excludes subjects who received lipid lowering agents during the treatment period. Pooled Data from the Week 96 Analysis of C209 and C215 Trials Rilpivirine + FTC/TDF N=550 Efavirenz + FTC/TDF N=546 N Baseline Week 96 N Baseline Week 96 Mean Mean (mg/dL) Mean (mg/dL) Mean Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Change (mg/dL) N=number of subjects per treatment group Total Cholesterol (fasted) 430 162 164 2 401 160 186 26 HDL-cholesterol (fasted) 429 42 45 4 399 40 50 11 LDL-cholesterol (fasted) 427 97 97 –1 397 96 110 14 Triglycerides (fasted) 430 123 109 –14 401 127 133 6 Adult Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In adult subjects coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The same increase was also observed in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection. 6.3 Clinical Trials Experience in Pediatric Subjects Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with EMTRIVA in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information. Rilpivirine: The safety assessment is based on the Week 48 analysis of the single-arm, open-label Phase 2 trial, TMC278-C213, in which 36 antiretroviral treatment-naïve HIV-1-infected subjects 12 to less than 18 years of age and weighing at least 32 kg received rilpivirine (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for subjects was 63.5 weeks. No subjects discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults. Adverse reactions were reported in 19 pediatric subjects (52.8%). Most adverse reactions were Grade 1 or 2. The most common adverse reactions reported in at least 2 subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%), and rash (5.6%). Observed laboratory abnormalities were comparable to those in adults. For additional information, please consult the Edurant prescribing information. Adrenal Function In trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL. Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known. 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 VIREAD were consistent with those observed in clinical trials of VIREAD in adults [See Warnings and Precautions (5.8) ]. For additional information, including information on bone mineral density changes, please consult the VIREAD prescribing information. 6.4 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving rilpivirine- or tenofovir DF-containing regimens. 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. COMPLERA: Metabolism and Nutrition Disorders weight increased Skin and Subcutaneous Tissue Disorders severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Rilpivirine: Renal and Urinary Disorders nephrotic 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, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

<table ID="Table1" width="75%"> <caption>Table 1 Selected Treatment-Emergent Adverse Reactions<footnote>Frequencies of adverse reactions are based on all Grades 2&#x2013;4 treatment-emergent adverse events assessed to be related to study drug.</footnote> (Grades 2&#x2013;4) Reported in &#x2265;2% of Adult Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis)</caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr> <th rowspan="2" styleCode="Lrule Rrule">System Organ Class Preferred Term</th> <th styleCode="Botrule Rrule">Rilpivirine + FTC/TDF</th> <th styleCode="Botrule Rrule">Efavirenz + FTC/TDF</th> </tr> <tr> <th align="center" styleCode="Rrule">N=550</th> <th styleCode="Rrule">N=546</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule">Gastrointestinal Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">2%</td> </tr> <tr> <td styleCode="Lrule Rrule">Nervous System Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">7%</td> </tr> <tr> <td styleCode="Lrule Rrule">Psychiatric Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule"> Depressive disorders<footnote>Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. </footnote> </td> <td styleCode="Lrule Rrule">2%</td> <td styleCode="Rrule">2%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Insomnia</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Abnormal dreams</td> <td styleCode="Lrule Rrule">1%</td> <td styleCode="Rrule">3%</td> </tr> <tr> <td styleCode="Lrule Rrule">Skin and Subcutaneous Tissue Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Rash</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">5%</td> </tr> </tbody> </table>

<table ID="Table2" width="75%"> <caption>Table 2 Selected Laboratory Abnormalities (Grades 1&#x2013;4) Reported in Adult Subjects Who Received Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis)</caption> <col align="left" valign="middle" width="31%"/> <col align="center" valign="middle" width="27%"/> <col align="center" valign="middle" width="21%"/> <col align="center" valign="middle" width="21%"/> <thead> <tr> <th rowspan="2" styleCode="Lrule Rrule">Laboratory Parameter Abnormality</th> <th rowspan="2" styleCode="Rrule">DAIDS Toxicity Range</th> <th styleCode="Botrule Rrule">Rilpivirine + FTC/TDF</th> <th styleCode="Botrule Rrule">Efavirenz + FTC/TDF</th> <th/> </tr> <tr styleCode="Botrule"> <th align="center" styleCode="Rrule">N=550</th> <th styleCode="Rrule">N=546</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4">N=number of subjects per treatment group Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine + tenofovir DF as background regimen.</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule"> <content styleCode="bold italics">BIOCHEMISTRY</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased Creatinine</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 1</td> <td styleCode="Rrule">1.1&#x2013;1.3 &#xD7; ULN<footnote>ULN=Upper limit of normal value.</footnote> </td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;1.3&#x2013;1.8 &#xD7; ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;1.8&#x2013;3.4 &#xD7; ULN</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt;3.4 &#xD7; ULN</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased AST</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 1</td> <td styleCode="Rrule">1.25&#x2013;2.5 &#xD7; ULN</td> <td styleCode="Rrule">16%</td> <td styleCode="Rrule">19%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;2.5&#x2013;5.0 &#xD7; ULN</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;5.0&#x2013;10.0 &#xD7; ULN</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt;10.0 &#xD7; ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased ALT</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 1</td> <td styleCode="Rrule">1.25&#x2013;2.5 &#xD7; ULN</td> <td styleCode="Rrule">19%</td> <td styleCode="Rrule">22%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;2.5&#x2013;5.0 &#xD7; ULN</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;5.0&#x2013;10.0 &#xD7; ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt;10.0 &#xD7; ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased Total Bilirubin</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 1</td> <td styleCode="Rrule">1.1&#x2013;1.5 &#xD7; ULN</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;1.5&#x2013;2.5 &#xD7; ULN</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;2.5&#x2013;5.0 &#xD7; ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased Total Cholesterol (fasted)</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 1</td> <td styleCode="Rrule">200&#x2013;239 mg/dL</td> <td styleCode="Rrule">14%</td> <td styleCode="Rrule">31%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">240&#x2013;300 mg/dL</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">18%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;300 mg/dL</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased LDL Cholesterol (fasted)</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 1</td> <td styleCode="Rrule">130&#x2013;159 mg/dL</td> <td styleCode="Rrule">13%</td> <td styleCode="Rrule">28%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">160&#x2013;190 mg/dL</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">13%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;190 mg/dL</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased Triglycerides (fasted)</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">500&#x2013;750 mg/dL</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">751&#x2013;1200 mg/dL</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">2%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt;1200 mg/dL</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">1%</td> </tr> </tbody> </table>

<table ID="Table3" width="90%"> <caption>Table 3 Lipid Values Reported in Adult Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215<footnote>Excludes subjects who received lipid lowering agents during the treatment period.</footnote> </caption> <col align="left" valign="middle" width="12%"/> <col align="center" valign="middle" width="11%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="11%"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th colspan="8" styleCode="Botrule Rrule">Pooled Data from the Week 96 Analysis of C209 and C215 Trials</th> </tr> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule"/> <th colspan="4" styleCode="Rrule">Rilpivirine + FTC/TDF N=550</th> <th colspan="4" styleCode="Rrule">Efavirenz + FTC/TDF N=546</th> </tr> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule"/> <th align="center" styleCode="Rrule">N</th> <th styleCode="Rrule">Baseline</th> <th colspan="2" styleCode="Rrule">Week 96</th> <th styleCode="Rrule">N</th> <th styleCode="Rrule">Baseline</th> <th colspan="2" styleCode="Rrule">Week 96</th> </tr> <tr> <th styleCode="Lrule Rrule">Mean</th> <th styleCode="Rrule"/> <th styleCode="Rrule">Mean (mg/dL)</th> <th styleCode="Rrule">Mean (mg/dL)</th> <th styleCode="Rrule">Mean Change<footnote ID="t3f1">The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.</footnote> (mg/dL)</th> <th styleCode="Rrule"/> <th styleCode="Rrule">Mean (mg/dL)</th> <th styleCode="Rrule">Mean (mg/dL)</th> <th styleCode="Rrule">Mean Change<footnoteRef IDREF="t3f1"/> (mg/dL)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="9">N=number of subjects per treatment group</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Total Cholesterol (fasted)</td> <td styleCode="Rrule">430</td> <td styleCode="Rrule">162</td> <td styleCode="Rrule">164</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">401</td> <td styleCode="Rrule">160</td> <td styleCode="Rrule">186</td> <td styleCode="Rrule">26</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">HDL-cholesterol (fasted)</td> <td styleCode="Rrule">429</td> <td styleCode="Rrule">42</td> <td styleCode="Rrule">45</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">399</td> <td styleCode="Rrule">40</td> <td styleCode="Rrule">50</td> <td styleCode="Rrule">11</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">LDL-cholesterol (fasted)</td> <td styleCode="Rrule">427</td> <td styleCode="Rrule">97</td> <td styleCode="Rrule">97</td> <td styleCode="Rrule">&#x2013;1</td> <td styleCode="Rrule">397</td> <td styleCode="Rrule">96</td> <td styleCode="Rrule">110</td> <td styleCode="Rrule">14</td> </tr> <tr> <td styleCode="Lrule Rrule">Triglycerides (fasted)</td> <td styleCode="Rrule">430</td> <td styleCode="Rrule">123</td> <td styleCode="Rrule">109</td> <td styleCode="Rrule">&#x2013;14</td> <td styleCode="Rrule">401</td> <td styleCode="Rrule">127</td> <td styleCode="Rrule">133</td> <td styleCode="Rrule">6</td> </tr> </tbody> </table>