FDA label 95d80140-58d3-4503-ad30-7fb7bc80dc74

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of COMPLERA, in combination with other antiretrovirals [See Warnings and Precautions (5.1) ] . 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 (5.2) ] . WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of COMPLERA. ( 5.1 ) 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. ( 5.2 )

5 WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with COMPLERA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering COMPLERA with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) Caution should be given to prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine. ( 5.4 ) Caution should be given to prescribing COMPLERA with drugs with a known risk of Torsade de Pointes. ( 5.4 ) Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.5 ) Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Monitor serum liver biochemistries before and during treatment with COMPLERA in patients with underlying hepatic disease or marked elevations in serum liver biochemistries. Also consider monitoring serum liver biochemistries in patients without risk factors. ( 5.6 ) 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. ( 5.7 ) Coadministration with other products: Do not use with drugs containing emtricitabine, rilpivirine or tenofovir disoproxil fumarate including ATRIPLA, EDURANT, EMTRIVA, STRIBILD, TRUVADA, VIREAD, or with drugs containing lamivudine. Do not administer in combination with HEPSERA. ( 5.8 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.9 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.10 ) 5.1 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, a component of COMPLERA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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). 5.2 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. 5.3 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 creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with COMPLERA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA ® . COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent. 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 creatinine clearance below 50 mL per minute should not receive COMPLERA. 5.4 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. 5.5 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. During the Phase 3 trials (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 Grade 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. 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. 5.6 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 serum liver biochemistries prior to treatment may be at increased risk for worsening or development of serum liver biochemistries elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in 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 serum liver biochemistries prior to treatment initiation. Serum liver biochemistries monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. 5.7 Decreases in Bone Mineral Density Bone mineral density (BMD) monitoring should be considered for HIV-1 infected 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. Tenofovir Disoproxil Fumarate: In a 144 week study of HIV-1 infected treatment-naive adult subjects treated with tenofovir DF (Study 903), decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir DF group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF-treated subjects vs. 21% of the comparator 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 tenofovir DF group and 6 subjects in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD ® prescribing information. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2) ] . 5.8 Coadministration with Other Products COMPLERA should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir DF (ATRIPLA ® , Edurant ® , EMTRIVA, STRIBILD™, TRUVADA ® , VIREAD), with medicinal products containing lamivudine (Epivir ® , Epivir-HBV ® , Epzicom ® , Combivir ® , Trizivir ® ), or with adefovir dipivoxil (HEPSERA) . 5.9 Fat Redistribution 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 antiretroviral therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established. 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 drug reactions are discussed in other sections of the labeling: Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning , Warnings and Precautions (5.1) ] . Severe Acute Exacerbations of Hepatitis B [See Boxed Warning , Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3) ] . Depressive Disorders [See Warnings and Precautions (5.5) ]. Hepatotoxicity [See Warnings and Precautions (5.6) ] . Decreases in Bone Mineral Density [See Warnings and Precautions (5.7) ] . Immune Reconstitution Syndrome [See Warnings and Precautions (5.10) ] . Most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2–4) are depressive disorders, insomnia, and headache. ( 6.1 ) Most common adverse drug reactions to emtricitabine and tenofovir disoproxil fumarate (incidence ≥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 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. 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-naive 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 drug reactions (ADR) observed at Week 96 in subjects who received rilpivirine or efavirenz plus 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 drug 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 ADR, regardless of severity, was 2% and 5%, respectively. The most common ADRs 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%) subjects in the rilpivirine + emtricitabine/tenofovir DF arm and 10 (1.8%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Common Adverse Drug Reactions Clinical ADRs 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 Drug Reactions (Grades 2–4) Reported in ≥2% of Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 analysis) Rilpivirine + FTC/TDF Efavirenz + FTC/TDF N=550 N=546 Gastrointestinal Disorder Nausea 1% 2% Nervous System Disorders Headache 2% 2% Dizziness 1% 7% Psychiatric Disorders Depressive disorders 2% 2% Insomnia 2% 2% Abnormal dreams 1% 3% Skin and Subcutaneous Tissue Disorders Rash 1% 5% Rilpivirine: Treatment-emergent adverse drug 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. Emtricitabine and Tenofovir Disoproxil Fumarate: The following adverse reactions were observed in clinical trials of emtricitabine or tenofovir DF in combination with other antiretroviral agents: The most common adverse drug reactions occurred in at least 10% of treatment-naive subjects in a phase 3 clinical trial of emtricitabine and tenofovir DF in combination with another antiretroviral agent are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. In addition, adverse drug reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include 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. Laboratory Abnormalities: 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 (Grade 1 to 4), representing worst grade toxicity are presented in Table 2. Table 2 Selected Laboratory Abnormalities (Grades 1–4) Reported in Subjects Who Received Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis) Rilpivirine + FTC/TDF Efavirenz + FTC/TDF Laboratory Parameter Abnormality, (%) DAIDS Toxicity Range 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 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 3 751–1,200 mg/dL 1% 2% Grade 4 >1,200 mg/dL 0 1% Emtricitabine or Tenofovir Disoproxil Fumarate: The following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of increased pancreatic amylase (>2.0 x ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 x 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) occurred. Adrenal Function In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (95% CI: -30.9; -7.4) nmol/L in the rilpivirine group, and of +0.1 (95% CI: -12.6; 12.8) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine group (+18.4± 8.36 nmol/L) than in the efavirenz group (+54.1± 7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. Effects on adrenal function were comparable by background N(t)RTIs. Serum Creatinine In the pooled Phase 3 trials of C209 and C215 trials in subjects treated with rilpivirine plus any of the allowed background regimen (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 four weeks of treatment with a mean change of 0.1 mg/dL (range: -0.3 mg/dL 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 Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 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 Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus In patients 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of emtricitabine or tenofovir DF. 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. Rilpivirine: Renal and Urinary Disorders nephrotic syndrome Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section. 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 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 width="75%" ID="i37a3d42e-5385-4343-839a-67be720836a7"> <caption>Table 1 Selected Treatment-Emergent Adverse Drug Reactions (Grades 2&#x2013;4) Reported in &#x2265;2% of Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 analysis)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule" rowspan="2"/> <th styleCode="Botrule Rrule">Rilpivirine + FTC/TDF</th> <th styleCode="Botrule Rrule">Efavirenz + FTC/TDF</th> </tr> <tr> <th styleCode="Rrule" align="center">N=550</th> <th styleCode="Rrule">N=546</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule">Gastrointestinal Disorder</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 Rrule"> Depressive disorders </td> <td styleCode="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 Rrule"> Abnormal dreams</td> <td styleCode="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 width="100%" ID="i19179b71-de98-444c-890c-d85703849bec"> <caption>Table 2 Selected Laboratory Abnormalities (Grades 1&#x2013;4) Reported in Subjects Who Received Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis)</caption> <col width="34%" align="left" valign="top"/> <col width="22%" align="center" valign="top"/> <col width="22%" align="center" valign="top"/> <col width="22%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule"/> <th styleCode="Rrule">Rilpivirine + FTC/TDF</th> <th styleCode="Rrule">Efavirenz + FTC/TDF</th> </tr> <tr> <th styleCode="Lrule Rrule">Laboratory Parameter Abnormality, (%)</th> <th styleCode="Rrule">DAIDS Toxicity Range</th> <th styleCode="Rrule" valign="middle">N=550</th> <th styleCode="Rrule" valign="middle">N=546</th> </tr> </thead> <tfoot> <tr> <td colspan="4" align="left">N = number of subjects per treatment group</td> </tr> <tr> <td colspan="4" align="left">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 styleCode="Lrule Rrule" colspan="4"> <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 </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" valign="middle">14%</td> <td styleCode="Rrule" valign="middle">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" valign="middle">6%</td> <td styleCode="Rrule" valign="middle">18%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;300 mg/dL</td> <td styleCode="Rrule" valign="middle">&lt;1%</td> <td styleCode="Rrule" valign="middle">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" valign="middle">13%</td> <td styleCode="Rrule" valign="middle">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" valign="middle">5%</td> <td styleCode="Rrule" valign="middle">13%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3 </td> <td styleCode="Rrule">&gt;190 mg/dL</td> <td styleCode="Rrule" valign="middle">1%</td> <td styleCode="Rrule" valign="middle">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;1,200 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;1,200 mg/dL</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">1%</td> </tr> </tbody> </table>

<table width="100%" ID="i3569b0ed-1ed7-472d-81d0-1bd24c0a235f"> <caption>Table 3 Lipid Values Reported in Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 </caption> <col width="18%" align="left" valign="top"/> <col width="6%" align="center" valign="middle"/> <col width="12%" align="center" valign="middle"/> <col width="12%" align="center" valign="middle"/> <col width="11%" align="center" valign="middle"/> <col width="6%" align="center" valign="middle"/> <col width="12%" align="center" valign="middle"/> <col width="12%" align="center" valign="middle"/> <col width="11%" align="center" valign="middle"/> <thead> <tr> <th styleCode="Lrule Rrule" rowspan="2"/> <th styleCode="Botrule Rrule" colspan="8">Pooled Data from the Week 96 Analysis of C209 and C215 Trials</th> </tr> <tr styleCode="Botrule"> <th styleCode="Rrule" colspan="4" align="center">Rilpivirine + FTC/TDF N=550</th> <th styleCode="Rrule" colspan="4">Efavirenz + FTC/TDF N=546</th> </tr> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule" align="center">N</th> <th styleCode="Rrule">Baseline</th> <th styleCode="Rrule" colspan="2">Week 96</th> <th styleCode="Rrule">N</th> <th styleCode="Rrule">Baseline</th> <th styleCode="Rrule" colspan="2">Week 96</th> </tr> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule" valign="middle">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="table3b">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="table3b"/> (mg/dL)</th> </tr> </thead> <tfoot> <tr> <td colspan="9" align="left">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">-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">-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>