Emtricitabineside effects

The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV. Skin and Hypersensitivity Reactions. Hepatotoxicity. Depressive Disorders. New Onset or Worsening Renal Impairment. Bone Loss and Mineralization Defects. Lactic Acidosis/Severe Hepatomegaly with Steatosis. Immune Reconstitution Syndrome. Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2–4) are depressive disorders, insomnia, and headache. 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. 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 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. Adverse Reactions from Clinical Trials Experience in Adult Subjects In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History Studies C209 and C215 The safety assessment of RPV, 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 RPV in combination with other antiretroviral drugs as background regimen; most (N=550) received FTC/TDF as background regimen. The number of subjects randomized to the control arm EFV was 682, of which 546 received FTC/TDF as background regimen. The median duration of exposure for subjects in either treatment arm was 104 weeks. Adverse reactions observed at Week 96 in subjects who received RPV or EFV + FTC/TDF 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 RPV or EFV + FTC/TDF 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 RPV + FTC/TDF arm and 12 (2.2%) subjects in the EFV + FTC/TDF arm. Rash led to discontinuation in 1 (0.2%) subject in the RPV + FTC/TDF arm and 10 (1.8%) subjects in the EFV + FTC/TDF arm.

Common Adverse Reactions: Clinical adverse reactions to RPV or EFV of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are shown in Table 1. Table 1 Selected 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 RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) Preferred Term RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 Depressive disorders Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 2% 2% Headache 2% 2% Insomnia 2% 2% Abnormal dreams 1% 3% Dizziness 1% 7% Nausea 1% 2% Rash 1% 5% Rilpivirine: Adverse reactions of at least moderate intensity (≥Grade 2) that occurred in less than 2% of subjects treated with RPV 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 FTC and TDF 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 FTC or TDF 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 FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities in Adult Subjects The percentage of subjects treated with RPV + FTC/TDF or EFV + FTC/TDF in studies C209 and C215 with selected 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 RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) Laboratory Parameter Abnormality DAIDS Toxicity Range RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 N=number of subjects per treatment group ULN=Upper limit of normal value.

Note: Percentages were calculated versus the number of subjects in ITT population with FTC + TDF 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 3 751–1200 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 FTC or TDF 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 RPV 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 RPV group, and of −0.02 (−0.48, 0.44) micrograms/dL in the EFV group. In the RPV 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 EFV group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the RPV group and 9 subjects in the EFV 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 RPV group is not known.

Serum Creatinine: In the pooled Phase 3 trials of C209 and C215 in subjects treated with RPV plus any of the allowed background regimens (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with RPV. 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 RPV or EFV in Combination with FTC/TDF 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 RPV + FTC/TDF N=550 EFV + 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 RPV in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving RPV who were not coinfected. The same increase was also observed in the EFV arm. The pharmacokinetic exposure of RPV in coinfected subjects was comparable to that in subjects without coinfection. Adverse Reactions from 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 FTC 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 RPV (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 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 TDF were consistent with those observed in clinical trials of TDF in adults. For additional information, including information on bone mineral density changes, please consult the VIREAD ® prescribing information.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postmarketing experience in patients receiving RPV- or TDF-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.