Emtricitabineside effects

The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B Skin and Hypersensitivity Reactions Hepatotoxicity Depressive Disorders New Onset or Worsening Renal Impairment Lactic Acidosis/Severe Hepatomegaly with Steatosis Immune Reconstitution Syndrome Most common adverse reactions (incidence greater than or equal to 2%, all grades) are headache and sleep disturbances. 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 (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of ODEFSEY in Virologically-Suppressed Adult Participants with HIV-1 The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult participants with HIV-1 who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively. A total of 754 participants received one tablet of ODEFSEY daily. The most common adverse reactions (all Grades) reported in at least 2% of participants in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1). Over 98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity. The proportion of participants who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator. (All Grades) Reported in ≥1% of Virologically-Suppressed Adults with HIV-1 in Trial 1160 or Trial 1216 (Week 48 analysis) Adverse Reaction Trial 1160 Trial 1216 ODEFSEY (N=438) EFV/FTC/TDF (N=437) Data from Trials 1160 and 1216 do not provide an adequate basis for comparison of adverse reaction incidences between ODEFSEY and the FTC/RPV/TDF and EFV/FTC/TDF groups. ODEFSEY (N=316) FTC/RPV/TDF (N=313) Headache 2% 1% 0 1% Sleep Disturbances 2% 1% 0 <1% Flatulence 1% <1% <1% 1% Abnormal Dreams 1% 1% 0 2% Diarrhea 1% 3% 1% 2% Nausea 1% 1% 1% 1% Renal Laboratory Tests In Trial 1216, the median baseline eGFR was 104 mL per minute for participants who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48. In Trial 1160, the median baseline eGFR was 110 mL per minute for participants who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Bone Mineral Density Effects Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160. In Trial 1216, mean bone mineral density (BMD) increased in participants who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in participants who remained on FTC/RPV/TDF (0.08% lumbar spine, −0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY participants and 3.0% of FTC/RPV/TDF participants. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY participants and 1.2% of FTC/RPV/TDF participants. In Trial 1160, mean BMD increased in participants who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in participantswho remained on EFV/FTC/TDF (−0.05% lumbar spine, −0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY participants and 4.9% of EFV/FTC/TDF participants. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY participants and 3.3% of EFV/FTC/TDF participants. The long-term clinical significance of these BMD changes is not known. Serum Lipids Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2. Table 2 Lipid Values, Mean Change from Baseline Reported in Participants Receiving ODEFSEY, FTC/RPV/TDF and EFV/FTC/TDF in Trials 1216 and 1160 at 48 Weeks Trial 1216 Trial 1160 ODEFSEY N=316 [n=235] FTC/RPV/TDF N=314 [n=245] ODEFSEY N=438 [n=295] EFV/FTC/TDF N=437 [n=308] Baseline Week 48 Baseline Week 48 Baseline Week 48 Baseline Week 48 mg/dL Change The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values., Participants who received lipid-lowering agents during the treatment period were excluded. mg/dL Change, mg/dL Change, mg/dL Change, Total Cholesterol (fasted) 176 +17 171 0 193 -7 192 -3 HDL-Cholesterol (fasted) 50 +3 48 0 56 -4 55 -2 LDL-Cholesterol (fasted) 111 +13 108 +1 118 [n=296] for ODEFSEY group in Study 1160 for LDL-Cholesterol (fasted) -1 119 -1 Triglycerides (fasted) 116 +12 119 -9 139 -12 133 +3 Total Cholesterol to HDL Ratio 3.7 +0.2 3.8 +0.1 3.7 +0.2 3.8 0 Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Treatment-Naïve Adult Participants with HIV-1 In pooled 96-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reactions in participantstreated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2−4) were headache, depressive disorders, and insomnia. The proportion of participants who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317). Adrenal Function In the pooled Phase 3 trials, 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%) of participants 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%) in the EFV group. Of the participants who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 participants in the RPV group and 9 participants 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. Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult Participants with HIV-1 In pooled 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reaction in participants treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of participants discontinued FTC+TAF with EVG+COBI due to adverse event. Antiretroviral treatment-naïve adult participants treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use. Renal Laboratory Tests In two 48-week trials in antiretroviral treatment-naïve adults with HIV-1 treated with FTC+TAF with elvitegravir (EVG) plus cobicistat (COBI) (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In clinical trials of FTC+TAF with EVG+COBI in treatment-naïve participants and in virologically-suppressed participants switched to FTC+TAF with EVG+COBI with estimated creatinine clearance greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) participants. Bone Mineral Density Effects In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by -1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI participants. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI participants. The long-term clinical significance of these BMD changes is not known. Adverse Reactions in Clinical Trials in Pediatric Participants with HIV-1 In an open-label 48-week trial (TMC278-C213 Cohort 1) of 36 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%). In an open-label 48-week trial (TMC278-C213 Cohort 2) of 18 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 6 to less than 12 years (weighing at least 17 kg) treated with RPV and other antiretrovirals, the most common adverse reactions were decreased appetite (17%), vomiting (11%), ALT increased (11%), AST increased (11%), and rash (11%). In an open-label 48-week trial (TMC278HTX2002) of 26 virologically suppressed participants with HIV-1 less than 12 years of age (weighing at least 16 kg) treated with RPV and other antiretrovirals, the most commen adverse reactions were vomiting (15%), abdominal pain (12%), nausea (8%), ALT increased (12%), AST increased (8%), and decreased appetite (8%). In a 48-week, open-label trial, 50 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (Cohort 1) and 52 virologically-suppressed pediatric participants aged 6 to less than 12 years and weighing at least 25 kg (Cohort 2) received FTC+TAF with EVG+COBI. With the exception of a decrease in the mean CD4+ cell count observed in Cohort 2 of this study, the safety profile in pediatric participants who received this combination was similar to that in adults. Bone Mineral Density Effects Among the pediatric participants in Cohort 1 receiving FTC+TAF with EVG+COBI, mean BMD increased from baseline to Week 48, +4.2% at the lumbar spine and +1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were -0.07 for lumbar spine and -0.20 for TBLH at Week 48. In cohort 1, one participant had significant (at least 4%) lumbar spine BMD loss at Week 48. Among the pediatric participants in Cohort 2 receiving FTC+TAF with EVG+COBI, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48. In Cohort 2, six participants had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 participants also had at least 4% TBLH BMD loss at Week 48. Change from Baseline in CD4+ Cell Counts Although all participants in Cohort 2 receiving FTC+TAF with EVG+COBI had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 are presented in Table 3. All participants maintained their CD4+ cell counts above 400 cells/mm 3. Table 3 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to FTC+TAF with EVG+COBI Mean Change from Baseline Baseline Week 2 Week 4 Week 12 Week 24 Week 32 Week 48 CD4+ Cell Count (cells/mm 3 ) 961 Mean (SD) -117 -114 -112 -118 -62 -66 CD4% 38 +0.3% -0.1% -0.8% -0.8% -1.0% -0.6% Adrenal Function in Clinical Trials of RPV in Pediatric Participants In trial TMC278-C213 Cohort 1, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 micrograms/dL. Six of 30 (20%) participants 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 participants 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. In trial TMC278-C213 Cohort 2, basal cortisol at baseline was normal (≥9 μg/dL) for 4/18 participants, low for 13/18 participants, and missing for 1/18 participants. Among the 4 participants with normal basal cortisol at baseline, 3 participants had either normal basal cortisol levels (≥9 μg/dL) or normal cortisol levels 1 hour after ACTH stimulation (≥18.1 μg/dL) throughout the trial and/or at the last available visit (Week 24 and Week 72), and 1 participant had low basal cortisol at the last available assessment (Week 48) and no ACTH stimulation test was performed. Among the 13 participants with low basal cortisol pre-dose at baseline, 2 participants had low basal and ACTH stimulated cortisol values throughout the trial, including ACTH stimulated cortisol at baseline before starting treatment with RPV. For both participants, no adverse events suggestive for adrenal insufficiency were reported. The remaining 11 participants had normal serum cortisol values after ACTH stimulation at baseline and/or during treatment. In trial TMC278HTX2002, 15/26 participants had either normal basal cortisol (≥9 μg/dL) or normal cortisol 1 hour after ACTH stimulation (≥18.1 μg/dL), 9 had low basal cortisol on Day 1, and in 2 participants the baseline value was missing. From the 19 participants with low basal cortisol at Week 48, in 15 participants, the Week 48 serum cortisol levels returned to normal (≥248 nmol/L) after repeat serum basal cortisol testing or was normal after ACTH stimulation testing (≥500 nmol/L). In 4 participants, the serum cortisol levels remained low after repeat serum basal cortisol testing or after ACTH stimulation testing. At Week 48, 6 participants had normal (basal) cortisol (≥9 ug/dL) and the Week 48 result was not available for 1 participant.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postmarketing experience in patients receiving RPV or TAF-containing regimens. Because these 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: 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) Renal and Urinary Disorders Nephrotic syndrome Tenofovir alafenamide: Skin and Subcutaneous Tissue Disorders Angioedema, urticaria, and rash Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome