DESCOVY

3) ] . The safety and effectiveness of DESCOVY coadministered with an HIV-1 protease inhibitor that is administered with either ritonavir or cobicistat have not been established in adults with creatinine clearance below 15 mL per minute, with or without hemodialysis.

For specific dosing recommendations for coadministered antiretroviral drugs, refer to their respective prescribing information [see Drug Interactions (7) ] . 4 Recommended Dosage for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 14 kg to Less than 35 kg The recommended dosage of DESCOVY for treatment of HIV-1 in pediatric patients is based on body weight and is provided in Table 1 .

3) ] who are receiving DESCOVY with other antiretroviral agents, including darunavir (DRV) and cobicistat (COBI) but not including other HIV-1 protease inhibitors that are administered with either ritonavir or cobicistat. Table 1 Dosing for Treatment of HIV-1 Infection in Pediatric Patients Weighing 14 to Less than 35 kg Body Weight (kg) DESCOVY Dosage 25 kg to less than 35 kg One tablet containing 200 mg of FTC and 25 mg of TAF taken orally once daily 14 kg to less than 25 kg One tablet containing 120 mg of FTC and 15 mg of TAF taken orally once daily For specific dosing recommendations for coadministered antiretroviral drugs, refer to their respective prescribing information [see Drug Interactions (7) ] .

5 Recommended Dosage for HIV-1 PrEP in Adults and Adolescents Weighing at Least 35 kg The dosage of DESCOVY for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 25 mg of TAF) once daily taken orally with or without food in: adults and adolescents without HIV-1 weighing at least 35 kg and with a creatinine clearance greater than or equal to 30 mL per minute; or adults without HIV-1 and with creatinine clearance below 15 mL per minute who are receiving chronic hemodialysis.

3) ]. 6) ] .

Across these trials, 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. 5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at 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).

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. 95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI participants. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI participants.

Adverse Reactions in a Clinical Trial of FTC+TAF with EVG+COBI in Virologically-Suppressed Adults with HIV-1 and End Stage Renal Disease (ESRD) Receiving Chronic Hemodialysis In a 48-week trial of virologically-suppressed adult participants with HIV-1 and end stage renal disease (ESRD) (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis treated with FTC+TAF with EVG+COBI (N=55), the most commonly reported adverse reaction (adverse event assessed as causally related by investigator and all grades) was nausea (7%).

Serious adverse events were reported in 53% of participants and the most common serious adverse events were pneumonia (13%), fluid overload (7%), hyperkalemia (7%) and osteomyelitis (7%). Overall 5% of participants permanently discontinued treatment due to an adverse event.

Adverse Reactions in Clinical Trials in Pediatric Participants with HIV-1 Study 106: Adverse Reactions in a Clinical Trial of FTC+TAF with EVG+COBI in Pediatric Participants Weighing at Least 25 kg The safety profile of FTC+TAF in pediatric participants weighing at least 25 kg is informed by an open-label trial of antiretroviral treatment-naïve pediatric participants with HIV-1 between the ages of 12 to less than 18 years weighing at least 35 kg through 48 weeks (N=50; cohort 1) and virologically-suppressed participants with HIV-1 between the ages of 6 to less than 12 years weighing at least 25 kg (N=52; cohort 2).

Participants received FTC+TAF with EVG+COBI through 48 weeks. With the exception of a decrease in the mean CD4+ cell count observed in cohort 2, the safety of this combination was similar to that in adults. 3% for the total body less head (TBLH).

20 for TBLH at Week 48. One participant had significant (at least 4%) lumbar spine BMD loss at Week 48. 2% for TBLH. 19 for TBLH at Week 48. Six participants had significant (at least 4%) lumbar spine BMD loss at Week 48 and 2 participants also had at least 4% TBLH BMD loss at Week 48.

Change from Baseline in CD4+ cell counts Cohort 2:

Virologically-suppressed children (6 to less than 12 years; at least 25 kg) Cohort 2 evaluated pediatric participants (N=52) who were virologically-suppressed and who switched from their antiretroviral regimen to FTC+TAF with EVG+COBI.

Although all participants 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 2 .

4) ]. 6% Study 1474: Adverse Reactions in a Clinical Trial of FTC+TAF with Bictegravir in Pediatric Participants Weighing at Least 14 to Less Than 25 kg In a separate open-label trial of virologically-suppressed participants at least 2 years of age and weighing at least 14 to less than 25 kg (N=22; cohort 3) who received FTC+TAF with bictegravir through 24 weeks, no new adverse reactions or laboratory abnormalities were identified compared to those observed in adults.

4%).

Study 128:

Adverse Reactions in a Clinical Trial of DESCOVY in combination with Darunavir+Cobicistat (DRV+COBI) in Pediatric Participants Weighing at Least 14 kg The safety profile of DESCOVY is also informed by a separate open-label trial of virologically-suppressed pediatric participants between the ages of 6 to less than 12 years and weighing at least 25 to less than 40 kg (N=9; cohort 2), and virologically-suppressed pediatric participants at least 2 years of age and weighing at least 14 to less than 25 kg (N=11; cohort 3) who received DESCOVY in combination with DRV+COBI through Week 48.

In this study, the safety profile of DESCOVY was similar to that in adults. 4% for TBLH. 9% for TBLH. 3) ] . Median duration of exposure was 86 and 87 weeks, respectively. The most common adverse reaction in participants who received DESCOVY (incidence greater than or equal to 5%, all grades) was diarrhea (5%).

Table 3 provides a list of the most common adverse reactions that occurred in 2% or more of participants in either treatment group. 8%, respectively. Table 3 Adverse Reactions (All Grades) Reported in ≥2% in Either Arm in the DISCOVER Trial of Participants without HIV-1 DESCOVY (N=2,694) TRUVADA (N=2,693) Diarrhea 5% 6% Nausea 4% 5% Headache 2% 2% Fatigue 2% 3% Abdominal pain Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain, and abdominal discomfort 2% 3% Renal Laboratory Tests Changes from baseline to Week 48 in renal laboratory data are presented in Table 4 .

The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between DESCOVY and TRUVADA is not known. Table 4 Laboratory Assessments of Renal Function Reported in Participants without HIV-1 Receiving DESCOVY or TRUVADA in the DISCOVER Trial DESCOVY (N=2,694) TRUVADA (N=2,693) eGFR CG =estimated Glomerular Filtration Rate by Cockcroft-Gault; UPCR=urine protein/creatinine ratio Serum Creatinine (mg/dL) Mean (SD).

111) eGFR CG (mL/min) Median (Q1, Q3). 2) Percentage of Participants who Developed UPCR >200 mg/g Based on N who had normal UPCR (≤ 200 mg/g) at baseline. 0% at the total hip (N=158) in participants receiving TRUVADA. BMD declines of 5% or greater at the lumbar spine and 7% or greater at the total hip were experienced by 4% and 1% of participants, respectively, in both treatment groups at Week 48.

The long-term clinical significance of these BMD changes is not known. Serum Lipids Changes from baseline to Week 48 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in Table 5 .

Table 5 Fasting Lipid Values, Mean Change from Baseline, Reported in Participants without HIV-1 Receiving DESCOVY or TRUVADA in the DISCOVER Trial Excludes participants who received lipid lowering agents during the treatment period.

DESCOVY (N=2,694) TRUVADA (N=2,693) Baseline Week 48 Baseline Week 48 mg/dL Change The baseline and change from baseline are for participants with both baseline and Week 48 values. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of products containing TAF.

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. 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

The time from initiation of DESCOVY for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

, consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals without HIV-1 about, and support their efforts in, reducing sexual risk behavior .

Use DESCOVY to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-1 negative. 4) ]; therefore, care should be taken to minimize the risk of initiating or continuing DESCOVY before confirming the individual is HIV-1 negative.

Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. , fever, fatigue, myalgia, skin rash). If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

While using DESCOVY for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs . If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

Counsel individuals without HIV-1 to strictly adhere to the once daily DESCOVY dosing schedule. The effectiveness of DESCOVY in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in a clinical trial of DESCOVY for HIV-1 PrEP.

3) ]. 3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients with HIV-1 treated with combination antiretroviral therapy, including FTC, a component of DESCOVY. During the initial phase of combination antiretroviral treatment, patients with HIV-1 whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

2) ] . DESCOVY is not recommended in individuals with estimated creatinine clearance of 15 to below 30 mL per minute, or in individuals with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis.

Individuals taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating DESCOVY, and during treatment with DESCOVY on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals.

In individuals with chronic kidney disease, also assess serum phosphorus. Discontinue DESCOVY in individuals who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. 5 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 emtricitabine, a component of DESCOVY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals.

Treatment with DESCOVY should be suspended in any individual 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).