Biktarvy

BIKTARVY is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 14 kg:

• with no antiretroviral treatment history, or
• with an antiretroviral treatment history and not virologically suppressed, with no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir, or
• to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known or suspected substitutions associated with resistance to bictegravir or tenofovir
  [see

  2.4 Recommended Dosage in Pregnant Individuals

  The recommended dosage of BIKTARVY in pregnant individuals is one tablet containing 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF taken orally once daily with or without food in pregnant individuals who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY. Lower exposures of BIKTARVY were observed during pregnancy; therefore, viral load should be monitored closely

  [see Drug Interactions (7.5), Use in Specific Populations (8.1), and Clinical Pharmacology (12.3)]

  .

  , and

  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to BIKTARVY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

  Risk Summary

  Available data from observational studies and the APR with BIC, FTC and TAF use during pregnancy have not established a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Reports of pregnant individuals treated with products containing BIC, FTC, or TAF contribute to APR’s overall risk assessment for these components. Available data from the APR show no statistically significant difference in the overall risk of major birth defects for BIC, FTC, or TAF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)

  (see Data)

  . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%.

  BIKTARVY safety has also been evaluated in an open-label trial that demonstrated safety findings that were consistent with other trials in adults

  (see Data).

  In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of BIKTARVY at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD) (

  see Data

  ). During organogenesis, systemic exposures (AUC) to BIC were approximately 36 (rats) and 0.6 times (rabbits), to FTC were approximately 60 (mice) and 108 times (rabbits), and to TAF were approximately 2 (rats) and 78 times (rabbits) the exposure at the RHD of BIKTARVY. In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 30 times (BIC), 60 times (FTC), and 19 times (TDF) the exposures of each component in humans at the RHD.

  Data

  Human Data

  BIKTARVY was evaluated in an open-label clinical trial of 33 virologically-suppressed (HIV-1 RNA < 50 copies/mL) pregnant adults with HIV-1 and no known substitutions associated with resistance to BIC, FTC, or TAF. Pregnant adults were administered BIKTARVY (containing 50 mg of BIC, 200 mg of FTC and 25 mg of TAF) once daily from the second or third trimester through postpartum. Exposures of BIC, FTC, and TAF were lower during pregnancy as compared to postpartum

  [see Clinical Pharmacology (12.3)]

  . All 32 adult participants who completed the study maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum. The median CD4+ cell count at baseline was 558 cells/µL, and the median change in CD4+ cell count from baseline to Week 12 postpartum was 159 cells/μL. All 29 neonate participants had negative/nondetectable HIV-1 PCR results at birth and/or at 4 to 8 weeks post-birth. The safety findings in this trial were consistent with other trials in adults.

  BIKTARVY was only studied in pregnant individuals who were virologically-suppressed, and lower plasma exposures of BIKTARVY were observed during pregnancy compared to post-partum. Therefore, BIKTARVY is recommended in pregnant individuals who are virologically-suppressed on a stable antiretroviral regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY.

  Bictegravir (BIC):

  Based on prospective reports to the APR of over 500 exposures to a BIC-containing regimen during pregnancy resulting in live births (including 423 exposed in the first trimester and 113 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.3% (95% CI: 2.5% to 6.6%) and 1.8% (0.2%, 6.2%) following first and second/third trimester exposure, respectively, to a BIC-containing regimen.

  Emtricitabine (FTC):

  Based on prospective reports to the APR of over 6,500 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 4,800 exposed in the first trimester and over 1,700 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.9% (95% CI: 2.5% to 3.4%) and 2.8% (95% CI: 2.1% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.

  Tenofovir Alafenamide (TAF):

  Based on prospective reports to the APR of over 1,200 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 1000 exposed in the first trimester and over 200 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.9% (95% CI: 2.8% to 5.2%) and 4.8% (95% CI: 2.5% to 8.3%) following first and second/third trimester exposure, respectively, to TAF-containing regimens.

  Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.

  Animal Data

  Bictegravir:

  BIC was administered orally to pregnant rats (5, 30, or 300 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) on gestation days 7 through 17, and 7 through 19, respectively. No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (AUC) of up to approximately 36 (rats) and 0.6 (rabbits) times the exposure in humans at the RHD of BIKTARVY. Spontaneous abortion, increased clinical signs [fecal changes, thin body, and cold-to-touch], and decreased body weight were observed at a maternally toxic dose in rabbits (1000 mg/kg/day; approximately 1.4 times higher than human exposure at the RHD).

  In a pre/postnatal development study, BIC was administered orally to pregnant rats (up to 300 mg/kg/day) from gestation days 6 to lactation/post-partum day 24. No significant adverse effects were observed in the offspring exposed daily from before birth (

  in utero

  ) through lactation at maternal and pup exposures (AUC) of approximately 30 and 11 times higher, respectively, than human exposures at the RHD.

  Emtricitabine:

  FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the RHD.

  In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (

  in utero

  ) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD.

  Tenofovir alafenamide:

  TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures of approximately 2 (rats) and 78 (rabbits) times higher than the exposure in humans at the recommended daily dose of BIKTARVY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 55 (rats) and 86 (rabbits) times higher than human tenofovir exposures at the RHD. Since TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 12 [19] times higher than the exposures in humans at the RHD of BIKTARVY.

  ].

• Testing: Prior to or when initiating BIKTARVY test for hepatitis B virus infection. Prior to or when initiating BIKTARVY, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus. (
  2.1 Testing When Initiating and During Treatment with BIKTARVY

  Prior to or when initiating BIKTARVY, test patients for hepatitis B virus infection

  [see Warnings and Precautions (5.1)]

  .

  Prior to or when initiating BIKTARVY, and during treatment with BIKTARVY, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus

  [see Warnings and Precautions (5.4)].
  )
• Recommended dosage in adults and pediatric patients weighing at least 25 kg, or virologically-suppressed adults with estimated creatinine clearance below 15 mL/min receiving chronic hemodialysis: One tablet containing 50 mg BIC, 200 mg FTC, and 25 mg TAF taken once daily with or without food. (
  2.2 Recommended Dosage in Adults and Pediatric Patients Weighing at Least 25 kg

  BIKTARVY is a three-drug fixed dose combination product containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF). The recommended dosage of BIKTARVY is one tablet containing 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF taken orally once daily with or without food in

  [see Dosage and Administration (2.4)]

  :

  • adults and pediatric patients weighing at least 25 kg with an estimated creatinine clearance greater than or equal to 30 mL/min; or
  • virologically-suppressed adults with an estimated creatinine clearance below 15 mL/min who are receiving chronic hemodialysis. On days of hemodialysis, administer the daily dose of BIKTARVY after completion of hemodialysis treatment
    [see Use in Specific Populations (8.4, 8.6), and Clinical Pharmacology (12.3)]
    .
  )
• Recommended dosage in pediatric patients weighing at least 14 kg to less than 25 kg: One tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food. (
  2.3 Recommended Dosage in Pediatric Patients Weighing at Least 14 kg to Less than 25 kg

  The recommended dosage of BIKTARVY is one tablet containing 30 mg of BIC, 120 mg of FTC, and 15 mg of TAF taken orally once daily with or without food in:

  • pediatric patients weighing at least 14 kg to less than 25 kg with an estimated creatinine clearance greater than or equal to 30 mL/min
    [see Use in Specific Populations (8.4, 8.6), and Clinical Pharmacology (12.3)]
    .

  For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes.
  )
• Recommended dosage in pregnant individuals who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known substitutions associated with resistance to the individual components of BIKTARVY: One tablet containing 50 mg BIC, 200 mg FTC, and 25 mg TAF taken orally once daily with or without food. (
  2.4 Recommended Dosage in Pregnant Individuals

  The recommended dosage of BIKTARVY in pregnant individuals is one tablet containing 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF taken orally once daily with or without food in pregnant individuals who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY. Lower exposures of BIKTARVY were observed during pregnancy; therefore, viral load should be monitored closely

  [see Drug Interactions (7.5), Use in Specific Populations (8.1), and Clinical Pharmacology (12.3)]

  .
  )
• Renal impairment: BIKTARVY is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL/min, or below 15 mL/min who are not receiving chronic hemodialysis, or below 15 mL/min who have no antiretroviral treatment history. (
  2.5 Not Recommended in Patients with Severe Renal Impairment

  BIKTARVY is not recommended in patients with

  [see Dosage and Administration (2.2, 2.3), and Use in Specific Populations (8.6)]

  :

  • severe renal impairment (estimated creatinine clearance of 15 to below 30 mL/min); or
  • end stage renal disease (ESRD; estimated creatinine clearance below 15 mL/min who are not receiving chronic hemodialysis; or
  • no antiretroviral treatment history and ESRD who are receiving chronic hemodialysis.
  )
• Hepatic impairment: BIKTARVY is not recommended in patients with severe hepatic impairment. (
  2.6 Not Recommended in Patients with Severe Hepatic Impairment

  BIKTARVY is not recommended in patients with severe hepatic impairment (Child-Pugh Class C)

  [see Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
  )

BIKTARVY tablets are available in two dose strengths:

• 50 mg/200 mg/25 mg tablets: 50 mg of bictegravir (BIC) (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate). These tablets are purplish brown, capsule-shaped, film-coated, and debossed with “GSI” on one side and “9883” on the other side.
• 30 mg/120 mg/15 mg tablets: 30 mg of BIC (equivalent to 31.5 mg of bictegravir sodium), 120 mg of FTC, and 15 mg of TAF (equivalent to 16.8 mg of tenofovir alafenamide fumarate). These tablets are pink, capsule-shaped, film-coated, and either debossed with “GSI” on one side and “B” on the other side; or with a non-functional bisecting score line on one side and “BVY” on the other side.

• Pediatrics: Not recommended for patients weighing less than 14 kg. (
  8.4 Pediatric Use

  The safety and effectiveness of BIKTARVY have been established as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric patients weighing at least 14 kg:

  • who have no antiretroviral treatment history, or
  • with an antiretroviral treatment history and not virologically suppressed, with no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir, or
  • to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known or suspected resistance to bictegravir or tenofovir
    [see Indications and Usage (1), and Dosage and Administration (2.2, 2.3)]
    .

  Use of BIKTARVY in pediatric patients weighing at least 14 kg is supported by the following:

  • trials in adults
    [see Clinical Studies (14.1, 14.3)]
  • an open-label trial in three age-based cohorts of virologically-suppressed pediatric participants
    [see Clinical Studies (14.4)]
    • Cohort 1: 12 to less than 18 years of age and weighing at least 35 kg receiving BIKTARVY through Week 48 (N=50),
    • Cohort 2: 6 to less than 12 years of age and weighing at least 25 kg receiving BIKTARVY through Week 24 (N=50), and
    • Cohort 3: at least 2 years of age and weighing at least 14 to less than 25 kg through Week 24 (N=22). No pediatric participants 2 years of age were enrolled; of the 6 pediatric participants who were 3 years of age at enrollment, 3 participants weighed between 14 to less than 15 kg.

  The safety and efficacy of BIKTARVY in these pediatric participants were similar to that in adults, and there was no clinically significant change in exposure for the components of BIKTARVY

  [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)]

  .

  Safety and effectiveness of BIKTARVY in pediatric patients weighing less than 14 kg have not been established.
  )