Bictegravir Sodium, Emtricitabine, and Tenofovir Alafenamide Fumarate

The fixed combination of bictegravir sodium, an HIV-1 integrase strand transfer inhibitor (INSTI), and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs), is an antiretroviral agent.1

Contraindications

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is contraindicated to be co-administered with: 1

• Dofetilide.1

• Rifampin.1

Warnings/Precautions

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Patients with HIV-1 should be tested for the presence of chronic HBV infection before or when initiating antiretroviral therapy.1

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Patients coinfected with HIV-1 and HBV who discontinue bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.1

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to: 1

• Loss of therapeutic effect of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate and possible development of resistance.1

• Possible clinically significant adverse reactions from greater exposures of concomitant drugs.1

See Drug Interactions section in Full Prescribing Information for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate therapy; review concomitant medications during bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate therapy; and monitor for the adverse reactions associated with the concomitant drugs.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. 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.1

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.1

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 prodrugs in both animal toxicology studies and human trials. In clinical trials of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate in subjects with no antiretroviral treatment history with eGFRs greater than 30 mL per minute, and in virologically suppressed subjects switched to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate with eGFRs greater than 50 mL per minute, renal serious adverse events were encountered in less than 1% of subjects treated with bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate through Week 48. Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute.1

Patients 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.1

Prior to or when initiating bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, and during treatment with bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, 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. Discontinue bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.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 emtricitabine, a component of the fixed combination of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate 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).1

Specific Populations

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.1

Risk Summary: There are insufficient human data on the use of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Bictegravir (BIC) and tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for FTC compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the US general population is 15–20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD). 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. 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.1

Emtricitabine Human Data: Based on prospective reports to the APR of 3,406 exposures to FTC-containing regimens during pregnancy resulting in live births (including 2,326 exposed in the first trimester and 1,080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with the second/third trimester exposure to FTC-containing regimens.1

Bictegravir Animal Data: 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. 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.1

Emtricitabine Animal Data: 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.1

Tenofovir Alafenamide Animal Data: 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Risk Summary: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate or all of the components of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate are present in human breast milk, affects human milk production, or has effects on the breastfed infant. Based on published data, FTC has been shown to be present in human breast milk. BIC was detected in the plasma of nursing rat pups likely due to the presence of BIC in milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF. It is unknown if TAF is present in animal milk. Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Bictegravir Animal Data: BIC was detected in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10), likely due to the presence of BIC in milk.1

Tenofovir Alafenamide Animal Data: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.1

Safety and effectiveness of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate in pediatric patients less than 18 years of age have not been established.1

Clinical trials of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.1

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with severe renal impairment (estimated creatinine clearance [CLcr] below 30 mL per minute, estimated by Cockcroft-Gault. No dosage adjustment of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is recommended in patients with CLcr greater than or equal to 30 mL per minute. 1

No dosage adjustment of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Therefore, bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended for use in patients with severe hepatic impairment.1

Common Adverse Effects

Most common adverse reactions (incidence greater than or equal to 5%, all grades) are diarrhea, nausea, and headache. 1

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Advise the patient to not discontinue bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate without first informing their healthcare provider.1

Drug Interactions

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort.1

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.1

Renal Impairment

Advise patients to avoid taking bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate with concurrent or recent use of nephrotoxic agents. Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs.1

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Advise patients that they should stop bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.1

Missed Dosage

Inform patients that it is important to take bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance.1

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.