Bictegravir sodium/Emtricitabine/Tenofovir alafenamide fumarate

Uses and Indications

BIKTARVY is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 14 kg. This drug is appropriate for the following patient populations:

• Patients with no prior antiretroviral treatment history.

• Patients with an antiretroviral treatment history who are not virologically suppressed, provided there are no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir.

• Patients who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) and wish to replace their current antiretroviral regimen, as long as they are on a stable regimen with no known or suspected substitutions associated with resistance to bictegravir or tenofovir.

No teratogenic or nonteratogenic effects have been mentioned in the available data.

Dosage and Administration

The recommended dosage of Biktarvy for adults and pediatric patients weighing at least 25 kg, as well as for virologically-suppressed adults with an estimated creatinine clearance below 15 mL/min who are receiving chronic hemodialysis, is one tablet containing 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF) taken once daily, with or without food.

For pediatric patients weighing at least 14 kg but less than 25 kg, the recommended dosage is one tablet containing 30 mg of BIC, 120 mg of FTC, and 15 mg of TAF, also taken once daily, with or without food.

In pregnant individuals who are virologically-suppressed (defined as having an HIV-1 RNA level of less than 50 copies per mL) and who are on a stable antiretroviral regimen with no known substitutions associated with resistance to the individual components of Biktarvy, the recommended dosage 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.

Contraindications

BIKTARVY is contraindicated for co-administration with dofetilide and rifampin. The use of BIKTARVY in patients receiving these medications is not recommended due to potential adverse interactions.

Warnings and Precautions

Severe acute exacerbations of hepatitis B have been reported in patients with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF). Such exacerbations may also occur with the discontinuation of BIKTARVY. Therefore, it is crucial to closely monitor hepatic function in these patients, and if appropriate, initiate anti-hepatitis B therapy.

General Precautions

Immune reconstitution syndrome may occur and could necessitate further evaluation and treatment. Patients should be monitored for new onset or worsening renal impairment. It is recommended to assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein when initiating BIKTARVY and during therapy as clinically appropriate for all patients. Additionally, serum phosphorus should be assessed in patients with chronic kidney disease.

Lactic acidosis and severe hepatomegaly with steatosis are serious conditions that may arise. Treatment should be discontinued in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Laboratory Tests

Routine laboratory assessments should include serum creatinine, estimated creatinine clearance, urine glucose, and urine protein at the initiation of BIKTARVY and throughout therapy as clinically indicated. For patients with chronic kidney disease, serum phosphorus levels should also be monitored.

Emergency Instructions

While specific instructions for emergency medical help are not provided, it is imperative for patients to be aware of the signs and symptoms of serious adverse effects and to seek immediate medical attention if they occur.

Discontinuation Instructions

Patients should discontinue treatment and contact their healthcare provider if they experience symptoms or laboratory findings indicative of lactic acidosis or significant hepatotoxicity.

Side Effects

Patients receiving Biktarvy may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Most Common Adverse Reactions

The most frequently reported adverse reactions (≥ 5% in clinical trials) include:

• Diarrhea (6%)

• Nausea (6%)

• Headache (5%)

Common Adverse Reactions

Additional common adverse reactions (3% to < 5%) observed in clinical trials include:

• Fatigue (3%)

• Abnormal dreams (3%)

• Dizziness (2%)

• Insomnia (2%)

• Abdominal distention (2%)

Less Common Adverse Reactions

Other adverse reactions reported at a frequency of < 2% include:

• Vomiting

• Flatulence

• Dyspepsia

• Abdominal pain

• Rash

• Depression

• Suicidal ideation, suicide attempt, and depression suicidal (2%); primarily in participants with a preexisting history of depression, prior suicide attempt, or psychiatric illness.

Serious Warnings

A significant warning associated with Biktarvy is the risk of post-treatment acute exacerbation of hepatitis B. Severe acute exacerbations of hepatitis B have been reported in patients with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF). This may also occur with the discontinuation of Biktarvy, necessitating close monitoring of hepatic function in these patients.

Postmarketing Experience

Postmarketing data have identified additional adverse reactions, including:

• Renal and Urinary Disorders:

  • Acute renal failure

  • Acute tubular necrosis

  • Proximal renal tubulopathy

  • Fanconi syndrome

• Skin and Subcutaneous Tissue Disorders:

  • Angioedema

  • Stevens-Johnson syndrome/toxic epidermal necrolysis

  • Urticaria

• Investigations:

  • Weight increased

Additional Considerations

Patients may also experience immune reconstitution syndrome, which may require further evaluation and treatment. New onset or worsening renal impairment should be assessed by evaluating serum creatinine, estimated creatinine clearance, urine glucose, and urine protein when initiating Biktarvy and during therapy as clinically appropriate. In patients with chronic kidney disease, serum phosphorus should also be assessed.

Furthermore, there is a risk of lactic acidosis and severe hepatomegaly with steatosis; treatment should be discontinued in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Drug Interactions

Biktarvy, in its tablet form, does not have any documented drug interactions or interactions with laboratory tests. As such, there are no specific pharmacokinetic or pharmacodynamic interactions to consider for this medication. Healthcare providers may proceed with prescribing Biktarvy without the need for additional monitoring related to drug interactions.

Pediatric Use

The safety and effectiveness of BIKTARVY have been established for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric patients weighing at least 14 kg. Eligible pediatric patients include those with no antiretroviral treatment history, those with a treatment history who are not virologically suppressed and have no known or suspected resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir, and those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen without known or suspected resistance to bictegravir or tenofovir.

The use of BIKTARVY in pediatric patients weighing at least 14 kg is supported by trials in adults and an open-label trial involving three age-based cohorts of virologically suppressed pediatric participants:

• Cohort 1: Ages 12 to less than 18 years and weighing at least 35 kg, receiving BIKTARVY through Week 48 (N=50).

• Cohort 2: Ages 6 to less than 12 years and weighing at least 25 kg, receiving BIKTARVY through Week 24 (N=50).

• Cohort 3: At least 2 years of age and weighing at least 14 to less than 25 kg, receiving BIKTARVY through Week 24 (N=22). Notably, no pediatric participants aged 2 years were enrolled; among the 6 participants who were 3 years old at enrollment, 3 weighed between 14 to less than 15 kg.

The safety and efficacy of BIKTARVY in these pediatric participants were found to be similar to those in adults, with no clinically significant change in exposure for the components of BIKTARVY. The safety and effectiveness of BIKTARVY in pediatric patients weighing less than 14 kg have not been established.

Geriatric Use

Clinical trials involving Biktarvy included 111 participants aged 65 years and older, with 90% of these individuals aged 65 to 74 years and 10% aged 75 to 84 years. No overall differences in safety or effectiveness were observed between elderly patients and those aged 18 to less than 65 years. While clinical experience has not identified significant differences in responses between geriatric and younger patients, it is important to consider that greater sensitivity may be present in some older individuals. Therefore, careful monitoring is recommended when administering Biktarvy to elderly patients. No specific dosage adjustments are indicated based solely on age.

Pregnancy

Available data from the Antiretroviral Pregnancy Registry (APR) and observational studies indicate that Biktarvy, which contains bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF), has not established a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes in pregnant patients. Healthcare providers are encouraged to register patients exposed to Biktarvy during pregnancy by contacting the APR at 1-800-258-4263.

The APR reports show no statistically significant difference in the overall risk of major birth defects for BIC, FTC, or TAF compared to the background rate of 2.7% for major birth defects in the U.S. reference population. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%, although the APR does not report specific rates of miscarriage associated with Biktarvy.

In clinical trials, Biktarvy has been evaluated in a cohort of 33 virologically-suppressed pregnant adults with HIV-1, demonstrating that all participants maintained viral suppression throughout pregnancy and postpartum. Safety findings in this trial were consistent with those observed in other adult studies. Notably, exposures to BIC, FTC, and TAF were lower during pregnancy compared to postpartum.

Animal reproduction studies have shown no evidence of adverse developmental outcomes at exposures that were not maternally toxic or were greater than those in humans at the recommended human dose. During organogenesis, systemic exposures to BIC, FTC, and TAF were observed to be significantly different across species, with some exposures being higher than those seen in humans.

Based on prospective reports to the APR, the prevalence of birth defects following first trimester exposure to a BIC-containing regimen was 4.3%, while the prevalence following second/third trimester exposure was 1.8%. For FTC-containing regimens, the prevalence was 2.9% after first trimester exposure and 2.8% after second/third trimester exposure. For TAF-containing regimens, the prevalence was 3.9% following first trimester exposure and 4.8% following second/third trimester exposure.

Biktarvy is recommended for use in pregnant individuals who are virologically suppressed on a stable antiretroviral regimen without known resistance substitutions to any of its components. However, methodological limitations of the APR should be noted, including the use of the Metropolitan Atlanta Congenital Defects Program as a comparator group, which may not be disease-specific and evaluates individuals from a limited geographic area.

Lactation

Data from the published literature indicate that Biktarvy (BIC, FTC, TAF, and tenofovir) is present in human milk. However, there are no specific data regarding the effects of BIC on breastfed infants. Similarly, the literature has not reported any adverse effects of FTC or TAF on breastfed children.

It is important to note that there is no information available on the impact of BIC, FTC, or TAF on milk production. Potential risks associated with breastfeeding while on Biktarvy include the transmission of HIV-1 to HIV-1-negative infants, the development of viral resistance in HIV-1-positive infants, and the possibility of adverse reactions in breastfed infants that may mirror those experienced by adults.

Healthcare providers should weigh these considerations when advising lactating mothers on the use of Biktarvy.

Renal Impairment

In patients with renal impairment, specific considerations regarding the use of Biktarvy are essential for ensuring safety and efficacy. For individuals with an estimated creatinine clearance (CrCl) of 30 mL/min or greater, no dosage adjustment is necessary. However, for patients with end-stage renal disease (ESRD) and a CrCl of less than 15 mL/min who are on chronic hemodialysis, Biktarvy can be administered without dosage modification, provided it is given after the completion of hemodialysis sessions.

It is important to note that Biktarvy is not recommended for patients with a CrCl below 30 mL/min, including those with ESRD who are not undergoing chronic dialysis. The safety and efficacy of Biktarvy in these populations have not been established.

To monitor renal function, it is advised to assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein at the initiation of therapy and periodically during treatment as clinically appropriate. Additionally, serum phosphorus levels should be evaluated in patients with chronic kidney disease to detect any new onset or worsening of renal impairment.

Hepatic Impairment

No dosage adjustment of Biktarvy is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, Biktarvy has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is therefore not recommended for use in this population.

In patients with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), it is essential to closely monitor hepatic function, as hepatic issues may arise with the discontinuation of Biktarvy. If indicated, anti-hepatitis B therapy may be warranted.

Overdosage

In the event of an overdose with Biktarvy, there is currently no specific data available regarding its effects in patients. It is essential to monitor the patient closely for any signs of toxicity. Management of an overdose should include general supportive measures, which encompass the monitoring of vital signs and ongoing observation of the patient's clinical status.

For patients who have ingested an excessive dose, hemodialysis may be considered as a treatment option. It has been noted that hemodialysis can remove approximately 30% of the emtricitabine (FTC) dose within a 3-hour dialysis session, provided that the treatment begins within 1.5 hours of FTC administration. Additionally, tenofovir is effectively eliminated through hemodialysis, with an extraction coefficient of around 54%. Therefore, healthcare professionals should evaluate the need for hemodialysis based on the timing and amount of the overdose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Bictegravir (BIC) demonstrated no carcinogenic potential in a 6-month rasH2 transgenic mouse study at doses up to 100 mg/kg/day in males and 300 mg/kg/day in females. Similarly, a 2-year rat study at doses up to 300 mg/kg/day, resulting in exposures approximately 31 times higher than those observed in humans at the recommended dose of BIKTARVY, also showed no evidence of carcinogenicity. Emtricitabine (FTC) did not induce drug-related tumor incidence in long-term carcinogenicity studies in mice at doses up to 750 mg/kg/day (25 times human exposure) or in rats at doses up to 600 mg/kg/day (30 times human exposure). Tenofovir Alafenamide (TAF) is rapidly converted to tenofovir, and carcinogenicity studies were conducted with tenofovir disoproxil fumarate (TDF). Long-term studies in mice and rats at exposures up to approximately 10 times and 4 times those observed in humans, respectively, revealed an increase in liver adenomas in female mice at tenofovir exposures approximately 151 times higher than human exposure. However, the study in rats was negative for carcinogenic findings.

Mutagenesis

BIC, FTC, and TAF were all found to be non-genotoxic in various assays, including the reverse mutation bacterial test (Ames test), mouse lymphoma, and rat micronucleus assays.

Impairment of Fertility

BIC did not adversely affect fertility, reproductive performance, or embryonic viability in male and female rats at exposures approximately 29 times higher than those in humans at the recommended dose of BIKTARVY. FTC also showed no effects on fertility in male rats at approximately 140 times human exposure and in male and female mice at approximately 60 times human exposure. Normal fertility was observed in the offspring of mice exposed in utero through sexual maturity at similar high exposures. TAF did not impact fertility, mating performance, or early embryonic development when administered to male rats at a dose equivalent to 155 times the human dose of BIKTARVY prior to mating and to female rats during the early gestation period.

Animal Toxicology

In animal studies, minimal to slight infiltration of mononuclear cells in the posterior uvea was noted in dogs after three and nine months of TAF administration, with reversibility observed following a three-month recovery period. No ocular toxicity was reported in dogs at systemic exposures of 7 times (TAF) and 14 times (tenofovir) the exposure seen in humans at the recommended daily dose of BIKTARVY.

Storage and Handling

Biktarvy is supplied in tablet form. The product should be stored in its original container to maintain its integrity.

The bottle must be kept tightly closed and stored at a temperature below 30 °C (86 °F). For the blister pack, it should be stored at a controlled room temperature of 25 °C (77 °F), with permissible excursions between 15–30 °C (59–86 °F) as per USP guidelines.

It is important to note that the desiccant packet should not be removed from the container to ensure optimal product stability.