Biktarvy

Description

BIKTARVY (bictegravir, emtricitabine, and tenofovir alafenamide) is a fixed dose combination tablet for oral administration. Bictegravir (BIC) is an integrase strand transfer inhibitor (INSTI). Emtricitabine (FTC) is a synthetic nucleoside analog of cytidine and functions as an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). Tenofovir alafenamide (TAF) is also an HIV NRTI, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

BIKTARVY tablets are available in two dose strengths: 50 mg/200 mg/25 mg and 30 mg/120 mg/15 mg. The 50 mg/200 mg/25 mg tablet contains 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate). The 30 mg/120 mg/15 mg tablet contains 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).

Inactive ingredients in both dose strengths include croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material that contains iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

The chemical name of bictegravir sodium is 2,5-Methanopyrido1’,2’:4,5pyrazino2,1-boxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorophenyl)methyl-, sodium salt (1:1), (2R,5S,13aR)-. Bictegravir sodium has a molecular formula of C21H17F3N3NaO5 and a molecular weight of 471.4. It appears as an off-white to yellow solid with a solubility of 0.1 mg per mL in water at 20 °C.

The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.2. It is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

The chemical name of tenofovir alafenamide fumarate is L-alanine, N-[(S)-[1R-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1). Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6P•½(C4H4O4) and a formula weight of 534.5. It is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

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 use in the following patient populations:

• Patients with no prior antiretroviral treatment history.

• Patients with a history of antiretroviral treatment 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 reported for BIKTARVY.

Dosage and Administration

In adults and pediatric patients weighing at least 25 kg, or in virologically-suppressed adults with an estimated creatinine clearance below 15 mL/min who are receiving chronic hemodialysis, the recommended dosage is one tablet containing 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF, administered orally once daily. This can be taken with or without food.

For pediatric patients weighing between 14 kg and 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 orally 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 conjunction with these medications may lead to significant drug interactions that could compromise patient safety and treatment efficacy.

Warnings and Precautions

Severe acute exacerbations of hepatitis B have been reported in patients co-infected with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF). This risk also applies to patients discontinuing BIKTARVY. Therefore, it is imperative to closely monitor hepatic function in these individuals. If indicated, anti-hepatitis B therapy should be initiated.

Immune reconstitution syndrome may occur in patients receiving BIKTARVY, necessitating further evaluation and treatment as clinically appropriate. Additionally, new onset or worsening renal impairment has been observed. It is recommended to assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein at the initiation of BIKTARVY and periodically during therapy. For patients with chronic kidney disease, serum phosphorus levels should also be monitored.

Lactic acidosis and severe hepatomegaly with steatosis are serious conditions that may arise during treatment. In patients who exhibit symptoms or laboratory findings indicative of lactic acidosis or significant hepatotoxicity, discontinuation of BIKTARVY is warranted.

In summary, regular laboratory assessments are crucial for safe use of BIKTARVY. Clinicians should ensure that serum creatinine, estimated creatinine clearance, urine glucose, and urine protein are evaluated at the start of treatment and throughout therapy. For patients with chronic kidney disease, serum phosphorus should be included in the monitoring regimen.

Side Effects

Patients receiving BIKTARVY may experience a range of adverse reactions. The most common adverse reactions observed in clinical trials include diarrhea (6%), nausea (6%), and headache (5%). Other common adverse reactions reported in Trials 1489 or 1490, occurring in at least 3% of participants, include fatigue (3%), abnormal dreams (3%), dizziness (2%), insomnia (2%), and abdominal distention (2%). Additional adverse reactions occurring at a frequency of less than 2% include vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression. Notably, suicidal ideation, suicide attempts, and depression were reported in 2% of participants, primarily among those with a preexisting history of depression, prior suicide attempts, or psychiatric illness.

A significant warning associated with BIKTARVY is the risk of severe acute exacerbations of hepatitis B in patients with HIV-1 and HBV who discontinue the medication. It is crucial to closely monitor hepatic function in these patients.

Postmarketing experience has revealed additional adverse reactions, particularly concerning renal and urinary disorders, which include acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome. Skin and subcutaneous tissue disorders reported include angioedema, Stevens-Johnson syndrome/toxic epidermal necrolysis, and urticaria. Investigations have also indicated an increase in weight among some patients.

Patients may 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 at the initiation of therapy and during treatment as clinically appropriate. In patients with chronic kidney disease, serum phosphorus should also be monitored. Furthermore, lactic acidosis and severe hepatomegaly with steatosis are serious conditions that necessitate discontinuation of treatment if symptoms or laboratory findings suggestive of these conditions develop.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Biktarvy (bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

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. 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 substitutions 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 conducted in adults and an open-label trial involving three age-based cohorts of virologically suppressed pediatric participants. Cohort 1 included participants aged 12 to less than 18 years and weighing at least 35 kg, receiving BIKTARVY through Week 48 (N=50). Cohort 2 comprised participants aged 6 to less than 12 years and weighing at least 25 kg, receiving BIKTARVY through Week 24 (N=50). Cohort 3 included participants aged at least 2 years and weighing between 14 to less than 25 kg 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 observed in adults, with no clinically significant change in exposure for the components of BIKTARVY. However, the safety and effectiveness of BIKTARVY in pediatric patients weighing less than 14 kg have not been established.

Geriatric Use

Clinical trials involving virologically-suppressed participants included 111 elderly patients aged 65 years and older who received BIKTARVY. Among these participants, 100 (90%) were aged 65 to 74 years, while 11 (10%) were aged 75 to 84 years.

No overall differences in safety or effectiveness were observed between elderly participants and adults aged 18 to less than 65 years. However, it is important to note that while other reported clinical experiences have not identified significant differences in responses between elderly and younger patients, the possibility of greater sensitivity in some older individuals cannot be ruled out.

Healthcare providers should exercise caution when prescribing BIKTARVY to geriatric patients, considering the potential for increased sensitivity and the need for careful monitoring. No specific dosage adjustments are recommended based solely on age; however, clinical judgment should guide treatment decisions in this population.

Pregnancy

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. Available data from observational studies and the APR regarding the use of BIC, FTC, and TAF 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 the APR’s overall risk assessment for these components.

Data from the APR indicate no statistically significant difference in the overall risk of major birth defects for BIC, FTC, or TAF compared to the background rate for major birth defects of 2.7% in a U.S. reference population from the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR; however, the estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.

BIKTARVY safety has also been evaluated in an open-label trial involving 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 compared to postpartum, yet all 32 adult participants who completed the study maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum. The safety findings in this trial were consistent with those observed in other trials involving adults.

BIKTARVY is recommended for use 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. Based on prospective reports to the APR of over 500 exposures to a BIC-containing regimen during pregnancy resulting in live births, the prevalence of birth defects in live births was 4.3% (95% CI: 2.5% to 6.6%) following first trimester exposure and 1.8% (0.2% to 6.2%) following second/third trimester exposure. For FTC-containing regimens, the prevalence of birth defects was 2.9% (95% CI: 2.5% to 3.4%) following first trimester exposure and 2.8% (95% CI: 2.1% to 3.7%) following second/third trimester exposure. For TAF-containing regimens, the prevalence of birth defects was 3.9% (95% CI: 2.8% to 5.2%) following first trimester exposure and 4.8% (95% CI: 2.5% to 8.3%) following second/third trimester exposure.

It is important to note that methodological limitations of the APR include the use of MACDP as the external comparator group, which is not disease-specific and evaluates individuals and infants from a limited geographic area.

Lactation

Data from the published literature report the presence of BIC, FTC, TAF, and tenofovir in human milk. However, there are no data on the effects of BIC on the breastfed child. Additionally, the literature has not reported adverse effects of FTC or TAF on a breastfed child. There is also a lack of data regarding the effects of BIC, FTC, or TAF on milk production.

Healthcare professionals should be aware of potential risks associated with breastfeeding. These include the possibility of HIV-1 transmission to HIV-1–negative infants, the development of viral resistance in HIV-1–positive infants, and adverse reactions in a breastfed infant that may be similar to those observed in adults.

Renal Impairment

In patients with renal impairment, the pharmacokinetics, safety, virologic, and immunologic responses of BIKTARVY, which contains FTC and TAF, were evaluated in a single-arm, open-label trial (Trial 1825) involving virologically-suppressed adults with end-stage renal disease (ESRD) characterized by an estimated creatinine clearance of less than 15 mL/min on chronic hemodialysis.

No dosage adjustment of BIKTARVY is necessary for patients with an estimated creatinine clearance of 30 mL/min or greater, or for virologically-suppressed adults with an estimated creatinine clearance below 15 mL/min who are receiving chronic hemodialysis. It is recommended that the daily dose of BIKTARVY be administered after the completion of hemodialysis treatment on days of hemodialysis.

BIKTARVY is not recommended for patients with an estimated creatinine clearance below 30 mL/min, as calculated by the Cockcroft-Gault equation, or for patients with ESRD who are not receiving chronic dialysis. Additionally, the safety and efficacy of BIKTARVY have not been established in patients with no antiretroviral treatment history and ESRD who are receiving chronic dialysis.

To monitor for new onset or worsening renal impairment, it is advised to assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein when initiating BIKTARVY and during therapy as clinically appropriate for all patients. Serum phosphorus should also be assessed in patients with chronic kidney disease.

Hepatic Impairment

Patients with hepatic impairment may use BIKTARVY without dosage adjustment if they have 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 its use is therefore not recommended in this population.

It is essential to closely monitor hepatic function in patients with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), as similar effects may occur with the discontinuation of BIKTARVY. If indicated, anti-hepatitis B therapy may be warranted for these patients.

Overdosage

In the event of an overdose of BIKTARVY, there is currently no specific data available regarding its effects in patients. Healthcare professionals are advised to closely monitor the patient for any signs of toxicity.

Management of an overdose primarily involves general supportive measures. This includes vigilant monitoring of vital signs and continuous observation of the patient's clinical status to ensure any emerging symptoms are promptly addressed.

For patients who have ingested an excessive dose of BIKTARVY, hemodialysis may be considered as a treatment option. It has been observed that hemodialysis can remove approximately 30% of the emtricitabine (FTC) dose within a 3-hour dialysis session, provided that the procedure is initiated within 1.5 hours following FTC administration. Additionally, tenofovir is effectively eliminated through hemodialysis, with an extraction coefficient of approximately 54%.

Healthcare professionals should remain vigilant and prepared to implement these management strategies in the event of an overdose.

Nonclinical Toxicology

Bictegravir (BIC) was evaluated for carcinogenic potential in a 6-month rasH2 transgenic mouse study, where it demonstrated no carcinogenicity at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females. Additionally, a 2-year rat study also indicated that BIC was not carcinogenic 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. Genotoxicity assessments revealed that BIC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays. Furthermore, 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.

Emtricitabine (FTC) was subjected to long-term carcinogenicity studies, which found no drug-related increases in tumor incidence in mice at doses up to 750 mg/kg/day (25 times the human systemic exposure at the recommended dose of BIKTARVY) or in rats at doses up to 600 mg/kg/day (30 times the human systemic exposure). FTC was also shown to be non-genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, and mouse micronucleus assays. In terms of reproductive toxicity, FTC did not affect fertility in male rats at approximately 140 times the human exposure, nor in male and female mice at approximately 60 times higher exposures than those in humans at the recommended dose of BIKTARVY. Offspring of mice exposed to FTC daily from before birth through sexual maturity exhibited normal fertility at daily exposures approximately 60 times higher than human exposures.

Tenofovir Alafenamide (TAF) is rapidly converted to tenofovir, and due to lower tenofovir exposure in rats and mice following TAF administration compared to tenofovir disoproxil fumarate (TDF), carcinogenicity studies were conducted exclusively with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were performed at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans after a 300 mg dose of TDF. The tenofovir exposure in these studies was approximately 151 times (mice) and 51 times (rats) higher than that observed in humans following the daily recommended dose of BIKTARVY. Notably, an increase in liver adenomas was observed in female mice at the high dose, corresponding to tenofovir exposures approximately 151 times those seen in humans. However, the study in rats yielded negative results for carcinogenic findings. TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays. Additionally, 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 for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

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

Postmarketing Experience

During post-approval use of BIKTARVY or products containing TAF, several events have been identified through voluntary reporting and surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Notable events include acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome. Additionally, cases of angioedema, Stevens-Johnson syndrome/toxic epidermal necrolysis, and urticaria have been reported. An increase in weight has also been observed among users.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is crucial to inform patients not to discontinue BIKTARVY without first consulting their healthcare provider. Patients should be encouraged to report any use of other prescription or non-prescription medications, as well as herbal products, including St. John’s wort, to their healthcare provider.

Patients must be made aware of the importance of notifying their healthcare provider immediately if they experience any symptoms of infection. In some individuals with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may arise shortly after initiating anti-HIV treatment. Additionally, patients should avoid taking BIKTARVY alongside nephrotoxic agents, whether concurrent or recently used.

Inform patients that they should discontinue BIKTARVY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity. It is essential for patients to take BIKTARVY on a regular dosing schedule, with or without food, and to avoid missing doses, as this can lead to the development of resistance.

For caregivers of children who are unable to swallow a whole tablet, advise that the tablet can be split, with each part taken separately, provided all parts are ingested within approximately 10 minutes. Inform patients about the existence of an antiretroviral pregnancy registry that monitors fetal outcomes for pregnant individuals exposed to BIKTARVY.

Patients with HIV-1 should be made aware of the potential risks of breastfeeding, which include the transmission of HIV-1 to infants who are not infected, the development of viral resistance in infants with HIV-1, and adverse reactions in breastfed infants similar to those seen in adults. Emphasize the importance of not running out of BIKTARVY and encourage patients to refill their prescription or consult their healthcare provider before their supply is depleted.

If patients stop taking BIKTARVY, their healthcare provider will need to monitor their health closely and conduct regular blood tests for several months to assess liver function. Patients should also inform their healthcare provider about any new or unusual symptoms experienced after discontinuation of BIKTARVY.

Instruct patients to take BIKTARVY exactly as prescribed, as it is intended to be taken alone (not in combination with other HIV-1 medications) for the treatment of HIV-1. The recommended dosage is one time each day, with or without food. For patients on dialysis, advise them to take their daily dose of BIKTARVY following dialysis.

Patients should not change their dose or discontinue BIKTARVY without prior consultation with their healthcare provider. It is important for patients to remain under the care of their healthcare provider throughout their treatment with BIKTARVY.

If patients are taking antacids that contain aluminum or magnesium, they should take BIKTARVY at least 2 hours before or 6 hours after these antacids. For those taking supplements or antacids containing iron or calcium, advise them to take BIKTARVY with food at the same time as these supplements or antacids. Pregnant patients should discuss with their healthcare provider how to appropriately take BIKTARVY alongside any supplements or antacids containing aluminum, magnesium, iron, or calcium.

Emphasize the importance of not missing a dose of BIKTARVY. Instruct patients that if they take too much BIKTARVY, they should contact their healthcare provider or go to the nearest hospital emergency room immediately. When patients notice their supply of BIKTARVY is running low, they should obtain more from their healthcare provider or pharmacy promptly, as even a short interruption in treatment can lead to an increase in the viral load and potential resistance to BIKTARVY, making it more challenging to treat.

Storage and Handling

The product is supplied in two configurations: a bottle and a blister pack. The bottle should be stored at a temperature below 30 °C (86 °F) and must remain tightly closed to maintain its integrity. The blister pack is to be stored at a controlled room temperature of 25 °C (77 °F), with permissible excursions between 15–30 °C (59–86 °F) as defined by USP guidelines.

It is essential to dispense the product only in its original containers to ensure proper handling and storage. Additionally, the desiccant packet included with the product should not be removed, as it plays a critical role in maintaining the product's stability.

Additional Clinical Information

No additional information is available regarding laboratory tests, abuse information, route, method, and frequency of administration, or patient counseling information.

Postmarketing experience has revealed several adverse events. Patients may experience renal and urinary disorders, including acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome. Skin and subcutaneous tissue disorders reported include angioedema, Stevens-Johnson syndrome/toxic epidermal necrolysis, and urticaria. Additionally, an increase in weight has been noted in some subjects.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Biktarvy as submitted by Gilead Sciences, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)