Bictegravir/Lenacapavir

BIXLENVO is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults 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 the individual components of BIXLENVO [see Clinical Studies (14) ] . BIXLENVO, a two-drug combination of bictegravir (BIC), a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and lenacapavir (LEN), an HIV-1 capsid inhibitor, is indicated as a complete regimen for the treatment of HIV-1 in adults 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 the individual components of BIXLENVO.

Each tablet contains 75 mg bictegravir (BIC) and 50 mg lenacapavir (LEN). The tablets are yellow, capsule-shaped, film-coated, and debossed with “GSI” on one side and “B/L” on the other side. Tablets: 75 mg BIC and 50 mg LEN ( 3 )

Concomitant administration of BIXLENVO is contraindicated with: dofetilide due to the potential for increased dofetilide plasma concentrations and associated serious and/or life-threatening events. strong CYP3A inducers due to decreased plasma concentrations of BIC and LEN, which may result in the loss of therapeutic effect and development of resistance to BIXLENVO. Concomitant administration of BIXLENVO is contraindicated with: Dofetilide Strong CYP3A inducers. ( 4 )

5.1 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of BIXLENVO with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) , and Drug Interactions (7.4) ]: Loss of therapeutic effect of BIXLENVO and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 4 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 BIXLENVO therapy; review concomitant medications during BIXLENVO therapy; and monitor for the adverse reactions associated with the concomitant drugs.

Most common adverse reactions (incidence greater than or equal to 2%, all grades) are headache, nausea, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The primary safety assessment of BIXLENVO in virologically suppressed adults with HIV-1 was based on 48-week data from participants in two Phase 3 randomized active-controlled clinical trials, ARTISTRY-1 (N=557) and ARTISTRY-2 (N=574) [see Clinical Studies (14) ] . ARTISTRY-1 was an open-label trial that enrolled participants who had been on a stable baseline regimen for at least 6 months and were randomized to receive BIXLENVO or to continue their stable baseline regimen. ARTISTRY-2 was a blinded trial that enrolled participants who had been on BIKTARVY for at least 6 months at baseline and were randomized to receive BIXLENVO or to continue BIKTARVY. The most common adverse reactions (all grades) reported in greater than or equal to 2% of participants in any treatment group from ARTISTRY-1 and ARTISTRY-2 through Week 48 are presented in Table 2 . The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 2 Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. (All Grades) Reported in ≥ 2% of Adults with HIV-1 Receiving BIXLENVO in Trials ARTISTRY-1 or ARTISTRY-2 (Week 48 Analysis). ARTISTRY-1 ARTISTRY-1 was open-label with a stable baseline regimen as the comparator. ARTISTRY-2 ARTISTRY-2 was blinded with BIKTARVY as the comparator. Adverse Reactions BIXLENVO N=371 Stable Baseline Regimen N=186 BIXLENVO N=383 BIKTARVY N=191 Headache 4% 0 1% 0 Nausea 3% 0 3% 4% Diarrhea 2% 0 2% 2% Laboratory Abnormalities Changes in Serum Creatinine BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology 12.2 ]. ALT and AST Elevations ALT and AST abnormalities from ARTISTRY-1 and ARTISTRY-2 trials are presented in Table 3 . Table 3 ALT and AST Abnormalities (All Grades) in ARTISTRY-1 or ARTISTRY-2 (Week 48 Analyses) ARTISTRY-1 Frequencies are based on treatment-emergent laboratory abnormalities. ARTISTRY-2 Laboratory Parameter Abnormality BIXLENVO N=371 Stable Baseline Regimen N=186 BIXLENVO N=383 BIKTARVY N=191 ULN = Upper limit of normal Alanine Aminotransferase (ALT) Grade 1: 1.25 – <2.5 x ULN 12% 1% 5% 9% Grade 2: 2.5 – <5.0 x ULN 2% 1% 2% 1% Grade 3: 5.0 – <10.0 x ULN 0 0 1% 0 Grade 4: ≥10.0 x ULN <1% 0 <1% 0 Aspartate Aminotransferase (AST) Grade 1: 1.25 – <2.5 x ULN 10% 4% 5% 9% Grade 2: 2.5 – <5.0 x ULN 2% 2% 2% 2% Grade 3: 5.0 – <10.0 x ULN 1% 0 1% 0 Grade 4: ≥10.0 x ULN <1% 0 <1% 0

6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a bictegravir-containing regimen. 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 Stevens-Johnson syndrome/toxic epidermal necrolysis Investigations Weight increased

Because BIXLENVO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended ( 7.1 ) Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.1 , 7 , 12.3 )

7.1 Other Antiretroviral Medications Because BIXLENVO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1) ] .

7.2 Potential for BIXLENVO to Affect Other Drugs Bictegravir (BIC), a component of BIXLENVO, inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro . Coadministration of BIC with drugs that are substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations (see Table 4 ). Lenacapavir (LEN), a component of BIXLENVO, is a moderate inhibitor of CYP3A and a P-gp inhibitor. Coadministration of LEN with sensitive substrates of CYP3A or P-gp may increase the concentrations of these substrates and result in the increased risk of their adverse events. See the prescribing information of these sensitive substrates for dosing recommendations or appropriate monitoring of safety.

7.3 Potential for Other Drugs to Affect the Components of BIXLENVO BIC is a substrate of CYP3A and UGT1A1. LEN is a substrate of P-gp, UGT1A1, and CYP3A. Strong or Moderate CYP3A Inducers A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC. Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of LEN [see Clinical Pharmacology (12.3) ] . Strong or moderate CYP3A inducers may result in loss of therapeutic effect of BIXLENVO and development of resistance. Concomitant administration of BIXLENVO with strong CYP3A inducers is contraindicated [see Contraindications (4) ] . Concomitant administration of BIXLENVO with moderate CYP3A inducers is not recommended. Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined UGT1A1 and strong CYP3A inhibitors may significantly increase plasma concentrations of BIC. Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of LEN. Concomitant administration of BIXLENVO with combined P-gp, UGT1A1, and strong CYP3A inhibitors is not recommended.

7.4 Established and Other Potentially Significant Drug Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with the components of BIXLENVO (BIC or LEN) as individual agents, or are drug interactions that may occur with BIXLENVO [see Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ] . Table 4 Drug Interactions with BIXLENVO Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease Clinical Comment Antiarrhythmics: digoxin dofetilide ↑ digoxin ↑ dofetilide Use digoxin with caution and monitor digoxin therapeutic concentration. Coadministration with dofetilide is contraindicated due to the potential for serious and/or life-threatening events associated with dofetilide therapy [see Contraindications (4) ]. Anticoagulants: Direct Oral Anticoagulants (DOACs) rivaroxaban dabigatran edoxaban ↑ DOAC Refer to the DOAC prescribing information for concomitant administration with moderate CYP3A inhibitors and/or P-gp inhibitors. Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ lenacapavir ↓ bictegravir Concomitant administration with carbamazepine or phenytoin is contraindicated. Concomitant administration with oxcarbazepine or phenobarbital is not recommended. Antimycobacterials: rifabutin Drug-drug interaction study was conducted for components of BIXLENVO dosed as individual agents (BIC or LEN). rifampin rifapentine ↓ lenacapavir ↓ bictegravir Concomitant administration with rifampin is contraindicated [see Contraindications (4) ] . Concomitant administration with rifabutin or rifapentine is not recommended. Corticosteroids (systemic): cortisone/hydrocortisone dexamethasone ↑ corticosteroids (systemic) ↓ lenacapavir (dexamethasone) Concomitant administration with systemic corticosteroids whose exposures are significantly increased by CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Initiate with the lowest starting dose and titrate carefully while monitoring for safety. Alternative corticosteroids to dexamethasone should be considered, particularly for long-term use. Ergot derivatives: dihydroergotamine ergotamine methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Concomitant administration with dihydroergotamine, ergotamine or methylergonovine is not recommended. Herbal Products: St. John’s wort The induction potency of St. John's wort may vary widely based on preparation. (Hypericum perforatum) ↓ lenacapavir ↓ bictegravir Concomitant administration with St. John's wort is contraindicated [see Contraindications (4) ] . HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g., myopathy). Metformin ↑ metformin Refer to the prescribing information of metformin for assessing the benefit and risk of concomitant use of BIXLENVO and metformin. Narcotic analgesics metabolized by CYP3A: e.g., fentanyl, oxycodone ↑ fentanyl ↑ oxycodone Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. Tramadol ↑ tramadol A decrease in dose may be needed for tramadol with concomitant use. Narcotic analgesic for treatment of opioid dependence: buprenorphine, methadone buprenorphine: effects unknown methadone: effects unknown Initiation of buprenorphine or methadone in patients taking BIXLENVO: Carefully titrate the dose of buprenorphine or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of BIXLENVO in patients taking buprenorphine or methadone: A dose adjustment for buprenorphine or methadone may be needed. Monitor clinical signs and symptoms. Opioid Antagonist: Naloxegol ↑ naloxegol Avoid use with BIXLENVO; if unavoidable, decrease the dosage of naloxegol and monitor for adverse reactions. Oral medications or supplements containing polyvalent cations (e.g., Mg, Al, Ca, Fe): Calcium or iron supplements Cation-containing antacids or laxatives Sucralfate Buffered medications ↓ bictegravir Antacids containing Al/Mg : Take BIXLENVO at least 2 hours before or 6 hours after taking antacids containing Al/Mg. Routine administration of BIXLENVO together with, or 2 hours after, antacids containing Al/Mg is not recommended. Supplements or Antacids containing Calcium or Iron : Take BIXLENVO and supplements or antacids containing calcium or iron together with food. Routine administration of BIXLENVO under fasting conditions together with, or 2 hours after, supplements or antacids containing calcium or iron is not recommended. In pregnant individuals: Antacids containing Al/Mg : Take BIXLENVO at least 2 hours before or 6 hours after antacids containing Al/Mg regardless of food intake. Supplements or Antacids containing Calcium or Iron : Take BIXLENVO and supplements or antacids containing calcium or iron together with food; but when taken on an empty stomach, BIXLENVO should be taken at least 2 hours before or 6 hours after supplements or antacids containing calcium or iron. […]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to BIXLENVO 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 use during pregnancy have not established a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from the APR show no statistically significant difference in the overall risk of major birth defects for BIC 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%. BIC safety has also been evaluated in an open-label trial in individuals with HIV-1 that demonstrated safety findings that were consistent with other trials in adults (see Data ). Available data from a randomized, controlled trial with LEN use during pregnancy in individuals without HIV-1 have not identified a drug-associated risk for miscarriage, or adverse maternal or fetal outcomes when compared to an active control (see Data ) . The rate of major birth defects in LEN-exposed pregnancies did not exceed the background prevalence rates. The risk estimates are imprecise due to small numbers of exposed pregnancies (see Data ) . In animal reproduction studies, no evidence of adverse developmental outcomes was observed with BIC 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 24 (rats) and 0.39 times (rabbits) the exposure at the RHD of BIXLENVO. In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 20 times (BIC) the exposure in humans at the RHD. In animal reproduction studies, no adverse developmental effects were observed when LEN was administered to rats and rabbits at exposures (AUC) ≥3 times the exposure in humans at the RHD of BIXLENVO (see Data ) . Data Human Data Bictegravir A BIC-containing regimen 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. Pregnant adults were administered a BIC-containing regimen once daily from the second or third trimester through postpartum. Exposures of BIC were lower during pregnancy as compared to postpartum. 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 of BIC-containing regimens in adults. 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. Lenacapavir In a randomized, controlled trial of individuals without HIV-1 in Uganda and South Africa, there were 208 pregnancies exposed to LEN received via injection with known outcomes and 132 deliveries (both live and non-live). In the active control arm of this study, there were 109 pregnancies with known outcomes and 61 deliveries (both live and non-live). The adverse pregnancy outcomes of spontaneous abortion, stillbirth, preterm birth, and small for gestational age were similar across both treatment groups. There were two major birth defects in the LEN arm. Both were ventricular septal defects. This resulted in a rate of major birth defects that fell within the background prevalence rate for major birth defects. Concentrations of LEN received via injection during each trimester of pregnancy and postpartum were comparable to those in non-pregnant participants. 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 24 (rats) and 0.39 (rabbits) times the exposure in humans at the RHD of BIXLENVO. 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 0.90 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 20. 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 20 and 7.3 times higher, respectively, than human exposures at the RHD. Lenacapavir LEN was administered intravenously to pregnant rabbits (up to 20 mg/kg/day on gestation days (GD) 7 to 19), orally to rats (up to 300 mg/kg/day on GD 6 to 17), and subcutaneously to rats (up to 300 mg/kg on GD 6). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at exposures (AUC) approximately ≥3 times (rats) and 75 times (rabbits) the exposure in humans at the RHD of BIXLENVO.

8.2 Lactation Risk Summary Bictegravir Data from the published literature reports on the presence of BIC in human milk. There are no data on the effects of BIC on the breastfed child. There is no data on the effects of BIC on milk production. Lenacapavir LEN is present in human milk. LEN was detected at very low levels in infants who were breastfed by individuals who became pregnant while receiving LEN via injection (see Data ) . No adverse effects of LEN in breastfed infants have been observed. It is not known if LEN affects milk production. Potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1–negative infants; (2) developing viral resistance in HIV-1–positive infants; and (3) adverse reactions in a breastfed infant similar to those seen in adults. Data Human data Lenacapavir The median LEN concentration in human breast milk to maternal plasma ratio in participants (n=8) who received LEN via injection was 0.63 (range: 0.29 to 1.90). The median infant-to-mother plasma ratio for LEN in infants (n=10) who were breastfed by individuals receiving LEN via injection from 0 to less than 13 weeks after delivery was 0.06 (range: 0.01 to 0.20). Data are not available in breastfeeding individuals receiving LEN orally.

8.4 Pediatric Use The safety and effectiveness of BIXLENVO have not been established in patients less than 18 years of age.

8.5 Geriatric Use Clinical studies included 159 (21%) participants 65 years and over who received BIXLENVO. Of the total number of BIXLENVO-treated patients in these studies, 148 (93%) were ages 65 to 74, and 11 (7%) were 75 to 84 years of age. […]

BIXLENVO is a fixed dose combination of the antiretroviral drugs bictegravir (BIC) and lenacapavir (LEN) [see Microbiology (12.4) ] .