Bictegravir and lenacapavir

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.

Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil ↑ PDE-5 inhibitors PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Concomitant administration with tadalafil for PAH is not recommended. PDE-5 inhibitors for erectile dysfunction (ED): Refer to the prescribing information of PDE-5 inhibitors for dose recommendations. Sedatives/Hypnotics: midazolam (oral) triazolam ↑ midazolam (oral) ↑ triazolam Use caution when midazolam or triazolam is concomitantly administered with BIXLENVO.

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…