bictegravir/lenacapavir

7 DRUG INTERACTIONS 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.

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Recommended Dosage: Two-day initiation regimen of BIXLENVO plus oral SUNLENCA ® , followed by a maintenance regimen of BIXLENVO. Tablets may be taken with or without food. ( 2.1 ) Treatment Time Dosage: Initiation Day 1 BIXLENVO 75 mg/50 mg (1 tablet) orally and SUNLENCA 600 mg orally (2 × 300 mg tablets) Day 2 BIXLENVO 75 mg/50 mg (1 tablet) orally and SUNLENCA 600 mg orally (2 × 300 mg tablets) Dosage: Maintenance Day 3 and thereafter BIXLENVO 75 mg/50 mg (1 tablet) orally once daily Missed dose: Patients should take missed initiation or maintenance doses as soon as possible. If more than 7 days have elapsed since the last maintenance dose, restart initiation dosage regimen from Day 1, if clinically appropriate to continue BIXLENVO. ( 2.2 ) 2.1 Recommended Dosage The BIXLENVO dosing schedule in adults requires a two-day initiation regimen of BIXLENVO tablets plus SUNLENCA tablets taken orally, followed by a maintenance regimen of one tablet of BIXLENVO taken orally once daily ( Table 1 ). BIXLENVO must be taken with SUNLENCA during the two-day initiation period. BIXLENVO and SUNLENCA tablets may be taken with or without food [see Clinical Pharmacology (12.3) ] . Table 1 Recommended Treatment Regimen for BIXLENVO Initiation and Maintenance Treatment Time Dosage: Initiation Day 1 BIXLENVO 75 mg/50 mg (1 tablet) orally and SUNLENCA 600 mg orally (2 × 300 mg tablets) Day 2 BIXLENVO 75 mg/50 mg (1 tablet) orally and SUNLENCA 600 mg orally (2 × 300 mg tablets) Dosage: Maintenance Day 3 and thereafter BIXLENVO 75 mg/50 mg (1 tablet) orally once daily 2.2 Recommended Dosing Schedule for Missed Dose Missed Initiation Dose During the initiation period, if the Day 1 or Day 2 doses of BIXLENVO or SUNLENCA are missed, patients should take them as soon as possible (see Table 1 ). Patients should not take Day 1 and Day 2 doses of SUNLENCA on the same day. Missed Maintenance Dose If a maintenance dose of BIXLENVO is missed, patients should take it as soon as possible. If more than 7 days have elapsed since the last maintenance dose, restart the initiation dosage regimen from Day 1, if clinically appropriate to continue BIXLENVO treatment (see Table 1 ). 2.3 BIXLENVO Use During Pregnancy Lower exposures of BIC were observed during pregnancy; therefore, viral load should be monitored closely in pregnant individuals [see Drug Interactions (7.4) , Use in Specific Populations (8.1) , and Clinical Pharmacology (12.3) ] .