Sunlenca

SUNLENCA, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, is indicated: in combination with other antiretroviral(s), for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. (1.1) for oral loading as a component of the initiation regimen for BIXLENVO (bictegravir [BIC]/lenacapavir [LEN]), a complete regimen for the treatment of 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. (1.2)

1.1Treatment

Of HIV-1 in Heavily Treatment-Experienced Adults SUNLENCA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. 1.2 Oral Loading for Initiation of BIXLENVO SUNLENCA tablets are indicated for oral loading as a component of the initiation regimen for BIXLENVO (bictegravir [BIC]/lenacapavir [LEN]), a complete regimen for treatment of 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 Dosage and Administration (2.3)].

Recommended dosage in heavily treatment-experienced adults: Initiation with one of two options followed by once every 6 months maintenance injection dosing. Tablets may be taken without regard to food. (2.2) Initiation Option 1 Day 1 927 mg by subcutaneous injection (2 × 1.5 mL injections) 600 mg orally (2 × 300 mg tablets) Day 2 600 mg orally (2 × 300 mg tablets) Initiation Option 2 Day 1 600 mg orally (2 × 300 mg tablets) Day 2 600 mg orally (2 × 300 mg tablets) Day 8 300 mg orally (1 × 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 × 1.5 mL injections) Maintenance 927 mg by subcutaneous injection (2 × 1.5 mL injections) every 6 months (26 weeks) from the date of the last injection +/-2 weeks. Recommended dosage for oral loading for initiation of BIXLENVO: Refer to Table 3 of the full prescribing information for dosing schedule. (2.3) Planned missed injections: If scheduled injection is to be missed by more than 2 weeks, SUNLENCA tablets may be used for oral bridging for up to 6 months until injections resume. Recommended dosage is 300 mg orally once every 7 days. (2.4) Unplanned missed injections: If more than 28 weeks have elapsed since last injection and tablets have not been taken for oral bridging, restart initiation from Day 1 (using Option 1 or Option 2) if clinically appropriate. (2.4) SUNLENCA injection is for subcutaneous administration only. Two 1.5 mL injections are required for complete dose. (2.5)

2.1Adherence to Treatment Regimen in Heavily Treatment-Experienced Adults

Prior to starting SUNLENCA for the treatment of HIV-1 in heavily treatment-experienced adults, healthcare providers should carefully select patients who agree to the required every 6 month injection dosing schedule and counsel patients about the importance of adherence to scheduled SUNLENCA dosing visits and concomitant oral antiretroviral therapy to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses [see Warnings and Precautions (5.2), Microbiology (12.4)]. 2.2 Recommended Dosage for Treatment of HIV-1 in Heavily Treatment-Experienced Adults SUNLENCA can be initiated using one of the two recommended dosage regimens in Table 1 and Table 2 below. Maintenance dosing is administered by subcutaneous injection every 6 months regardless of the initiation regimen. Healthcare providers should determine the appropriate initiation regimen for the patient. SUNLENCA oral tablets may be taken with or without food [see Clinical Pharmacology (12.3)]. Table 1 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance for Treatment of HIV-1 in Heavily Treatment-Experienced Adults, Option 1 Treatment Time Dosage of SUNLENCA: Initiation Day 1 927 mg by subcutaneous injection (2 × 1.5 mL injections) and 600 mg orally (2 × 300 mg tablets) Day 2 600 mg orally (2 × 300 mg tablets) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) From the date of the last injection. +/-2 weeks 927 mg by subcutaneous injection (2 × 1.5 mL injections) Table 2 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance for Treatment of HIV-1 in Heavily Treatment-Experienced Adults, Option 2 Treatment Time Dosage of SUNLENCA: Initiation Day 1 600 mg orally (2 × 300 mg tablets) Day 2 600 mg orally (2 × 300 mg tablets) Day 8 300 mg orally (1 × 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 × 1.5 mL injections) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) From the date of the last injection. +/-2 weeks 927 mg by subcutaneous injection (2 × 1.5 mL injections)

2.3Recommended Dosage for Oral Loading for

Initiation of BIXLENVO SUNLENCA tablets are used as a component of the initiation regimen for BIXLENVO. See BIXLENVO prescribing information. 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 (see Table 3). BIXLENVO must be taken with SUNLENCA tablets during the two-day initiation period. SUNLENCA is only indicated for the oral initiation of BIXLENVO treatment and is not to be used for the maintenance of BIXLENVO treatment. BIXLENVO and SUNLENCA tablets may be taken with or without food. Table 3 SUNLENCA Tablets: Recommended Dosage for Oral Loading for Initiation of BIXLENVO Treatment Time Dosage: Initiation (BIXLENVO and SUNLENCA) Day 1 BIXLENVO 75 mg/50 mg (1 tablet) orally See BIXLENVO prescribing information. 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 (BIXLENVO only) Day 3 and thereafter BIXLENVO 75 mg/50 mg (1 tablet) orally once daily

2.4Recommended Dosing Schedule for Missed Dose

Treatment of HIV-1 in Heavily Treatment-Experienced Adults: Planned Missed Injections During the maintenance period, if a patient plans to miss a scheduled 6-month injection visit by more than 2 weeks, SUNLENCA tablets may be taken for up to 6 months until injections resume. Refer to Table 4 below for the recommended dosage after planned missed injections. Table 4 Recommended Dosage after Planned Missed Injections: Weekly Oral Maintenance Time since Last Injection Recommendation 26 to 28 weeks Maintenance oral dosage of 300 mg taken once every 7 days for up to 6 months. Resume the maintenance injection dosage within 7 days after the last oral dose. Unplanned Missed Injections Patients who miss a scheduled injection visit should be clinically reassessed, including consideration of lenacapavir resistance testing, to ensure resumption of therapy remains appropriate. During the maintenance period, if more than 28 weeks have elapsed since the last injection and SUNLENCA tablets have not been taken, see Table 5 below for the recommended dosage after unplanned missed injections. Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration (2.1) and Microbiology (12.4)]. Table 5 Recommended Dosage after Unplanned Missed Injections Time since Last Injection Recommendation More than 28 weeks Reinitiate with Option 1 (Table 1) or Option 2 (Table 2) and then continue with maintenance injection dosing. Oral Loading for Initiation of BIXLENVO: Missed Oral Initiation Dose If the Day 1 or Day 2 oral initiation dose of SUNLENCA (600 mg; see Table 3) is missed, take it as soon as possible. Do not take SUNLENCA Day 1 and Day 2 oral initiation doses on the same day. For BIXLENVO missed dose instructions, see BIXLENVO prescribing information. 2.5 Preparation and Administration of Subcutaneous Injection SUNLENCA injection is only for subcutaneous administration into the abdomen by a healthcare provider. Do NOT administer intradermally due to risk of serious injection site reactions [see Warnings and Precautions (5.3)]. Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. SUNLENCA injection is a yellow solution. Do not use SUNLENCA injection if the solution is discolored or if it contains particulate matter. Once the solution is withdrawn from the vials, the subcutaneous injections should be administered as soon as possible [see How Supplied/Storage and Handling (16)]. There are two SUNLENCA injection kits available [see How Supplied/Storage and Handling (16)]: Vial Access Device Injection Kit Withdrawal Needle Injection Kit (withdrawal needle may be supplied with or without a safety shield) The Vial Access Device Injection Kit differs from the Withdrawal Needle Injection Kit only in how SUNLENCA injection is prepared (the components and associated method for withdrawal of the solution from the vials. The Withdrawal Needle Injection Kit contains withdrawal needles that may be supplied with or without a safety shield. The presence or absence of a safety shield does not change how SUNLENCA injection is prepared. Refer to the figures below for the relevant injection kit. The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose. Vial Access Device Injection Kit Figure 1 identifies the components for use in the administration steps for the Vial Access Device Injection Kit, and the administration steps are provided in Figure 2. Use of a vial access device is required in this kit. Figure 1 SUNLENCA Vial Access Device Injection Kit Components Figure 2 SUNLENCA Injection Steps for Vial Access Device Injection Kit Withdrawal Needle Injection Kit (withdrawal needle without safety shield) Figure 3 identifies the components for use in the administration steps for the Withdrawal Needle Injection Kit (withdrawal needle supplied without a safety shield), and the administration steps are provided in Figure 4. The 18-gauge needle is for withdrawal only in this kit. Figure 3 SUNLENCA Withdrawal Needle Injection Kit Components (withdrawal needle without safety shield) Figure 4 SUNLENCA Injection Steps for Withdrawal Needle Injection Kit (withdrawal needle without safety shield) Withdrawal Needle Injection Kit (withdrawal needle with safety shield) Figure 5 identifies the components for use in the administration steps for the Withdrawal Needle Injection Kit (withdrawal needle supplied with a safety shield), and the administration steps are provided in Figure 6. The 18-gauge safety needle is for withdrawal only in this kit. Figure 5 SUNLENCA Withdrawal Needle Injection Kit Components (withdrawal needle with safety shield) Figure 6 SUNLENCA Injection Steps for Withdrawal Needle Injection Kit (withdrawal needle with safety shield) Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.1) Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance. (5.2) May increase exposure and risk of adverse reactions to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA. (5.2) If discontinued, initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs, switch to an alternative regimen if possible. (5.2) Injection site reactions may occur, and nodules and indurations may be persistent. Improper administration (intradermal injection) has been associated with serious injection site reactions. (5.3)

5.1Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA Residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer after the last subcutaneous dose). It is important to counsel patients that maintenance dosing by injection is required every 6 months, because missed doses or non-adherence to injections could lead to loss of virologic response and development of resistance [see Dosage and Administration (2.1)]. Lenacapavir, a moderate CYP3A inhibitor, may increase the exposure to, and therefore potential risk of adverse reactions from, drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA [see Drug Interactions and Clinical Pharmacology (7.2, 12.3)]. If SUNLENCA is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible [see Dosage and Administration (2.1)]. 5.3 Injection Site Reactions Administration of SUNLENCA may result in local injection site reactions (ISRs). If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow-up. Manifestations of ISRs may include swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass. Nodules and indurations at the injection site may take longer to resolve than other ISRs. In clinical studies, after a median follow-up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Measurements and qualitative assessments of ISRs were not routinely reported. Where described, the majority of the injection site nodules and indurations were palpable but not visible, and had a maximum size of approximately 1 to 4 cm [see Adverse Reactions (6.1)]. The mechanism driving the persistence of injection site nodules and indurations in some patients is not fully understood, but based on available data, they may be related to the presence of the subcutaneous drug depot. In some patients who had a skin biopsy performed of an injection site nodule or induration, dermatopathology revealed foreign body inflammation or granulomatous response. Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer [see Adverse Reactions (6)]. Ensure SUNLENCA is only administered subcutaneously in the abdomen [see Dosage and Administration (2.5)].

The following adverse reactions are discussed in other sections of the labeling: Immune Reconstitution Syndrome [see Warnings and Precautions (5.1)] Injection Site Reactions [see Warnings and Precautions (5.3)]. Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions. (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. Treatment of HIV-1 in Heavily Treatment-Experienced Adults The primary safety assessment of SUNLENCA was based on data from heavily treatment-experienced adult participants with HIV who received SUNLENCA in a Phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks) [see Clinical Studies (14.1)], as well as supportive data in treatment-naïve adult participants with HIV who received SUNLENCA in a Phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks). The most common adverse reactions (all Grades) reported in at least 3% of participants in CAPELLA were nausea and injection site reactions. The proportion of participants in CAPELLA who discontinued treatment with SUNLENCA due to adverse events, regardless of severity, was 1% (Grade 1 injection site nodule in 1 participant). Table 6 displays the frequency of adverse reactions (all Grades) greater than or equal to 3% in the SUNLENCA group. Table 6 Adverse Reactions (All Grades) Reported in ≥ 3% Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all participants (cohorts 1 and 2) in CAPELLA. of Heavily Treatment Experienced Adults with HIV-1 Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Adverse Reactions SUNLENCA + Background Regimen (N=72) Injection Site Reactions 65% Nausea 4% The majority (96%) of all adverse reactions associated with SUNLENCA were mild or moderate in severity. Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs): The most frequent adverse reactions were ISRs. Of the 72 participants in CAPELLA, 65% had experienced an ISR attributed to study drug through at least the Week 52 visit. Most participants had mild (Grade 1, 44%) or moderate (Grade 2, 17%) ISRs. Four percent of participants experienced a severe (Grade 3) ISR (erythema, pain, swelling) that resolved within 15 days. The ISRs reported in more than 1% of participants were swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%) and mass (3%). ISRs reported in 1% of participants included discomfort, hematoma, edema, and ulcer. Nodules and indurations at the injection site took longer to resolve than other ISRs. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days (range: 1 to 183). The median time to resolution of nodules and indurations associated with the first injections of SUNLENCA was 148 (range: 41 to 727) and 70 (range: 3 to 252) days, respectively. After a median follow up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Qualitative descriptions of injection site nodules and indurations were not routinely reported, but, where reported, the majority of injection site nodules and indurations were palpable but not visible. Measurements of injection site nodules and indurations were not routinely performed or standardized, but where measurements were reported, the maximum size for the majority of injection site nodules and indurations was approximately 1 to 4 cm [see Warnings and Precautions (5.3)]. Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3 to 4) occurring in at least 2% of participants in CAPELLA are presented in Table 7. A causal association between SUNLENCA and these laboratory abnormalities has not been established. Table 7 Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥ 2% of Participants Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Laboratory Parameter Abnormality SUNLENCA + Background Regimen (N=72) Frequencies are based on treatment-emergent laboratory abnormalities in all participants (cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of participants with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except hyperglycemia fasting n=57). ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN = upper limit of normal Creatinine (>1.8 × ULN or ≥1.5 × baseline) 13% Glycosuria (>2+) Grade 3 only (no Grade 4 values reported). 6% Hyperglycemia (fasting) (>250 mg/dL) 5% Proteinuria (>2+) 4% ALT (≥5 × ULN) 3% AST (≥5 × ULN) 3% Direct Bilirubin (>ULN) 3%

6.2Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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. General disorders and administration site conditions Injection site necrosis [see Warnings and Precautions (5.3)].

Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 7, 12.3)

7.1Effect of Other

Drugs on SUNLENCA Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A. Strong or Moderate CYP3A Inducers Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of lenacapavir [see Clinical Pharmacology (12.3)], which may result in loss of therapeutic effect of SUNLENCA and development of resistance. Concomitant administration of SUNLENCA with strong CYP3A inducers during SUNLENCA treatment is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with moderate CYP3A inducers during SUNLENCA treatment is not recommended. Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of SUNLENCA. Concomitant administration of SUNLENCA with these inhibitors is not recommended. 7.2 Effect of SUNLENCA on Other Drugs Lenacapavir is a moderate inhibitor of CYP3A. Due to the long half-life of lenacapavir following subcutaneous administration, SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A [see Clinical Pharmacology (12.3)] initiated within 9 months after the last subcutaneous dose of SUNLENCA, which may increase the potential risk of adverse reactions. See the prescribing information of the sensitive CYP3A substrate for dosing recommendations with moderate inhibitors of CYP3A. 7.3 Established and Other Potentially Significant Drug Interactions Table 8 provides a listing of 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 SUNLENCA or are drug interactions that may occur with SUNLENCA [see Contraindications (4) and Clinical Pharmacology (12.3)]. Table 8 Drug Interactions with SUNLENCA Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease. Clinical Comment Antiarrhythmics: digoxin ↑ digoxin Use with caution and monitor digoxin therapeutic concentration. 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 Concomitant administration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin may result in loss of therapeutic effect and development of resistance. Concomitant administration of SUNLENCA with carbamazepine or phenytoin is contraindicated. Concomitant administration of SUNLENCA with oxcarbazepine or phenobarbital is not recommended. Consider use of alternative anticonvulsants. Antiretroviral Agents: atazanavir/cobicistat Drug-drug interaction study was conducted. atazanavir/ritonavir ↑ lenacapavir (atazanavir/cobicistat, atazanavir/ritonavir) Concomitant administration of efavirenz, nevirapine, or tipranavir/ritonavir may result in loss of therapeutic effect and development of resistance. efavirenz nevirapine tipranavir/ritonavir ↓ lenacapavir (efavirenz, nevirapine, tipranavir/ritonavir) Concomitant administration with atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, or tipranavir/ritonavir is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ lenacapavir Concomitant administration of rifabutin, rifampin and rifapentine may result in loss of therapeutic effect and development of resistance. Concomitant administration of SUNLENCA with rifampin is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with rifabutin or rifapentine is not recommended. Corticosteroids (systemic): cortisone/hydrocortisone dexamethasone ↑ corticosteroids (systemic) 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. ↓ lenacapavir (dexamethasone) Concomitant administration of systemic dexamethasone may result in loss of therapeutic effect of lenacapavir and development of resistance. Alternative corticosteroids to dexamethasone should be considered, particularly for long-term use. Ergot derivatives: dihydroergotamine ergotamine methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Concomitant administration of SUNLENCA 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 Concomitant administration of St. John's wort may result in loss of therapeutic effect and development of resistance. Concomitant administration of SUNLENCA with St. John's wort is contraindicated. 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). 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 SUNLENCA: Carefully titrate the dose of buprenorphine or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SUNLENCA 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 SUNLENCA; if unavoidable, decrease the dosage of naloxegol and monitor for adverse reactions. Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil ↑ PDE-5 inhibitors Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Concomitant administration of SUNLENCA with tadalafil for the treatment of PAH is not recommended. Use of 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 with caution when midazolam or triazolam is concomitantly administered with SUNLENCA

7.4Drugs

Without Clinically Significant Interactions with SUNLENCA Based on drug interaction studies conducted with SUNLENCA, no clinically significant drug interactions have been observed with: darunavir/cobicistat, cobicistat, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole.

8.1Pregnancy Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SUNLENCA 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 a randomized, controlled trial with lenacapavir 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 lenacapavir-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 adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. The background rate of major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. Data Human Data In a randomized, controlled trial of individuals without HIV-1 in Uganda and South Africa, there were 208 pregnancies exposed to lenacapavir with known outcomes and 132 deliveries (both live and non-live). In the active control arm of this trial, 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 lenacapavir 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 lenacapavir during each trimester of pregnancy and postpartum were comparable to those in non-pregnant participants. Animal Data Lenacapavir 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 16 times (rats) and 39 times (rabbits) the exposure in humans at the RHD of SUNLENCA. 8.2 Lactation Risk Summary Lenacapavir is present in human milk. Lenacapavir was detected at very low levels in infants who were breastfed by individuals who became pregnant while receiving lenacapavir (see Data). No adverse effects of lenacapavir in breastfed infants have been observed. It is not known if lenacapavir affects milk production. Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults. Data Human data The median lenacapavir concentration in human breast milk to maternal plasma ratio in participants (n=8) who received lenacapavir was 0.63 (range: 0.29 to 1.90). The median infant-to-mother plasma ratio for lenacapavir in infants (n=10) who were breastfed by individuals receiving lenacapavir from 0 to less than 13 weeks after delivery was 0.06 (range: 0.01 to 0.20). 8.4 Pediatric Use The safety and effectiveness of SUNLENCA have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SUNLENCA did not include sufficient numbers of participants aged 65 and over to determine whether they respond differently from younger patients. 8.6 Renal Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). SUNLENCA has not been studied in patients with ESRD (estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUNLENCA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SUNLENCA 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 a randomized, controlled trial with lenacapavir 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 lenacapavir-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 adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. The background rate of major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. Data Human Data In a randomized, controlled trial of individuals without HIV-1 in Uganda and South Africa, there were 208 pregnancies exposed to lenacapavir with known outcomes and 132 deliveries (both live and non-live). In the active control arm of this trial, 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 lenacapavir 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 lenacapavir during each trimester of pregnancy and postpartum were comparable to those in non-pregnant participants. Animal Data Lenacapavir 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 16 times (rats) and 39 times (rabbits) the exposure in humans at the RHD of SUNLENCA.

SUNLENCA tablets and SUNLENCA injection contain lenacapavir sodium, a capsid inhibitor. The chemical name of lenacapavir sodium is: Sodium (4-chloro-7-(2-((S)-1-(2-((3b S ,4a R)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1 H -cyclopropa[3,4]cyclopenta[1,2- c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1 H -indazol-3-yl)(methylsulfonyl)amide. Lenacapavir sodium has a molecular formula of C 39 H 31 ClF 10 N 7 NaO 5 S 2, a molecular weight of 990.3, and the following structural formula: Lenacapavir sodium is a light yellow to yellow solid and is practically insoluble in water. Chemical Structure SUNLENCA tablets are for oral administration. Each film-coated tablet contains 300 mg of lenacapavir (present as 306.8 mg lenacapavir sodium) and the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection is for subcutaneous administration. Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium) as a sterile, preservative-free, clear, yellow solution and the following inactive ingredients: 896.3 mg of polyethylene glycol 300 (as solvent) and water for injection. The apparent pH range of the injection is 9.0-10.2. The vial stoppers are not made with natural rubber latex.

SUNLENCA tablets, 300 mg are beige, capsule-shaped, and film-coated with "GSI" debossed on one side and "62L" on the other side. SUNLENCA tablets are available in a bottle and blister packs, packaged as follows: Bottle SUNLENCA bottle contains 4 tablets (NDC 61958-3001-3). The bottle also contains a silica gel desiccant and polyester coil, and is closed with a child-resistant closure. Do not remove the desiccant packet. Keep bottle tightly closed. Blister Packs SUNLENCA 4-Tablets™ blister pack contains 4 tablets (NDC 61958-3001-1) SUNLENCA 5-Tablets™ blister pack contains 5 tablets (NDC 61958-3001-2) Within the blister packs, tablets are packaged in a clear blister film sealed to a foil lidding material. The blister card is fitted between two paperboard cards, and packaged with silica gel desiccant in a sealed child-resistant flexible laminated pouch. Store bottle and blister packs at 20 °C - 25 °C (68 °F - 77 °F), excursions permitted to 15 °C - 30 °C (59 °F - 86 °F) (see USP Controlled Room Temperature). Dispense and store only in original bottle or blister pack. SUNLENCA injection is packaged in one of two different injection kits containing the following: Vial Access Device Injection Kit (NDC 61958-3002-1): 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. 2 vial access devices, 2 disposable syringes, and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). Withdrawal Needle Injection Kit (NDC 61958-3005-1): 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. 2 disposable syringes, 2 withdrawal needles (18-gauge, 1.5 inch; may be supplied with or without a safety shield), and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). The vial stoppers are not made with natural rubber latex. Store at 20 °C to 25 °C (68 °F to 77 °F), excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). Keep the vials in the original carton until just prior to preparation of the injections in order to protect from light. Once the solution has been drawn into the syringes, the injections should be administered as soon as possible. Discard any unused portion of the solution.