Lenacapavir

12.1 Mechanism of Action YEZTUGO is an HIV-1 antiretroviral agent with long-acting properties [see Microbiology (12.4) ].

1 INDICATIONS AND USAGE YEZTUGO is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating YEZTUGO [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. YEZTUGO, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating YEZTUGO. ( 1 )

2 DOSAGE AND ADMINISTRATION HIV-1 screening: Screen all individuals for HIV-1 infection prior to initiating YEZTUGO, prior to each injection of YEZTUGO, and additionally as clinically appropriate. ( 2.1 ) Dosing schedule: Initiation dosing (injection and tablets) followed by once every 6-months continuation injection dosing. Tablets may be taken without regard to food. ( 2.3 ) Initiation Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) and 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Continuation 927 mg by subcutaneous injection (2 x 1.5 mL injections) every 6-months (26 weeks) from the date of the last injection +/-2 weeks. Anticipated delayed injections: If scheduled injection is anticipated to be delayed by more than 2 weeks, YEZTUGO tablets may be used on an interim basis (for up to 6 months if needed) until injections resume. Dosing schedule for delayed injection is 300 mg orally once every 7 days. ( 2.4 ) Missed injections: If more than 28 weeks have elapsed since the last injection and tablets have not been taken, restart initiation from Day 1 if clinically appropriate. ( 2.4 ) Dosage modifications (supplemental doses) of YEZTUGO are recommended when initiating strong or moderate CYP3A inducers. ( 2.5 ) YEZTUGO injection is for subcutaneous administration only. Two 1.5 mL injections are required for complete dose. ( 2.6 ) 2.1 HIV-1 Screening for Individuals Receiving YEZTUGO for HIV-1 Pre-Exposure Prophylaxis Screen all individuals for HIV-1 infection prior to initiating YEZTUGO, prior to each subsequent injection of YEZTUGO, and additionally as clinically appropriate, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. When screening for HIV-1 infection prior to initiating YEZTUGO, if an antigen/antibody-specific test is used and provides negative results, then such negative results should be confirmed using an RNA-specific assay, even if the results of the RNA-assay are available after YEZTUGO initiation. When screening for HIV-1 infection prior to continuing YEZTUGO, negative results from a rapid, point-of-care antigen/antibody test should be confirmed using a more sensitive assay [see Indications and Usage (1) , Contraindications (4) , Warnings and Precautions (5.1 , 5.2) and Clinical Studies (14) ]. 2.2 Adherence to YEZTUGO Prior to starting YEZTUGO, healthcare providers should select individuals who agree to the required testing and every 6 month injection dosing schedule, and counsel individuals about the importance of adherence to scheduled YEZTUGO dosing visits to help reduce the risk of acquiring HIV-1 infection and development of resistance [see Dosage and Administration (2.1) , Warnings and Precautions (5.1 , 5.2) , and Microbiology (12.4) ] . 2.3 Recommended Dosage The YEZTUGO dosing schedule in adults and adolescents weighing at least 35 kg consists of a required initiation dosing (subcutaneous injections and oral tablets) followed by once every 6-months continuation dosing (subcutaneous injections) ( Table 1 ). YEZTUGO oral tablets may be taken with or without food [see Clinical Pharmacology (12.3) ] . Table 1. Dosing Schedule for YEZTUGO Initiation and Continuation in Adults and Adolescents Weighing at Least 35 kg Time Dosage of YEZTUGO: Initiation The complete initiation dosing schedule, consisting of subcutaneous injections and oral tablets, is required; the efficacy of YEZTUGO has only been established with this dosing schedule. Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) and 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Dosage of YEZTUGO: Continuation Every 6-months (26 weeks) From the date of the last injection. +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) 2.4 Dosing Schedule for Missed Dose Missed Oral Initiation Dose If the Day 2 oral initiation dose (600 mg; see Table 1 ) is missed, take it as soon as possible. Do not take Day 1 and Day 2 oral initiation doses on the same day. Anticipated Delayed Injections During continuation dosing, if the scheduled 6-month injection is anticipated to be delayed by more than 2 weeks, YEZTUGO tablets may be taken on an interim basis (for up to 6 months if needed), until injections resume. Refer to Table 2 below for the dosing schedule for delayed injections. Table 2. Dosing Schedule for Anticipated Delayed Injections: Weekly Oral Dosage Time since Last Injection Dosage of YEZTUGO 26 to 28 weeks Oral dosage of 300 mg taken once every 7 days. Use on an interim basis only (for up to 6 months if needed). Resume the continuation injection dosage within 7 days after the last oral dose. Missed Injections Individuals who miss a scheduled injection visit should be clinically reassessed to ensure resumption of YEZTUGO remains appropriate and that the individual remains HIV-1 negative. During continuation dosing, if more than 28 weeks have elapsed since the last injection and YEZTUGO tablets

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Serious Injection Site Reactions with Improper Administration [see Warnings and Precautions (5.4) ]. Most common adverse reactions (incidence greater than or equal to 5%, all grades) are injection site reactions, headache, and nausea. ( 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 YEZTUGO is based on data from two randomized, double-blind, active-controlled trials, PURPOSE 1 and PURPOSE 2, in which a total of 8616 adult and adolescent participants received YEZTUGO (N=4323), DESCOVY (emtricitabine [FTC]/tenofovir alafenamide [TAF]; N=2135) once daily, or TRUVADA (FTC/tenofovir disoproxil fumarate [TDF]; N=2158) once daily for HIV-1 PrEP. In PURPOSE 1, the median duration of exposure to YEZTUGO, DESCOVY, and TRUVADA was 43, 42, and 41 weeks, respectively. In PURPOSE 2, the median duration of exposure to both YEZTUGO and TRUVADA was 39 weeks. The most common adverse reactions (all Grades) reported in at least 5% of participants receiving YEZTUGO in either PURPOSE 1 or PURPOSE 2 were injection site reactions, headache, and nausea. In PURPOSE 1, <1% of participants in the groups receiving YEZTUGO, DESCOVY or TRUVADA, discontinued due to adverse events (all causality). In PURPOSE 2, 1% of participants in the group receiving YEZTUGO and <1% of participants receiving TRUVADA discontinued due to adverse events (all causality). Table 6 presents the frequency of adverse reactions (all Grades) in at least 2% of participants receiving YEZTUGO in either PURPOSE 1 or PURPOSE 2. Table 6. Adverse Drug Reactions (All Grades) Reported in ≥2% Frequencies of adverse reactions are based on all adverse events attributed to study drug (or to the procedure for injection site reactions) by the investigator. of Participants Receiving YEZTUGO in PURPOSE 1 or PURPOSE 2 PURPOSE 1 PURPOSE 2 Adverse Reaction YEZTUGO N=2140 TRUVADA Participants received placebo subcutaneous injections (polyethylene glycol 400). N=1070 YEZTUGO N=2183 TRUVADA N=1088 Injection Site Reactions 69% 34% 83% 69% Headache 7% 8% 2% 2% Nausea 5% 11% 2% 4% Dizziness 4% 6% <1% 1% Vomiting 4% 7% <1% 1% Diarrhea 4% 4% 2% 2% Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs) The most frequent adverse reactions associated with lenacapavir injection for subcutaneous use in PURPOSE 1 and PURPOSE 2 were ISRs. The most commonly reported ISRs (all grades) in at least 2% of participants who received YEZTUGO in either PURPOSE 1 or PURPOSE 2 are presented in Table 7 . PURPOSE 1 In PURPOSE 1, 69% of participants receiving YEZTUGO experienced ISRs, compared to 35% of participants receiving placebo injections (and DESCOVY or TRUVADA). Most participants who received YEZTUGO had mild (Grade 1, 50%) or moderate (Grade 2, 19%) severity ISRs. Grade 3 ISRs were reported in 4 (0.2%) participants, and included ulcer and nodule. YEZTUGO was discontinued due to ISRs in 4 (0.2%) participants. None of the ISRs were serious. The incidence of reported ISRs decreased with subsequent injections. Nodules: Injection site nodule was reported in 64% of participants who received YEZTUGO and resolved more slowly than other ISRs. The median duration of nodules associated with the first injections of YEZTUGO was 350 (interquartile range: 182, 470) days. The median of the maximum observed nodule diameter from each participant was 3.0 (interquartile range: 2.0, 3.5) cm. Other ISRs: The other ISRs reported in more than 2% of participants who received YEZTUGO were pain (31%), swelling (4%), induration (4%), and pruritus (2%). The median duration of induration, which resolved more slowly than most other ISRs, was 173 (interquartile range: 22, 267) days. The median duration of ISRs, excluding nodules and indurations, was 9 (interquartile range: 4 to 30) days. PURPOSE 2 In PURPOSE 2, 83% of participants receiving YEZTUGO experienced ISRs, compared to 69% of participants receiving placebo injections (and TRUVADA). Most participants had mild (Grade 1, 66%) or moderate (Grade 2, 17%) severity ISRs. Grade 3 ISRs were reported in 14 (0.6%) participants, and included ulcer, pain, erythema, edema, and dermatitis. YEZTUGO was discontinued due to ISRs in 26 (1.2%) participants. None of the ISRs were serious. The incidence of reported ISRs decreased with subsequent injections. Nodules: Injection site nodule was reported in 63% of participants who received YEZTUGO and resolved more slowly than other ISRs. The median duration of nodules associated with the first injections of YEZTUG

7 DRUG INTERACTIONS Consult the Full Prescribing Information for important drug interactions with YEZTUGO. ( 7 , 12.3 ) 7.1 Effect of Other Drugs on YEZTUGO 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, which may reduce the effectiveness of YEZTUGO. Therefore, dosage modifications (supplemental doses) of YEZTUGO are recommended when initiating strong or moderate CYP3A inducers [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of YEZTUGO. Concomitant administration of YEZTUGO with these inhibitors is not recommended. 7.2 Effect of YEZTUGO on Other Drugs CYP3A and P-gp Substrates Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. The co-administration of YEZTUGO 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. Due to the long half-life of lenacapavir following subcutaneous administration, YEZTUGO 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 YEZTUGO. 7.3 Drugs without Clinically Significant Interactions with YEZTUGO Based on drug interaction studies conducted with YEZTUGO, no clinically significant drug interactions have been observed with: atorvastatin, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole.