These Highlights Do Not Include All The Information Needed To Use Yeztugo Safely And Effectively. See Full Prescribing Information For Yeztugo.

WARNING: RISK OF DRUG RESISTANCE WITH USE OF YEZTUGO FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED HIV-1 INFECTION

Individuals must be tested for HIV-1 infection prior to initiating YEZTUGO, and with each subsequent injection of YEZTUGO, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of YEZTUGO by individuals with undiagnosed HIV-1 infection. Do not initiate YEZTUGO unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving YEZTUGO must transition to a complete HIV-1 treatment regimen [see Dosage and Administration (2.1), Contraindications (4), Warnings and Precautions (5.1, 5.2)].

YEZTUGO tablets: Each tablet contains 300 mg of lenacapavir (present as 306.8 mg of lenacapavir sodium). The tablets are beige, capsule-shaped, film-coated, and debossed with ‘GSI’ on one side of the tablet and ‘62L’ on the other side of the tablet.

No data are available on overdose of YEZTUGO. If overdose occurs, monitor the individual for evidence of toxicity. Treatment of overdose with YEZTUGO consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual. As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis.

YEZTUGO tablets and YEZTUGO injection contain lenacapavir sodium, a capsid inhibitor.

The chemical name of lenacapavir sodium is: Sodium (4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-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)-1H-indazol-3-yl)(methylsulfonyl)amide.

Lenacapavir sodium has a molecular formula of C₃₉H₃₁ClF₁₀N₇NaO₅S_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.

The safety and effectiveness of YEZTUGO for HIV-1 PrEP in adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition is supported by 2 adequate and well-controlled trials, PURPOSE 1 and PURPOSE 2, that enrolled both adults and adolescents [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

PURPOSE 1 and PURPOSE 2 enrolled a total of 128 adolescent participants. In the 59 adolescents who received YEZTUGO, the safety data were comparable to the safety data reported in adults receiving YEZTUGO.

HIV-1 testing should be conducted 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. Adolescents may benefit from additional counseling and appointment reminders to support adherence to the dosing and testing schedule [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

The safety, effectiveness, and pharmacokinetics of YEZTUGO in pediatric populations weighing less than 35 kg have not been established.

Clinical studies of YEZTUGO did not include sufficient numbers of participants aged 65 and over to determine whether they respond differently from younger individuals. In general, caution should be exercised in administration of YEZTUGO in elderly individuals, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

The efficacy and safety of YEZTUGO in reducing the risk of HIV-1 acquisition were evaluated in two randomized, double-blind, active-controlled, multinational trials (PURPOSE 1 and PURPOSE 2).

PURPOSE 1 was in cisgender adolescent girls and young women between 16 and 25 years of age in South Africa and Uganda who had unknown HIV-1 status at screening and who were at risk of acquiring HIV-1 based on sexual activity with male partners. Participants who tested negative for HIV-1 at screening and baseline were randomized to receive YEZTUGO (N=2134), once daily DESCOVY (N=2136), or once daily TRUVADA (N=1068) in a 2:2:1 ratio.

PURPOSE 2 was in cisgender men, transgender women, transgender men, and gender nonbinary individuals 16 years of age and older who had unknown HIV-1 status at screening and who were at risk of acquiring HIV-1 based on sexual activity with male partners. PURPOSE 2 enrolled participants in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States. Participants who tested negative for HIV-1 at screening and baseline were randomized to receive YEZTUGO (N=2179) or once daily TRUVADA (N=1086) in a 2:1 ratio.

PURPOSE 1

In PURPOSE 1, the median age of participants was 21 years (range, 16-26); and 99.9% were Black. Baseline characteristics in the randomized participants were similar to the screened population. Over 99% of YEZTUGO injections were administered into the abdomen and each dose was administered in two locations. A total of 32 pregnant participants received YEZTUGO injections into the thigh and each dose was administered bilaterally (i.e., one injection in the right thigh and one injection in the left thigh).

The efficacy endpoint was the rate of incident HIV-1 infections per 100 person-years in participants randomized to YEZTUGO compared with the rate of incident HIV-1 infections per 100 person-years in participants randomized to TRUVADA. YEZTUGO demonstrated superiority with a 100% reduction in the risk of incident HIV-1 infection over TRUVADA (Table 13).

PURPOSE 2

In PURPOSE 2, the median age of participants was 29 years (range, 17-74); 67% were non White; 63% were Hispanic/Latine; and 22% identified as gender-diverse (transgender women, transgender men, and gender nonbinary people). Baseline characteristics in the randomized participants were similar to the screened population. YEZTUGO injections were administered into the abdomen and each dose was administered in two locations.

The efficacy endpoint was the rate of incident HIV-1 infections per 100 person-years in participants randomized to YEZTUGO compared with the rate of incident HIV-1 infections per 100 person-years in participants randomized to TRUVADA. YEZTUGO demonstrated superiority with an 89% reduction in the risk of incident HIV-1 infection over TRUVADA (Table 14).

YEZTUGO is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.1)].

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)].

• Consult the Full Prescribing Information for important drug interactions with YEZTUGO. (7, 12.3)

No dosage adjustment of YEZTUGO is recommended in individuals with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). YEZTUGO has not been studied in individuals with ESRD (estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)].

The pharmacokinetic (PK) properties of lenacapavir are provided in Table 8. The population PK parameter estimates of YEZTUGO after oral and subcutaneous administration to adults are provided in Table 9. Similar exposures are achieved when YEZTUGO is administered subcutaneously in the abdomen or thigh.

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)].

No dosage adjustment of YEZTUGO is recommended in individuals with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. YEZTUGO has not been studied in individuals with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

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 is an HIV-1 antiretroviral agent with long-acting properties [see Microbiology (12.4) ].

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)].

• Comprehensive management to reduce the risk of HIV-1 acquisition. (5.1)
• Potential risk of developing resistance to lenacapavir if an individual acquires HIV-1 either before or when receiving YEZTUGO, or following discontinuation of YEZTUGO. Test before each injection and additionally as clinically appropriate to confirm HIV-1 negative status (5.2)
• Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. (5.3)
• Improper administration (intradermal injection) has been associated with serious injection site reactions. (5.4)

• 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)

• 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)

Tablets: 300 mg of lenacapavir

Injection: 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir in single-dose vials. (3)

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.

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 YEZTUGO was 297 (interquartile range: 176, 423) days. The median of the maximum observed nodule diameter for each participant was 3.0 (interquartile range: 2.0, 4.0) cm.

Other ISRs: The other ISRs reported in more than 2% of participants who received YEZTUGO were pain (56%), erythema (17%), induration (16%), swelling (7%), bruising (3%), pruritus (3%), and warmth (2%). The median duration of induration, which resolved more slowly than most other ISRs, was 151 (interquartile range: 15, 267) days. The median duration of ISRs, excluding nodules and indurations, was 4 (interquartile range: 2 to 8) days.

Advise the individual to read the FDA-approved patient labeling (Patient Information).

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.

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 have not been taken, see Table 3 below for the dosing schedule after missed injections. Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration (2.2) and Microbiology (12.4)].

Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A.

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.

Rx only

NDC 61958-3402-1

Yeztugo^®

(lenacapavir) injection

463.5 mg/1.5 mL (309 mg/mL)

For Subcutaneous Injection

Contents

• 2 x 1.5 mL lenacapavir single-dose vials
• 2 withdrawal needles (18 gauge, 1½ inch)
• 2 syringes
• 2 injection needles (22 gauge, ½ inch)
• Prescribing Information
• Instructions for Use
• Patient Information

Both 463.5 mg/1.5 mL (2 single-dose vials) must be

administered to receive the 927 mg dose.

For Healthcare Professional administration only.

GILEAD

There is a potential risk of developing resistance to YEZTUGO if an individual acquires HIV-1 either before or when receiving YEZTUGO, or following discontinuation of YEZTUGO. HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only YEZTUGO, because YEZTUGO alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology (12.4)].

To minimize this risk, it is essential to test before each injection and additionally as clinically appropriate (e.g., upon diagnosis of other sexually transmitted infections or if clinical symptoms consistent with acute HIV-1 infection are present) to confirm HIV-1 negative status using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Individuals who are confirmed to have HIV-1 must immediately begin a complete HIV-1 treatment regimen to reduce the risk of developing resistance.

In addition, due to the long-acting properties of YEZTUGO, alternative forms of PrEP should be considered following discontinuation of YEZTUGO for those individuals with HIV-1 negative status who are at continuing risk of HIV-1 acquisition and initiated within 28 weeks of the last YEZTUGO injection [see Warnings and Precautions (5.3)].

NDC 61958-3401-1

4 tablets

Yeztugo^®

(lenacapavir) tablets

300 mg per tablet

Talk to your healthcare provider

before taking Yeztugo tablets.

Your healthcare provider will tell you

when to take Yeztugo tablets.

GILEAD

© 2025 Gilead Sciences, Inc.

YEZTUGO injection is only for subcutaneous administration into the abdomen by a healthcare provider. The thigh can be used as an alternative injection site if preferred. Do NOT administer intradermally due to risk of serious injection site reactions [see Warnings and Precautions (5.4)].

Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. YEZTUGO injection is a yellow solution. Do not use YEZTUGO 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)].

Figure 1 identifies the components for use in the administration steps for the withdrawal needle injection kit, and the administration steps are provided in Figure 2. The 18-gauge needle is for withdrawal only in this kit.

The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose.

Figure 1 YEZTUGO Withdrawal Needle Injection Kit Components

Figure 2 YEZTUGO Injection Steps for Withdrawal Needle Injection Kit

Improper administration (intradermal injection) of lenacapavir has been associated with serious injection site reactions, including necrosis and ulcer. Ensure YEZTUGO is only administered subcutaneously [see Dosage and Administration (2.6)].

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.

Healthcare providers should take the long-acting properties of YEZTUGO into consideration when YEZTUGO is prescribed. Residual concentrations of lenacapavir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer after the last subcutaneous dose).

It is important to select individuals who agree to the required injection dosing schedule because non-adherence to every-6-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance.

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 YEZTUGO [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Supplemental doses of YEZTUGO are recommended for individuals initiating therapy with either strong CYP3A inducers (see Table 4) or moderate CYP3A inducers (see Table 5) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Strong CYP3A inducers may be initiated starting at least 2 days after YEZTUGO is first initiated, while moderate CYP3A inducers may be started any time after YEZTUGO is first initiated.

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)].

Use YEZTUGO to reduce the risk of HIV-1 acquisition as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). YEZTUGO is not always effective in preventing HIV-1 acquisition [see Clinical Studies (14)]. The time from initiation of YEZTUGO for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals about and support their efforts in reducing sexual behaviors associated with HIV-1 acquisition risk.

Use YEZTUGO to reduce the risk of HIV-1 acquisition only in individuals confirmed to be HIV-1 negative [see Contraindications (4)]. Evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash). Confirm HIV-1 negative status prior to initiating YEZTUGO, prior to each subsequent injection of YEZTUGO, and additionally as clinically appropriate (e.g., upon diagnosis of other sexually transmitted infections or if clinical symptoms consistent with acute HIV-1 infection are present) using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection [see Dosage and Administration (2.1)].

Counsel and support individuals on adhering to the YEZTUGO administration schedule, on the use of other measures to reduce the risk of STIs, and on the importance of routine testing for HIV-1 and other STIs. Some individuals, such as adolescents, may benefit from additional counseling and appointment reminders to support adherence to the dosing and testing schedule [see Use in Specific Populations (8.4)].

WARNING: RISK OF DRUG RESISTANCE WITH USE OF YEZTUGO FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED HIV-1 INFECTION

Individuals must be tested for HIV-1 infection prior to initiating YEZTUGO, and with each subsequent injection of YEZTUGO, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of YEZTUGO by individuals with undiagnosed HIV-1 infection. Do not initiate YEZTUGO unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving YEZTUGO must transition to a complete HIV-1 treatment regimen [see Dosage and Administration (2.1), Contraindications (4), Warnings and Precautions (5.1, 5.2)].

YEZTUGO tablets: Each tablet contains 300 mg of lenacapavir (present as 306.8 mg of lenacapavir sodium). The tablets are beige, capsule-shaped, film-coated, and debossed with ‘GSI’ on one side of the tablet and ‘62L’ on the other side of the tablet.

No data are available on overdose of YEZTUGO. If overdose occurs, monitor the individual for evidence of toxicity. Treatment of overdose with YEZTUGO consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual. As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis.

YEZTUGO tablets and YEZTUGO injection contain lenacapavir sodium, a capsid inhibitor.

The chemical name of lenacapavir sodium is: Sodium (4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-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)-1H-indazol-3-yl)(methylsulfonyl)amide.

Lenacapavir sodium has a molecular formula of C₃₉H₃₁ClF₁₀N₇NaO₅S_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.

The safety and effectiveness of YEZTUGO for HIV-1 PrEP in adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition is supported by 2 adequate and well-controlled trials, PURPOSE 1 and PURPOSE 2, that enrolled both adults and adolescents [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

PURPOSE 1 and PURPOSE 2 enrolled a total of 128 adolescent participants. In the 59 adolescents who received YEZTUGO, the safety data were comparable to the safety data reported in adults receiving YEZTUGO.

HIV-1 testing should be conducted 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. Adolescents may benefit from additional counseling and appointment reminders to support adherence to the dosing and testing schedule [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

The safety, effectiveness, and pharmacokinetics of YEZTUGO in pediatric populations weighing less than 35 kg have not been established.

Clinical studies of YEZTUGO did not include sufficient numbers of participants aged 65 and over to determine whether they respond differently from younger individuals. In general, caution should be exercised in administration of YEZTUGO in elderly individuals, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

The efficacy and safety of YEZTUGO in reducing the risk of HIV-1 acquisition were evaluated in two randomized, double-blind, active-controlled, multinational trials (PURPOSE 1 and PURPOSE 2).

PURPOSE 1 was in cisgender adolescent girls and young women between 16 and 25 years of age in South Africa and Uganda who had unknown HIV-1 status at screening and who were at risk of acquiring HIV-1 based on sexual activity with male partners. Participants who tested negative for HIV-1 at screening and baseline were randomized to receive YEZTUGO (N=2134), once daily DESCOVY (N=2136), or once daily TRUVADA (N=1068) in a 2:2:1 ratio.

PURPOSE 2 was in cisgender men, transgender women, transgender men, and gender nonbinary individuals 16 years of age and older who had unknown HIV-1 status at screening and who were at risk of acquiring HIV-1 based on sexual activity with male partners. PURPOSE 2 enrolled participants in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States. Participants who tested negative for HIV-1 at screening and baseline were randomized to receive YEZTUGO (N=2179) or once daily TRUVADA (N=1086) in a 2:1 ratio.

PURPOSE 1

In PURPOSE 1, the median age of participants was 21 years (range, 16-26); and 99.9% were Black. Baseline characteristics in the randomized participants were similar to the screened population. Over 99% of YEZTUGO injections were administered into the abdomen and each dose was administered in two locations. A total of 32 pregnant participants received YEZTUGO injections into the thigh and each dose was administered bilaterally (i.e., one injection in the right thigh and one injection in the left thigh).

The efficacy endpoint was the rate of incident HIV-1 infections per 100 person-years in participants randomized to YEZTUGO compared with the rate of incident HIV-1 infections per 100 person-years in participants randomized to TRUVADA. YEZTUGO demonstrated superiority with a 100% reduction in the risk of incident HIV-1 infection over TRUVADA (Table 13).

PURPOSE 2

In PURPOSE 2, the median age of participants was 29 years (range, 17-74); 67% were non White; 63% were Hispanic/Latine; and 22% identified as gender-diverse (transgender women, transgender men, and gender nonbinary people). Baseline characteristics in the randomized participants were similar to the screened population. YEZTUGO injections were administered into the abdomen and each dose was administered in two locations.

The efficacy endpoint was the rate of incident HIV-1 infections per 100 person-years in participants randomized to YEZTUGO compared with the rate of incident HIV-1 infections per 100 person-years in participants randomized to TRUVADA. YEZTUGO demonstrated superiority with an 89% reduction in the risk of incident HIV-1 infection over TRUVADA (Table 14).

YEZTUGO is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.1)].

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)].

• Consult the Full Prescribing Information for important drug interactions with YEZTUGO. (7, 12.3)

No dosage adjustment of YEZTUGO is recommended in individuals with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). YEZTUGO has not been studied in individuals with ESRD (estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)].

The pharmacokinetic (PK) properties of lenacapavir are provided in Table 8. The population PK parameter estimates of YEZTUGO after oral and subcutaneous administration to adults are provided in Table 9. Similar exposures are achieved when YEZTUGO is administered subcutaneously in the abdomen or thigh.

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)].

No dosage adjustment of YEZTUGO is recommended in individuals with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. YEZTUGO has not been studied in individuals with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

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 is an HIV-1 antiretroviral agent with long-acting properties [see Microbiology (12.4) ].

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)].

• Comprehensive management to reduce the risk of HIV-1 acquisition. (5.1)
• Potential risk of developing resistance to lenacapavir if an individual acquires HIV-1 either before or when receiving YEZTUGO, or following discontinuation of YEZTUGO. Test before each injection and additionally as clinically appropriate to confirm HIV-1 negative status (5.2)
• Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. (5.3)
• Improper administration (intradermal injection) has been associated with serious injection site reactions. (5.4)

• 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)

• 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)

Tablets: 300 mg of lenacapavir

Injection: 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir in single-dose vials. (3)

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.

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 YEZTUGO was 297 (interquartile range: 176, 423) days. The median of the maximum observed nodule diameter for each participant was 3.0 (interquartile range: 2.0, 4.0) cm.

Other ISRs: The other ISRs reported in more than 2% of participants who received YEZTUGO were pain (56%), erythema (17%), induration (16%), swelling (7%), bruising (3%), pruritus (3%), and warmth (2%). The median duration of induration, which resolved more slowly than most other ISRs, was 151 (interquartile range: 15, 267) days. The median duration of ISRs, excluding nodules and indurations, was 4 (interquartile range: 2 to 8) days.

Advise the individual to read the FDA-approved patient labeling (Patient Information).

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.

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 have not been taken, see Table 3 below for the dosing schedule after missed injections. Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration (2.2) and Microbiology (12.4)].

Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A.

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.

Rx only

NDC 61958-3402-1

Yeztugo^®

(lenacapavir) injection

463.5 mg/1.5 mL (309 mg/mL)

For Subcutaneous Injection

Contents

• 2 x 1.5 mL lenacapavir single-dose vials
• 2 withdrawal needles (18 gauge, 1½ inch)
• 2 syringes
• 2 injection needles (22 gauge, ½ inch)
• Prescribing Information
• Instructions for Use
• Patient Information

Both 463.5 mg/1.5 mL (2 single-dose vials) must be

administered to receive the 927 mg dose.

For Healthcare Professional administration only.

GILEAD

There is a potential risk of developing resistance to YEZTUGO if an individual acquires HIV-1 either before or when receiving YEZTUGO, or following discontinuation of YEZTUGO. HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only YEZTUGO, because YEZTUGO alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology (12.4)].

To minimize this risk, it is essential to test before each injection and additionally as clinically appropriate (e.g., upon diagnosis of other sexually transmitted infections or if clinical symptoms consistent with acute HIV-1 infection are present) to confirm HIV-1 negative status using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Individuals who are confirmed to have HIV-1 must immediately begin a complete HIV-1 treatment regimen to reduce the risk of developing resistance.

In addition, due to the long-acting properties of YEZTUGO, alternative forms of PrEP should be considered following discontinuation of YEZTUGO for those individuals with HIV-1 negative status who are at continuing risk of HIV-1 acquisition and initiated within 28 weeks of the last YEZTUGO injection [see Warnings and Precautions (5.3)].

NDC 61958-3401-1

4 tablets

Yeztugo^®

(lenacapavir) tablets

300 mg per tablet

Talk to your healthcare provider

before taking Yeztugo tablets.

Your healthcare provider will tell you

when to take Yeztugo tablets.

GILEAD

© 2025 Gilead Sciences, Inc.

YEZTUGO injection is only for subcutaneous administration into the abdomen by a healthcare provider. The thigh can be used as an alternative injection site if preferred. Do NOT administer intradermally due to risk of serious injection site reactions [see Warnings and Precautions (5.4)].

Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. YEZTUGO injection is a yellow solution. Do not use YEZTUGO 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)].

Figure 1 identifies the components for use in the administration steps for the withdrawal needle injection kit, and the administration steps are provided in Figure 2. The 18-gauge needle is for withdrawal only in this kit.

The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose.

Figure 1 YEZTUGO Withdrawal Needle Injection Kit Components

Figure 2 YEZTUGO Injection Steps for Withdrawal Needle Injection Kit

Improper administration (intradermal injection) of lenacapavir has been associated with serious injection site reactions, including necrosis and ulcer. Ensure YEZTUGO is only administered subcutaneously [see Dosage and Administration (2.6)].

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.

Healthcare providers should take the long-acting properties of YEZTUGO into consideration when YEZTUGO is prescribed. Residual concentrations of lenacapavir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer after the last subcutaneous dose).

It is important to select individuals who agree to the required injection dosing schedule because non-adherence to every-6-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance.

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 YEZTUGO [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Supplemental doses of YEZTUGO are recommended for individuals initiating therapy with either strong CYP3A inducers (see Table 4) or moderate CYP3A inducers (see Table 5) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Strong CYP3A inducers may be initiated starting at least 2 days after YEZTUGO is first initiated, while moderate CYP3A inducers may be started any time after YEZTUGO is first initiated.

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)].

Use YEZTUGO to reduce the risk of HIV-1 acquisition as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). YEZTUGO is not always effective in preventing HIV-1 acquisition [see Clinical Studies (14)]. The time from initiation of YEZTUGO for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals about and support their efforts in reducing sexual behaviors associated with HIV-1 acquisition risk.

Use YEZTUGO to reduce the risk of HIV-1 acquisition only in individuals confirmed to be HIV-1 negative [see Contraindications (4)]. Evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash). Confirm HIV-1 negative status prior to initiating YEZTUGO, prior to each subsequent injection of YEZTUGO, and additionally as clinically appropriate (e.g., upon diagnosis of other sexually transmitted infections or if clinical symptoms consistent with acute HIV-1 infection are present) using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection [see Dosage and Administration (2.1)].

Counsel and support individuals on adhering to the YEZTUGO administration schedule, on the use of other measures to reduce the risk of STIs, and on the importance of routine testing for HIV-1 and other STIs. Some individuals, such as adolescents, may benefit from additional counseling and appointment reminders to support adherence to the dosing and testing schedule [see Use in Specific Populations (8.4)].