Yeztugo

Description for Yeztugo

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 C39H31ClF10N7NaO5S2, 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.

YEZTUGO 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 19 material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

YEZTUGO 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.

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)].

Dosage for Yeztugo

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)].

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)] .

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: Initiationa
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)b +/-2 weeks	927 mg by subcutaneous injection (2 x 1.5 mL injections)
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. From the date of the last

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.a Resume the continuation injection dosage within 7 days after the last oral dose.
Use on an interim basis only (for up to 6 months if needed).

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)].

Table 3. Dosing Schedule after Missed Injections

Time since Last Injection	Dosage of YEZTUGO
More than 28 weeks	Reinitiate with initiation dosing schedule from Day 1 (Table 1) and then continue with continuation injection dosing.

Dosage Modifications for Co-administration with Strong or Moderate CYP3A Inducers

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.

Table 4. Dosing Recommendations for Individuals Receiving YEZTUGO and Initiating Therapy with Strong CYP3A Inducersa^a

Maintain Scheduled Continuation Injection Dosing	Schedule for Supplemental Doses of YEZTUGO
	Time	Dosage
Continue to administer once every 6-months scheduled continuation dosing of YEZTUGO 927 mg subcutaneously (2 x 1.5 mL injections) (see Table 1), plus administer supplemental doses of YEZTUGO as shown in this table	On day b CYP3A inducer is initiated (which should be at least 2 days after YEZTUGO is first initiated)	Supplemental dosage: Step 1 927 mg subcutaneously (2 x 1.5 mL injections) and 600 mg orally (2 x 300 mg tablets)
	On day after b CYP3A inducer is initiated	Supplemental dosage: Step 2 600 mg orally (2 x 300 mg tablets)
	If b CYP3A inducer is co-administered for longer than 6 months	Subsequent supplemental dosage Every 6-monthsb from initiation of b CYP3A inducer, continue to administer supplemental doses of YEZTUGO as described above in Steps 1 and 2.
	After stopping the b CYP3A inducer, continue the once every 6-months scheduled continuation injection dosing of YEZTUGO (see Table 1).
Dosing recommendations are not available for the initiation of YEZTUGO in individuals already receiving b CYP3A inducers, nor in individuals receiving the weekly oral dosage of YEZTUGO (see Table 2). 26 weeks +/-2

Table 5. Dosing Recommendations for Individuals Receiving YEZTUGO and Initiating Therapy with Moderate CYP3A Inducersa^a

Maintain Scheduled Continuation Injection Dosing	Schedule for Suppliental Doses of YEZTUGO
	Time	Dosage
Continue to administer once every 6-months scheduled continuation dosing of YEZTUGO 927 mg subcutaneously (2 x 1.5 mL injections) (see Table 1), plus administer suppliental doses of YEZTUGO as shown in this table	On day moderate CYP3A inducer is initiated	Suppliental dosage 463.5 mg subcutaneously (1 x 1.5 mL injection)
	If moderate CYP3A inducer is co-administered for longer than 6 months	Subsequent suppliental dosage Every 6-monthsb from initiation of moderate CYP3A inducer, continue to administer a suppliental dose of YEZTUGO as described above.
	After stopping the moderate CYP3A inducer, continue the once every 6- months scheduled continuation injection dosing of YEZTUGO (see Table 1).
Dosing recommendations are not available for the initiation of YEZTUGO in individuals already receiving moderate CYP3A inducers, nor in individuals receiving the weekly oral dosage of YEZTUGO (see Table 2). 26 weeks +/-2

Preparation and Administration of Subcutaneous Injection

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

HOW SUPPLIED

DOSAGE FORMS AND STRENGTHS

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.

YEZTUGO injection: 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). The lenacapavir injectable solution is sterile, preservative-free, clear, and yellow with no visible particles.

HOW SUPPLIED/STORAGE AND HANDLING

YEZTUGO tablets, 300 mg are beige, capsule-shaped, and film-coated with “GSI” debossed on one side and “62L” on the other side.

Each YEZTUGO bottle contains 4 tablets (NDC 61958-3401-1), a silica gel desiccant, polyester coil, and is closed with a child resistant closure. Do not remove the desiccant packet.

Keep bottle tightly closed.

Store bottle 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 container.

YEZTUGO injection is packaged in a dosing kit (NDC 61958-3402-1) containing:

• 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 aluminum overseal with flip-off cap.
• 2 disposable syringes, 2 withdrawal needles (18-gauge, 1½ inch), 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 - 25 °C (68 °F - 77 °F), excursions permitted to 15 °C - 30 °C (59 °F - 86 °F).

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.

Manufactured for: Gilead Sciences, Inc. 333 Lakeside Dr. Foster City, CA 94404.© 2025 Gilead Sciences, Inc. All rights reserved.

Side Effects for Yeztugo

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)].

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%^a of Participants Receiving YEZTUGO in PURPOSE 1 or PURPOSE 2

	PURPOSE 1		PURPOSE 2
Adverse Reaction	YEZTUGO N=2140	TRUVADAb N=1070	YEZTUGO N=2183	TRUVADAb 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%
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. Participants received placebo subcutaneous injections (polyethylene glycol 400).

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.

Table 7. Injection Site Reactions (All Grades) Reported in ≥2%a of Participants Receiving YEZTUGO in PURPOSE 1 or PURPOSE 2

	PURPOSE 1		PURPOSE 2
Injection Site Reactions	YEZTUGO N=2140	DESCOVY or TRUVADAb N=3205	YEZTUGO N=2183	TRUVADAb N=1088
Nodule	64%	17%	63%	39%
Pain	31%	24%	56%	53%
Induration	4%	<1%	16%	10%
Swelling	4%	5%	7%	10%
Pruritus	2%	1%	3%	3%
Erythema	1%	1%	17%	19%
Bruising	<1%	<1%	3%	4%
Warmth	<1%	<1%	2%	2%
Frequencies are based on all injection site reactions attributed to study drug (or to the procedure) by the investigator. Participants received placebo subcutaneous injections (polyethylene glycol 400).

Drug Interactions for Yeztugo

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.

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.

Drugs without Clinically Significant Interactions with YEZTUGO

Drugs without Clinically Significant Interactions with YEZTUGO

Warnings for Yeztugo

Included as part of the PRECAUTIONS section.

Precautions for Yeztugo

Comprehensive Management to Reduce the Risk of HIV-1 Infection and Other Sexually Acquired Infections

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)].

Potential Risk of Resistance with YEZTUGO

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)].

Long-Acting Properties and Potential Associated Risks with YEZTUGO

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)].

Serious Injection Site Reactions with Improper Administration

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)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study in males or females at doses of up to 300 mg/kg/dose once every 13-weeks.

A 104-week carcinogenicity study was conducted in male and female rats at lenacapavir doses of 0, 102, 309, or 927 mg/kg by subcutaneous injection once every 13-weeks.

A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg). This dose in rats resulted in an exposure approximately 44-times the human exposure at the RHD, based on AUC. These tumors are considered to be a secondary response to chronic tissue irritation and granulomatous inflammation, due to the depot effect of lenacapavir following subcutaneous injection. The clinical relevance of these findings are unknown.

Mutagenesis

Lenacapavir was not mutagenic in a battery of in vitro and in vivo genotoxicity assays, including microbial mutagenesis, chromosome aberration in human peripheral blood lymphocytes, and in in vivo rat micronucleus assays.

Impairment of Fertility

There were no effects on fertility, mating performance or early embryonic development when lenacapavir was administered to rats at systemic exposures (AUC) 8 times the exposure to humans at the RHD of YEZTUGO.

Overdose Information for Yeztugo

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.

Contraindications for Yeztugo

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

Clinical Pharmacology for Yeztugo

Mechanism of Action

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

Pharmacodynamics

Cardiac Electrophysiology

At supratherapeutic exposures of lenacapavir (16-fold higher than the therapeutic exposures of YEZTUGO), YEZTUGO does not prolong the QTcF interval to any clinically relevant extent.

Pharmacokinetics

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.

Table 8. Pharmacokinetic Properties of Lenacapavir

		Oral	Subcutaneous
Absorption
% Absolute bioavailability		4 to 7	91a
Tmaxb		4 hours	77 to 84 daysc
Effect of Food
Effect of low- fat meal (relative to fasting)d	AUCinf ratio	98.6 (58.2,167.2)	-
	Cmax ratio	115.8 (55.4, 242.1)	-
Effect of high- fat meal (relative to fasting)e	AUCinf ratio	115.2 (72.0, 184.5)	-
	Cmax ratio	145.2 (77.9, 270.5)	-
Distribution
Steady state volume of distribution (L)		1657
% bound to human plasma proteins		>98.5
Blood-to-plasma ratio		0.5 to 0.7f
Elimination
Apparent t1/2		10 to 12 days	8 to 12 weeks
Clearance (L/h)		3.4
% of dose of unchanged drug in plasmag		69
Metabolism
Metabolic pathway(s)		CYP3A UGT1A1 (minor)
Excretion
Major routes of elimination		Excretion of unchanged drug into fecesh
% of dose excreted in urineg		<1
% of dose excreted in feces (% unchanged)h		76 (33)
Values reflect absolute bioavailability following subcutaneous administration of the 927 mg Values reflect administration of lenacapavir with or without Subcutaneously administered lenacapavir forms a drug depot whereby lenacapavir is slowly released from the site of administration. Values refer to geometric mean ratio [low-fat meal/fasting] in PK parameters and (90% confidence interval). Low fat meal is approximately 400 kcal, 25% fat. Values refer to geometric mean ratio [high-fat meal/fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 1000 kcal, 50% fat. Values reflect the blood-to-plasma ratio of lenacapavir following a single dose intravenous administration of [14C] lenacapavir through 336 hours postdose. Dosing in mass balance studies: single dose intravenous administration of [14C] lenacapavir to Metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; via CYP3A and UGT1A1 and no single circulating metabolite accounted for >10% of plasma drug-related exposure.

Table 9. Pharmacokinetic Parameters of Lenacapavir Following Oral and Subcutaneous Administration to Adult Participants Receiving YEZTUGO

Parameter Mean (%CV)	Day 1 to end of Month 6	Steady State
Cmax (ng/mL)	73.8 (48.6)	82.4 (40.4)
AUCtau (h•ng/mL)	188108 (41.0)	257334 (38.7)
Ctrough (ng/mL)	27.0 (51.1)	36.9 (53.5)
CV = coefficient of variation

Specific Populations

There were no clinically significant differences in the pharmacokinetics of lenacapavir based on age, sex assigned at birth, gender identity, ethnicity, race, body weight, severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir [see Use in Specific Populations (8.6, 8.7)].

Pediatrics

The population PK parameter estimates of YEZTUGO after oral and subcutaneous administration to adolescents (weighing at least 35 kg) are provided in Table 10.

Table 10. Pharmacokinetic Parameters of Lenacapavir Following Oral and Subcutaneous Administration to Adolescent Participants Receiving YEZTUGO

Parameter Mean (%CV)	Day 1 to end of Month 6	Steady State
Cmax (ng/mL)	81.4 (50.8)	90.1 (41.7)
AUCtau (h•ng/mL)	205420 (42.1)	279630 (39.3)
Ctrough (ng/mL)	29.1 (51.4)	39.8 (53.7)
CV = coefficient of variation

Pregnancy

Changes in lenacapavir exposures during pregnancy and postpartum in participants who received YEZTUGO were not considered clinically relevant compared to lenacapavir exposures observed in non-pregnant participants.

Clinical Studies

A clinical drug-drug interaction study indicated that lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1. Table 11 summarizes the pharmacokinetic effects of other drugs on lenacapavir.

Lenacapavir is a moderate inhibitor of CYP3A. Lenacapavir is an inhibitor of P-gp and BCRP but does not inhibit OATP. Table 12 summarizes the pharmacokinetic effects of lenacapavir on other drugs.

Table 11. Effect of Other Drugs on Lenacapavira^a

Co-administered Drug	Dose of Co-administered Drug (mg)	Mean Ratio of Lenacapavir Pharmacokinetic Parameters (90% CI); No effect = 1.00
		Cmax	AUC
Cobicistat (fed) (Inhibitor of CYP3A [strong] and P-gp)	150 once daily	2.10 (1.62, 2.72)	2.28 (1.75, 2.96)
Darunavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and inhibitor and inducer of P-gp)	800/150 once daily	2.30 (1.79, 2.95)	1.94 (1.50, 2.52)
Voriconazole (fasted) (Inhibitor of CYP3A [strong])	400 twice daily, 200 twice dailyb	1.09 (0.81, 1.47)	1.41 (1.10, 1.81)
Atazanavir / cobicistat (fed) (Inhibitor of CYP3A [strong], UGT1A1, and P-gp)	300/150 once daily	6.60 (4.99, 8.73)	4.21 (3.19, 5.57)
Rifampin (fasted) (Inducer of CYP3A [strong], P- gp, and UGT)	600 once daily	0.45 (0.34, 0.60)	0.16 (0.12, 0.20)
Efavirenz (fasted) (Inducer of CYP3A [moderate] and P-gp)	600 once daily	0.64 (0.45, 0.92)	0.44 (0.32, 0.59)
Famotidine (2 hours before, fasted)	40 once daily	1.01 (0.75, 1.34)	1.28 (1.00, 1.63)
Single dose of lenacapavir 300 mg administered orally. 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily.

Table 12. Effect of Lenacapavir on Other Drugsa

Co-administered Drug	Dose of Co-administered Drug (mg)	Mean Ratio of Co-administered Drug Pharmacokinetic Parameters (90% CI)b; No effect = 1.00
		Cmax	AUC
Tenofovir alafenamide (fed) (substrate of P-gp)	25 single dose	1.24 (0.98, 1.58)	1.32 (1.09, 1.59)
Tenofovirc (substrate of P-gp)		1.23 (1.05, 1.44)	1.47 (1.27, 1.71)
Pitavastatin (simultaneous administration, fed) (substrate of OATP)	2 single dose	1.00 (0.84, 1.19)	1.11 (1.00, 1.25)
Pitavastatin (3 days after lenacapavir, fed) (substrate of OATP)	2 single dose	0.85 (0.69, 1.05)	0.96 (0.87, 1.07)
Rosuvastatin (fed) (substrate of BCRP and OATP)	5 single dose	1.57 (1.38, 1.80)	1.31 (1.19, 1.43)
Midazolam (simultaneous administration, fed) (substrate of CYP3A)	2.5 single dose	1.94 (1.81, 2.08)	3.59 (3.30, 3.91)
1-hydroxymidazolamd (substrate of CYP3A)		0.54 (0.50, 0.59)	0.76 (0.72, 0.80)
Midazolam (1 day after lenacapavir, fed) (substrate of CYP3A)	2.5 single dose	2.16 (2.02, 2.30)	4.08 (3.77, 4.41)
1-hydroxymidazolamd (substrate of CYP3A)		0.52 (0.48, 0.57)	0.84 (0.80, 0.88)
Following 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each co-administered drug, resulting in lenacapavir exposures similar to or higher than those at the usual YEZTUGO dosing schedule [see Dosage and Administration (2.3)]. All No Effect Boundaries are 70% to 143%. Tenofovir alafenamide is converted to tenofovir in vivo. Major active metabolite of midazolam.

In Vitro Studies

Lenacapavir is not a substrate, inducer, or inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Lenacapavir is not an inducer of CYP3A.

Lenacapavir is not an inhibitor of UGT1A1.

Lenacapavir is not an inhibitor of OAT1, OAT3, OCT1, OCT2, MATE1, or MATE 2-K.
Lenacapavir is not a substrate of BCRP, OATP1B1, or OATP1B3.

Patient Information for Yeztugo

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

Important Information for Individuals Receiving YEZTUGO for HIV-1 PrEP

Advise individuals about the following [see Warnings and Precautions (5.1)]:

• YEZTUGO should be used for PrEP as part of an overall HIV-1 prevention strategy, including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of 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.
• Counsel individuals on the use of other prevention measures (e.g., knowledge of partner HIV-1 status, testing for STIs, condom use). Inform individuals about and support their efforts in reducing sexual behaviors associated with HIV-1 acquisition risk.
• YEZTUGO should be used to reduce the risk of HIV-1 acquisition only in individuals confirmed to be HIV-1 negative. Individuals must have a negative HIV-1 test prior to initiating YEZTUGO, prior to each subsequent injection of YEZTUGO, and additionally as clinically appropriate, with a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection [see Dosage and Administration (2.1), Contraindications (4), and Warnings and Precautions (5.1, 5.2)].
• Counsel and support individuals on adhering to the required initiation and continuation dosing schedule, on the use of other measures to reduce the risk of STIs, and on the importance of testing for HIV-1 and other STIs.
• Some individuals, such as adolescents, may benefit from additional counseling and appointment reminders to support adherence.

Risk of Resistance

Advise individuals that there is a risk of developing resistance to YEZTUGO if HIV-1 is acquired 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 Warnings and Precautions (5.2)]. Inform individuals that YEZTUGO can remain in the body for up to 12 months or longer after receiving their last injection [see Warnings and Precautions (5.3)].

To minimize this risk, it is essential that individuals are routinely tested to confirm HIV-1 negative status. Advise individuals that if they are confirmed to have HIV-1, they must immediately be transitioned to a complete HIV-1 treatment regimen [see Warnings and Precautions (5.2)].

Inform individuals that alternative forms of PrEP should be considered and initiated within 28 weeks of the last YEZTUGO injection [see Warnings and Precautions (5.2)].

Anticipated Delayed Injections

Advise individuals to contact their healthcare provider if the scheduled 6-month injection is anticipated to be delayed by more than 2 weeks. Advise that YEZTUGO tablets may be taken for up to 6 months, if needed, until injections resume. Advise individuals that oral dosing should be used on an interim basis only and that the continuation injection dosage should be resumed at the earliest possible opportunity [see Dosage and Administration (2.4)].

Injection Site Reactions

Inform individuals that a subcutaneous drug depot forms following YEZTUGO injection. Advise that, in some individuals, this may lead to a nodule at the injection site [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Drug Interactions

YEZTUGO may interact with certain drugs; therefore, advise individuals to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products [see Drug Interactions (7)].

If YEZTUGO is discontinued, advise individuals that YEZTUGO may remain in the body and affect certain other drugs for up to 9 months after receiving their last injection [see Drug Interactions (7.2)].

Pregnancy Registry

Inform individuals that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to YEZTUGO [see Use in Specific Populations (8.1)].

YEZTUGO, DESCOVY, and TRUVADA are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.