1.5 ML lenacapavir 309 MG/ML Injection [Yeztugo]

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 )

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 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. 2.5 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 Inducers Dosing recommendations are not available for the initiation of YEZTUGO in individuals already receiving strong CYP3A inducers, nor in individuals receiving the weekly oral dosage of YEZTUGO (see Table 2 ) . 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 strong 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 strong CYP3A inducer is initiated Supplemental dosage: Step 2 600 mg orally (2 x 300 mg tablets) If strong CYP3A inducer is co-administered for longer than 6 months Subsequent supplemental dosage Every 6-months 26 weeks +/-2 weeks. from initiation of strong CYP3A inducer, continue to administer supplemental doses of YEZTUGO as described above in Steps 1 and 2. After stopping the strong CYP3A inducer, continue the once every 6-months scheduled continuation injection dosing of YEZTUGO (see Table 1 ) . Table 5. Dosing Recommendations for Individuals Receiving YEZTUGO and Initiating Therapy with Moderate CYP3A Inducers 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 ) . 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 moderat

WARNINGS AND PRECAUTIONS 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 ) 5.1 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) ] . 5.2 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) ]. 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) ] . 5.4 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) ] .

CONTRAINDICATIONS YEZTUGO is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.1) ]. Unknown or positive HIV-1 status. ( 4 )

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