LENACAPAVIR Drug Interactions: What You Need to Know

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

7.1 Effect of Other Drugs on SUNLENCA Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A. Strong or Moderate CYP3A Inducers Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of lenacapavir <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may result in loss of therapeutic effect of SUNLENCA and development of resistance. Concomitant administration of SUNLENCA with strong CYP3A inducers during SUNLENCA treatment is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Concomitant administration of SUNLENCA with moderate CYP3A inducers during SUNLENCA treatment is not recommended. Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of SUNLENCA. Concomitant administration of SUNLENCA with these inhibitors is not recommended.

7.2 Effect of SUNLENCA on Other Drugs Lenacapavir is a moderate inhibitor of CYP3A. Due to the long half-life of lenacapavir following subcutaneous administration, SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> initiated within 9 months after the last subcutaneous dose of SUNLENCA, which may increase the potential risk of adverse reactions. See the prescribing information of the sensitive CYP3A substrate for dosing recommendations with moderate inhibitors of CYP3A.

7.3 Established and Other Potentially Significant Drug Interactions Table 5 provides a listing of clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with SUNLENCA or are drug interactions that may occur with SUNLENCA <span class="opacity-50 text-xs">[see Contraindications (4) and Clinical Pharmacology (12.3) ]</span> .

Table

5 Drug Interactions with SUNLENCA Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease.

Clinical Comment

Antiarrhythmics: digoxin ↑ digoxin Use with caution and monitor digoxin therapeutic concentration. Anticoagulants: Direct Oral Anticoagulants (DOACs) rivaroxaban dabigatran edoxaban ↑ DOAC Refer to the DOAC prescribing information for concomitant administration with moderate CYP3A inhibitors and/or P-gp inhibitors. Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ lenacapavir Concomitant administration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin may result in loss of therapeutic effect and development of resistance. Concomitant administration of SUNLENCA with carbamazepine or phenytoin is contraindicated. Concomitant administration of SUNLENCA with oxcarbazepine or phenobarbital is not recommended. Consider use of alternative anticonvulsants.

Antiretroviral

Agents: atazanavir/cobicistat Drug-drug interaction study was conducted. atazanavir/ritonavir ↑ lenacapavir (atazanavir/cobicistat, atazanavir/ritonavir) Concomitant administration of efavirenz, nevirapine, or tipranavir/ritonavir may result in loss of therapeutic effect and development of resistance. efavirenz nevirapine tipranavir/ritonavir ↓ lenacapavir (efavirenz, nevirapine, tipranavir/ritonavir) Concomitant administration with atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, or tipranavir/ritonavir is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ lenacapavir Concomitant administration of rifabutin, rifampin and rifapentine may result in loss of therapeutic effect and development of resistance. Concomitant administration of SUNLENCA with rifampin is contraindicated [see Contraindications (4) ] . Concomitant administration of SUNLENCA with rifabutin or rifapentine is not recommended. Corticosteroids (systemic): cortisone/hydrocortisone dexamethasone ↑ corticosteroids (systemic) Concomitant administration with systemic corticosteroids whose exposures are significantly increased by CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Initiate with the lowest starting dose and titrate carefully while monitoring for safety. ↓ lenacapavir (dexamethasone) Concomitant administration of systemic dexamethasone may result in loss of therapeutic effect of lenacapavir and development of resistance. Alternative corticosteroids to dexamethasone should be considered, particularly for long-term use. Ergot derivatives: dihydroergotamine ergotamine methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Concomitant administration of SUNLENCA with dihydroergotamine, ergotamine or methylergonovine is not recommended.

Herbal

Products: St. John's wort The induction potency of St. John's wort may vary widely based on preparation. (Hypericum perforatum) ↓ lenacapavir Concomitant administration of St. John's wort may result in loss of therapeutic effect and development of resistance. Concomitant administration of SUNLENCA with St. John's wort is contraindicated. HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g., myopathy). Narcotic analgesics metabolized by CYP3A: e.g., fentanyl, oxycodone ↑ fentanyl ↑ oxycodone Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. tramadol ↑ tramadol A decrease in dose may be needed for tramadol with concomitant use. Narcotic analgesic for treatment of opioid dependence: buprenorphine, methadone buprenorphine: effects unknown methadone: effects unknown Initiation of buprenorphine or methadone in patients taking SUNLENCA: Carefully titrate the dose of buprenorphine or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SUNLENCA in patients taking buprenorphine or methadone: A dose adjustment for buprenorphine or methadone may be needed. Monitor clinical signs and symptoms.

Opioid

Antagonist: naloxegol ↑ naloxegol Avoid use with SUNLENCA; if unavoidable, decrease the dosage of naloxegol and monitor for adverse reactions. Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil ↑ PDE-5 inhibitors Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Concomitant administration of SUNLENCA with tadalafil for the treatment of PAH is not recommended. Use of PDE-5 inhibitors for erectile dysfunction (ED): Refer to the prescribing information of PDE-5 inhibitors for dose recommendations. Sedatives/Hypnotics: midazolam (oral) triazolam ↑ midazolam (oral) ↑ triazolam Use with caution when midazolam or triazolam is concomitantly administered with SUNLENCA

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

Concomitant administration of SUNLENCA with strong CYP3A inducers is contraindicated due to decreased lenacapavir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to SUNLENCA [see Drug Interactions (7.1) ] . Concomitant administration of SUNLENCA is contraindicated with strong CYP3A inducers. ( 4 )

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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

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 <span class="opacity-50 text-xs">[see Microbiology (12.4) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .