DRUG INTERACTIONS-(summary)

 • Consult the Full Prescribing Information prior to and during treatment for important drug interactions.

DRUG INTERACTIONS -(details)

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 ], 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 ].

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.

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   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.

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 

BRIEF SUMMARY

LENECAPVIR-(Dec 2022)

Indn-  To treat adults with HIV infections  which  cannot  be treated sucessfully  treated with  other available treatment  due to resistence, intolerance, or safety consideration

Comp- Tablets: 300 mg Injection: 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials.• Recommended dosage – Initiation with one of two options followed by once every 6-months maintenance dosing. Tablets may be taken without regard to food.

ADR- Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions.

CI-  Concomitant administration is contraindicated with strong CYP3A inducers.

WARNINGS -

 Immune reconstitution syndrome: May necessitate further evaluation and treatment.

 Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer.

Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance.

Pat Inform-

Drug Interactions -                                                                                                           may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products, including St. John’s wort, during treatment.

If  discontinued, advise patients that  may remain in the body and affect certain other drugs for up to 9 months after receiving their last injection.

Immune Reconstitution Syndrome-                                                                           Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started..

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U.S.  APPROVED DRUGS DURING 2022                                        

Serial No 33

Name-        SUNLENCA

Active  Ingredient -  Lenacapavir

Phar macological clssificiation-        To treat adults with HIV infections  which                                                                       cannot  be treated sucessfully  treated with                                                                 other available treatment  due to resistence,                                                                intolerance, or safety consideration                                                                                                                                          

 Date of Approved-         12/12/2022       

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                             SUNLENCA safely and effectively.                                                                                See full prescribing information for SUNLENCA. SUNLENCA® (lenacapavir) tablets, for oral use SUNLENCA® (lenacapavir) injection, for subcutaneous use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

 SUNLENCA, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. 

ADVERSE REACTIONS-

 Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions.

CONTRAINDICATIONS-

 Concomitant administration of SUNLENCA is contraindicated with strong CYP3A inducers.

WARNINGS AND PRECAUTIONS-

 Immune reconstitution syndrome: May necessitate further evaluation and treatment.

 Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer.

Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance.

 May increase exposure and risk of adverse reactions to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA.

 If discontinued, initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA.

If virologic failure occurs, switch to an alternative regimen if possible.

 Injection site reactions may occur, and nodules and indurations may be persistent.

DOSAGE AND ADMINISTRATION-

 • Recommended dosage – Initiation with one of two options followed by once every 6-months maintenance dosing. Tablets may be taken without regard to food.

 Initiation Option 1 Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Initiation Option

2 Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets)

Day 8 300 mg orally (1 x 300 mg tablet)

Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections)

Maintenance 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.

• Missed dose: If more than 28 weeks since last injection and clinically appropriate to continue SUNLENCA, restart initiation from Day 1, using either Option 1 or Option 2.

 • Two 1.5 mL subcutaneous injections are required for complete dose. 

DOSAGE FORMS AND STRENGTHS-

 Tablets: 300 mg Injection: 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials.

PATIENT COUNSELING INFORMATION- 

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

Drug Interactions -                                                                                                   SUNLENCA may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products, including St. John’s wort, during treatment with SUNLENCA . Interactions.

If SUNLENCA is discontinued, advise patients that SUNLENCA may remain in the body and affect certain other drugs for up to 9 months after receiving their last injection.

Immune Reconstitution Syndrome-                                                                       Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started..

Adherence to SUNLENCA -                                                                                   Counsel patients about the importance of continued medication adherence and scheduled visits to maintain viral suppression and to reduce risk of loss of virologic response and development of resistance.

Advise patients to contact their healthcare provider immediately if they stop taking SUNLENCA or any other drug in their antiretroviral regimen.

Injection Site Reactions-                                                                                            Inform patients that injection site reactions (ISRs), such as swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass, may occur. Nodules and indurations at the injection site may take longer to resolve than other ISRs and may be persistent. Instruct patients when to contact their healthcare provider about these reactions,         

Pregnancy Registry-                                                                                                     Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to SUNLENCA.

Lactation-                                                                                                                 Instruct individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk

SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2022 Gilead Sciences, Inc. All rights reserved.

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                           SUNLENCA is an HIV-1 antiretroviral agent].

2. Pharmacodynamics-                                                                                               Exposure-Response In CAPELLA, oral loading doses (600 mg on Day 1 and Day 2, 300 mg on Day 8) followed by subcutaneous doses (927 mg every 6 months starting on Day 15) of SUNLENCA in heavily treatment-experienced subjects with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of subjects with HIV-1 RNA less than 50 copies/mL at Week 26) were similar across the range of observed lenacapavir exposures.

Cardiac Electrophysiology-                                                                                            At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of SUNLENCA), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                      The pharmacokinetic (PK) properties of lenacapavir are provided in Table 6 and Table 7.

The estimated lenacapavir exposures are comparable between the two recommended dosing regimens.                                                                                                             

Table 6 Pharmacokinetic Properties of Lenacapavir Oral Subcutaneous Absorption % Absolute bioavailability 6 to 10 100 a b Tmax 4 hours 77 to 84 days                                  c Effect of Food Effect of lowfat meal (relative to fasting) d AUCinf ratio 98.6 (58.2,167.2) - Cmax ratio 115.8 (55.4, 242.1) -

Effect of highfat meal (relative to fasting) e AUCinf ratio 115.2 (72.0, 184.5) - Cmax ratio 145.2 (77.9, 270.5) -

Distribution-                                                                                                                 Apparent volume of distribution (Vd/F, L) 19240 9500 to 11700 % bound to human plasma proteins >98.5 Blood-to-plasma ratio 0.5 to 0.7 

Elimination-                                                                                                                       t1/2 10 to 12 days 8 to 12 weeks Clearance (mean apparent clearance, L/h) 55 4.2 % of dose of unchanged drug in plasma g 69

Metabolism-                                                                                                                     Metabolic pathway(s) CYP3A (minor) UGT1A1 (minor)

Excretion-                                                                                                                   Major routes of elimination Excretion of unchanged drug into feces h % of dose excreted in urine g <1 % of dose excreted in feces (% unchanged) h 76 (33) a. Values reflect absolute bioavailability following subcutaneous administration of the 927 mg dose. b. Values reflect administration of lenacapavir with or without food. 

Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Pregnancy Exposure Registry-                                                        There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SUNLENCA during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry 

Risk Summary-                                                                                                             There are insufficient human data on the use of SUNLENCA during pregnancy to inform a drug-associated risk of birth defects and miscarriage.

In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) =16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA 

The background risk of major birth defects and miscarriage for the indicated population is unknown.

The background rate of major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%.

The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%.

2. Lactation Risk Summary-                                                                                             The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

It is not known whether SUNLENCA is present in human breast milk, affects human milk production, or has effects on the breastfed infant.

After administration to pregnant rats, lenacapavir was detected in the plasma of nursing rat pups, without effects on these nursing pups.

Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving SUNLENCA.

3.Pediatric Use-                                                                                                                   The safety and effectiveness of SUNLENCA have not been established in pediatric patients. 

4.Geriatric Use-                                                                                                                Clinical studies of SUNLENCA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

5. Renal Impairment-                                                                                                     No dosage adjustment of SUNLENCA is recommended in patients with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute).

SUNLENCA has not been studied in patients with ESRD (estimated creatinine clearance less than 15 mL per minute).

6.Hepatic Impairment-                                                                                                      No dosage adjustment of SUNLENCA is recommended in patients with mild (ChildPugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUNLENCA has not been studied in patients with severe hepatic impairment ..

 OVERDOSAGE-

No data are available on overdose of SUNLENCA in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with SUNLENCA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis.