Yeztugo® (lenacapavir)
Coadministration with Fentanyl
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Yeztugo® (lenacapavir)
Coadministration With Fentanyl
Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.
The full indication, important safety information, and boxed warning are available at: www.gilead.com/-/media/files/pdfs/medicines/hiv/yeztugo/yeztugo_pi.
PK DDI Evaluation
Based on the PK profile of LEN and fentanyl, a weak PK interaction would be predicted. Narcotic analgesics metabolized by CYP3A, such as fentanyl, that are coadministered with LEN, a moderate inhibitor of CYP3A, may result in increased concentrations of fentanyl; however, the clinical interaction potential between SUBQ LEN and IV fentanyl is predicted to be low.1,2 PK/pharmacodynamic modeling predicts that any change in fentanyl exposure from coadministration with LEN would not significantly increase the risk of respiratory depression. Fentanyl is not a sensitive clinical CYP3A substrate due to its diverse elimination involving multiple enzymes (eg, CYP2D6, CES2, UGT1A4), which helps to potentially explain its modest interactions with potent CYP3A inhibitors.2
Refer to the product labeling of fentanyl for more information on the coadministration with moderate CYP3A inhibitors. Dose adjustments may be required; monitor for therapeutic effects and adverse reactions, including respiratory depression.3
LEN PK
DDI Mechanism | LEN | |
Drug Transporters | OCT2 | N/A |
MATE1 | N/A | |
P-gp | Substratea and weak inhibitor | |
BCRP | Weak inhibitor | |
OATP1B1 | N/A | |
OATP1B3 | N/A | |
Drug Metabolizing Enzymes | CYP3A | Substratea,b and moderate inhibitor |
UGT1A1 | Substratea | |
Abbreviations: BCRP=breast cancer resistance protein; MATE=multidrug and toxin extrusion protein; OATP=organic anion transporting polypeptide; OCT=organic cation transporter.
aCombined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of LEN. Concomitant administration of LEN with these inhibitors is not recommended.
bDrugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of LEN, which may result in reduced effectiveness of LEN. Therefore, dosage modifications (supplemental doses) of LEN are recommended when initiating strong or moderate CYP3A inducers. Please refer to Section 2.5, Dosage Modifications for Coadministration With Strong or Moderate CYP3A Inducers, of the LEN US Prescribing Information for more information.
Relevant LEN Label Information1
Drug Interactions
Effect of LEN on other drugs: CYP3A and P-gp substrates
LEN is a moderate inhibitor of CYP3A and a P-gp inhibitor. The coadministration of LEN with sensitive substrates of CYP3A or P-gp may increase the concentrations of these substrates and result in the increased risk of their AEs. See the prescribing information for these sensitive substrates for dosing recommendations or appropriate monitoring of safety.
Due to the long half-life of LEN following subcutaneous administration, LEN may increase the exposure of drugs primarily metabolized by CYP3A initiated within 9 months after the last SUBQ dose of LEN.
Clinical Data on Coadministration of LEN and Fentanyl
PURPOSE 1 and PURPOSE 2 Studies
In the phase 3 studies evaluating the efficacy and safety of LEN for HIV-1 PrEP, 4 participants in PURPOSE 1 and one participant in PURPOSE 2 received fentanyl. There were no reports of AEs due to concomitant use.5
PURPOSE 2 Study
PURPOSE 2 (NCT04925752) is an ongoing, phase 3, double-blind, randomized study evaluating the efficacy and safety of twice-yearly SUBQ LEN (n=2179) and once-daily oral FTC/TDF (n=1086) for HIV-1 PrEP in cisgender gay, bisexual, and other men, transgender women, transgender men, and gender nonbinary individuals aged ≥16 years in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the US who have condomless receptive anal sex with partners assigned male at birth (N=3265). The primary efficacy endpoint is the incidence of HIV among randomized participants.6
DDIs between LEN and fentanyl7
A subanalysis included participants who self-reported drug use (ie, oral use, injection, or inhalation use of cocaine, amphetamine-type stimulants, inhalants, sedatives or sleeping pills, hallucinogens, opioids, or prescription drugs for nonprescription purposes; cannabis was excluded) in the past 12 weeks and assessed any potential DDI between LEN and fentanyl. Among the participants treated with LEN, 37.2% (767/2061) reported drug use, including cocaine or amphetamine-type stimulant use (409/2058 [19.9%]), opioid use (33/2086 [1.6%]), and injection drug use (17/2092 [0.8%]).
According to a preliminary physiologically based PK model, there was no clinically meaningful interaction between SUBQ LEN and fentanyl. No substance use-related overdoses were reported.
PURPOSE 4 Study8
The interaction between LEN and fentanyl is being evaluated in PURPOSE 4 (NCT06101342), an ongoing phase 2 study evaluating LEN and FTC/TDF for PrEP among people who inject drugs in the US. The study will include participants who screen positive for misuse of any drug, including, but not limited to, fentanyl.
References
5. Gilead Sciences Inc. Data on File.
8. Gilead Sciences. Study of Lenacapavir and Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) for Prevention of HIV in People Who Inject Drugs (HPTN-103) (PURPOSE-4) Available at: https://clinicaltrials.gov/study/NCT06101342?intr=lenacapavir&rank=5 Accessed: 07 November 2023. 2023.
Abbreviations
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AE=adverse event
CES2=carboxylesterase 2
CYP=cytochrome P450
DDI=drug-drug interaction
FTC=emtricitabine
LEN=lenacapavir
P-gp=P-glycoprotein
PK=pharmacokinetic(s)
PrEP=pre-exposure prophylaxis
SUBQ=subcutaneous(ly)
TDF= tenofovir disoproxil fumarate
UGT1A4/1=uridine 5’-diphospho- glucuronosyltransferase family 1 member A4/1
Product Label
For the full indication, important safety information, and boxed warning, please refer to the Yeztugo US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/yeztugo/yeztugo_pi.
Follow-Up
For any additional questions, please contact Gilead Medical Information at:
☎1‐866‐MEDI‐GSI (1‐866‐633‐4474) or www.askgileadmedical.com
Adverse Event Reporting
Please report all adverse events to:
Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
www.gilead.com/utility/contact/report-an-adverse-event
FDA MedWatch Program by ☎ 1-800-FDA-1088 or MedWatch, FDA, 5600 Fishers Ln, Rockville, MD 20852 or www.accessdata.fda.gov/scripts/medwatch
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