Breastfeeding warning
Use during breastfeeding only on medical advice.
Leaflet YEYTUO 464mg solution for injection
- Product code:
- W72176001
- Indicated for:
- HIV-1 infection
- Route of administration:
- injectable
- Substance:
- lenacapavir (viral entry inhibitor)
- ATC
- J05AX31 — Antiinfectives for systemic use | Direct acting antivirals | Other antivirals
Lenacapavir is an antiretroviral medication used for the treatment of HIV-1 infection. It acts as a capsid inhibitor, interfering with multiple stages of the viral replication cycle.
The medication is administered as a subcutaneous injection, usually once every six months, under the supervision of a specialist. It is used in combination with other antiretroviral drugs to enhance treatment efficacy.
Side effects may include injection site reactions, nausea, fatigue, or headaches. In rare cases, severe allergic reactions may occur.
Lenacapavir is not recommended for patients with hypersensitivity to this medication or those taking drugs that interact with capsid metabolism.
The medication is administered as a subcutaneous injection, usually once every six months, under the supervision of a specialist. It is used in combination with other antiretroviral drugs to enhance treatment efficacy.
Side effects may include injection site reactions, nausea, fatigue, or headaches. In rare cases, severe allergic reactions may occur.
Lenacapavir is not recommended for patients with hypersensitivity to this medication or those taking drugs that interact with capsid metabolism.
General data about YEYTUO 464mg
- Substance:
- lenacapavir
- Product code:
- W72176001
- Concentration:
- 464mg
- Pharmaceutical form:
- solution for injection
- Product type:
- Generic medicine
- Prescription status:
- S — Medicines dispensed with a restricted medical prescription, reserved for use in certain specialized fields.
Pharmaceutical forms available for lenacapavir
Concentrations available for lenacapavir
- 300mg
- 464mg
Official documents
- Added to database:
- 03/09/2025
- Source record updated:
- 22/09/2026
Precautions:
Pregnancy warning
Use during pregnancy only on medical advice.
Contents of the package leaflet for the medicine YEYTUO 464mg solution for injection
Find in leaflet
Leaflet YEYTUO 464mg
1. NAME OF THE MEDICINAL PRODUCT
Yeytuo 464 mg solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each single-dose vial contains lenacapavir sodium equivalent to 463.5 mg of lenacapavir in 1.5 mL.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection).
Clear, yellow to brown solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Yeytuo injection is indicated in combination with safer sex practices for pre-exposure prophylaxis(PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents with increased
HIV-1 acquisition risk, weighing at least 35 kg (see sections 4.2, pct. 4.4 and 5.1).
4.2 Posology and method of administration
Yeytuo should be prescribed by a healthcare professional experienced in the management of HIVprevention.
Each injection should be administered by a healthcare professional.
All individuals must be screened for HIV-1 prior to initiating lenacapavir, prior to each subsequentinjection, and additionally as clinically appropriate (see sections 4.3 and 4.4). A combinedantigen/antibody test as well as an HIV-RNA-based test should be negative. Prescribers are advised toperform both tests, even if the result of the HIV-RNA-based test will become available after initiationof lenacapavir. If a combined testing strategy including both tests is not available, testing shouldfollow local guidelines.
Prior to starting Yeytuo, healthcare professionals should identify individuals for whom the requiredinitiation and every 6-month continuation injection dosing schedule is appropriate, and counselindividuals about the importance of adherence to scheduled dosing visits (see section 4.4).
PosologyThe dosing schedule in adults and adolescents weighing at least 35 kg consists of a required initiationdosing (subcutaneous injections and oral tablets) followed by once every 6-month continuation dosing(subcutaneous injections) (Table 1).
Oral tablets can be taken with or without food (see Yeytuo tablet SmPC).
Table 1: Dosing schedule for lenacapavir initiation and continuation
Time
Dose of lenacapavir: Initiationa
Day 1 927 mg subcutaneous injection (2 x 1.5 mL injectionsb)600 mg orally (2 x 300 mg tablets)
Day 2 600 mg orally (2 x 300 mg tablets)
Dose of lenacapavir: Continuation
Every 6 Months 927 mg subcutaneous injection (2 x 1.5 mL injectionsb)(26 weeks)c+/- 2 weeksa The complete initiation dosing schedule, consisting of subcutaneous injections and oral tablets, is required; the efficacyof lenacapavir has only been established with this dosing schedule.
b Two injections, with the second injection at least 5 centimetres from the first injection (see Method of Administration).c From the date of the last injection.
Missed doseAnticipated delayed injections
During continuation dosing, if the scheduled 6-month injection is anticipated to be delayed by morethan 2 weeks, lenacapavir tablets may be used for oral bridging on an interim basis (for up to 6 monthsif needed), until injections resume. Oral bridging should be initiated within 26 to 28 weeks from thelast injection. The dosing schedule is 300 mg (1 tablet) taken orally once every 7 days. Resume thecontinuation injection dosage within 7 days after the last oral dose (see Table 1).
Missed injections
During the continuation period, if more than 28 weeks have elapsed since the last injection andlenacapavir tablets have not been taken for oral bridging, restart the initiation dosing schedule from
Day 1 (see Table 1).
Special populationsElderly
No dose adjustment of lenacapavir is required for elderly individuals. There are limited data availableon the use of lenacapavir in individuals aged 65 years and above (see section 5.2).
Renal impairmentNo dose adjustment of lenacapavir is required in individuals with mild, moderate, or severe renalimpairment (creatinine clearance [CrCl] ≥ 15 mL/min). Lenacapavir has not been studied inindividuals with end stage renal disease (CrCl < 15 mL/min or on renal replacement therapy) (seesection 5.2), therefore lenacapavir should be used with caution in these individuals.
Hepatic impairmentNo dose adjustment of lenacapavir is required in individuals with mild or moderate hepaticimpairment (Child-Pugh Class A or B). Lenacapavir has not been studied in individuals with severehepatic impairment (Child-Pugh Class C) (see section 5.2), therefore lenacapavir should be used withcaution in these individuals.
Paediatric populationSafety and efficacy of lenacapavir in children and adolescents weighing less than 35 kg have not beenestablished. No data are available.
Method of administrationFor subcutaneous use only.
Lenacapavir injections must only be administered subcutaneously into the abdomen or thigh (twoinjections, with the second injection at least 5 centimetres from the first injection) by a healthcareprofessional (see section 6.6). Do NOT administer intradermally (see section 4.4).
For instructions on preparation and administration, see ‘Instructions for Use’ in the package leaflet.‘Instructions for Use’ are also available as a card in the injection kit.
Following lenacapavir injection, a subcutaneous drug depot forms whereby lenacapavir is slowlyreleased from the site of administration. In some individuals, this may lead to a nodule at the injectionsite (see sections 4.8 and 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use in individuals with unknown HIV-1 status (see section 4.4).
Co-administration with strong inducers of CYP3A, P-gp, and UGT1A1, such as:
* antimycobacterials: rifampicin
* anticonvulsants: carbamazepine, phenytoin
* herbal products: St. John’s wort (Hypericum perforatum)(see section 4.5).
4.4 Special warnings and precautions for use
Prevention strategy
Yeytuo should only be used to prevent HIV-1 acquisition in individuals confirmed to be
HIV-negative. HIV-1 negative status should be confirmed prior to initiation of lenacapavir.
Individuals should be re-tested for HIV-1 prior to each subsequent injection of lenacapavir, andadditionally as clinically appropriate.
If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute
HIV-1 infection are present, HIV-1 status should be reconfirmed.
Yeytuo should be used to prevent HIV-1 acquisition as part of a strategy to reduce the risk of sexuallytransmitted infections (STIs). Individuals should be identified for whom the required initiation andevery 6-month continuation injection dosing schedule is appropriate. Non-adherence to the requiredinitiation and continuation dosing schedule (see section 4.2) may lead to HIV-1 acquisition.
Individuals should be counselled and supported on adhering to the lenacapavir administrationschedule, on the use of other measures to prevent STIs, and on the importance of testing for HIV-1 andother STIs.
Mean lenacapavir plasma concentrations associated with significant antiviral activity were reached by
Day 2 of the required initiation dosing and were maintained through the dosing interval of 26 weeks(see section 5.2). The exact time from initiation of lenacapavir for HIV-1 PrEP to maximal protectionagainst HIV-1 infection is unknown.
Risk of resistance
Lenacapavir may not always be effective in preventing HIV-1 infection (see section 5.1). There is arisk of developing resistance to lenacapavir if an individual acquires HIV-1 either before or whenreceiving Yeytuo, or following discontinuation of Yeytuo. To minimise this risk, it is essential toconfirm HIV-1 negative status before each subsequent injection, and additionally as clinicallyappropriate. Yeytuo alone does not constitute a complete regimen for HIV-1 treatment and mutationshave emerged in some individuals with undetected HIV-1 infection who were only taking Yeytuo.
Individuals who are confirmed to have HIV-1 must immediately begin a complete HIV-1 treatmentregimen to reduce the risk of developing resistance.
Long-acting properties
Residual concentrations of lenacapavir may remain in the systemic circulation of individuals forprolonged periods (up to 12 months or longer).
These concentrations may affect the exposures of other medicinal products (i.e. sensitive CYP3Aand/or P-gp substrates) that are initiated within 9 months after the last subcutaneous dose oflenacapavir (see section 4.5).
If lenacapavir is discontinued and it is clinically appropriate to continue PrEP, alternative forms of
PrEP should be considered and initiated within 28 weeks of the last lenacapavir injection.
Injection site reactionsInjection site reactions with improper administration
Improper administration (intradermal injection) has been associated with serious injection sitereactions, including necrosis and ulcer. Yeytuo injections must only be administered subcutaneously(see section 4.2).
Slow or non-resolving injection site nodules and indurations
Administration of Yeytuo may result in local injection site reactions (ISRs), including nodules andindurations. The healthcare professional should inform patients that nodules and indurations at theinjection site may take longer to resolve than other ISRs or may not resolve (see section 4.8). Themechanism driving the persistence of injection site nodules in some individuals is not fully understoodbut may be related to the presence of the subcutaneous drug depot and an associated foreign bodyresponse at the injection site. Non-resolving ISRs should be subject to clinical monitoring.
Co-administration of other medicinal productsCo-administration with medicinal products that are moderate inducers of CYP3A and P-gp is notrecommended (see section 4.5).
Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1together (i.e. all 3 pathways) is not recommended (see section 4.5).
ExcipientsThis medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to sayessentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on the pharmacokinetics of lenacapavir
Lenacapavir is a substrate of CYP3A, P-gp and UGT1A1. Strong inducers of CYP3A, P-gp, and
UGT1A1 may significantly decrease plasma concentrations of lenacapavir which may result inreduced effectiveness of lenacapavir. Concomitant administration of lenacapavir with strong inducersof CYP3A, P-gp, and UGT1A1 is contraindicated (see section 4.3). Moderate inducers of CYP3A and
P-gp may decrease plasma concentrations of lenacapavir. Concomitant administration of lenacapavirwith moderate inducers of CYP3A and P-gp is not recommended (see section 4.4).
Strong inhibitors of CYP3A, P-gp and UGT1A1 together (i.e., all 3 pathways) may significantlyincrease plasma concentrations of lenacapavir, therefore co-administration is not recommended (seesection 4.4).
Strong CYP3A4 inhibitors alone or strong inhibitors of CYP3A4 and P-gp together do not result in aclinically meaningful increase in lenacapavir exposure.
Effect of lenacapavir on the pharmacokinetics of other medicinal productsLenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if lenacapaviris co-administered with a sensitive CYP3A and/or P-gp substrate with a narrow therapeutic index.
Lenacapavir is not a clinically meaningful inhibitor of BCRP and does not inhibit OATP.
Clinical drug interaction data for lenacapavir as victim are from studies with oral lenacapavir. Clinicaldrug interaction data for subcutaneous lenacapavir are not available.
Table 2: Interactions between Yeytuo and other medicinal products
Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, Cmax co-administration with Yeytuo
ANTIMYCOBACTERIALS
Rifampicina,b Lenacapavir: Co-administration is(600 mg once daily) AUC: ↓84% contraindicated (see section 4.3).(strong inducer of CYP3A, and Cmax: ↓55%an inducer of P-gp and UGT)
Rifabutin Interaction not studied. Co-administration is not
Rifapentine recommended (see section 4.4).
Co-administration of rifabutin orrifapentine may decrease lenacapavirplasma concentrations.
ANTICONVULSANTS
Carbamazepine Interaction not studied. Co-administration is
Phenytoin contraindicated (see section 4.3).
Oxcarbazepine Co-administration of carbamazepine, Co-administration is not
Phenobarbital oxcarbazepine, phenobarbital, or recommended (see section 4.4).
phenytoin with lenacapavir maydecrease lenacapavir plasma Alternative anticonvulsants shouldconcentrations. be considered.
HERBAL PRODUCTS
St. John’s wort (Hypericum Interaction not studied. Co-administration isperforatum) contraindicated (see section 4.3).
Co-administration of St.
John’s wort may decreaselenacapavir plasma concentrations.
Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, Cmax co-administration with Yeytuo
ANTIRETROVIRAL AGENTS
Atazanavir/cobicistat b,c,d Lenacapavir: Co-administration of lenacapavir(300 mg/150 mg once daily) AUC: ↑ 321% and strong inhibitors of CYP3A, P-(strong inhibitor of CYP3A, and Cmax: ↑ 560% gp, and UGT1A1 is notan inhibitor UGT1A1 and P-gp) recommended (see section 4.4).
Efavirenz b,c,d (600 mg once Lenacapavir: Co-administration is notdaily) (moderate inducer of AUC:↓ 56% recommended (see section 4.4).
CYP3A and an inducer of P-gp) Cmax:↓ 36%
Cobicistat b,c,d (150 mg once Lenacapavir: No dose adjustment of lenacapavirdaily) (strong inhibitor of AUC: ↑ 128% is required.
CYP3A and an inhibitor of Cmax:↑ 110%
P-gp)
Darunavir/cobicistat b,c,d Lenacapavir:(800 mg/150 mg once daily) AUC:↑ 94%(strong inhibitor of CYP3A, and Cmax:↑ 130%an inhibitor and inducer of
P-gp)
Tenofovir alafenamidec,e Tenofovir alafenamide: No dose adjustment of tenofovir(25 mg) AUC:↑ 32% alafenamide is required.(substrate of P-gp) Cmax:↑ 24%
Tenofovirf:
AUC:↑ 47%
Cmax:↑ 23%
ERGOT DERIVATIVES
Dihydroergotamine Interaction not studied. Caution is warranted when
Ergotamine dihydroergotamine or ergotamine,
Plasma concentrations of these is co-administered withmedicinal products may be increased lenacapavir.when co-administered withlenacapavir.
PHOSPHODIESTERASE-5 (PDE-5) INHIBITORS
Sildenafil Interaction not studied. Use of PDE-5 inhibitors for
Tadalafil pulmonary arterial hypertension:
Vardenafil Plasma concentration of PDE-5 Co-administration with tadalafil isinhibitors may be increased when not recommended.co-administered with lenacapavir.
Use of PDE-5 inhibitors for erectiledysfunction:
Sildenafil: A starting dose of 25 mgis recommended.
Vardenafil: No more than 5 mg in a24-hour period.
Tadalafil:
* For use as needed: no more than10 mg every 72 hours
* For once daily use: dose not toexceed 2.5 mg
Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, Cmax co-administration with Yeytuo
CORTICOSTEROIDS (systemic)
Dexamethasone Interaction not studied. Co-administration of lenacapavir
Hydrocortisone/cortisone with corticosteroids whose
Plasma concentrations of exposures are significantlycorticosteroids may be increased increased by CYP3A inhibitors canwhen co-administered with increase the risk for Cushing'slenacapavir. syndrome and adrenal suppression.
Initiate with the lowest starting
Plasma concentrations of lenacapavir dose and titrate carefully whilemay decrease when co-administered monitoring for safety.with systemic dexamethasone.
Caution is warranted whensystemic dexamethasone isco-administered with lenacapavir,particularly for long-term use.
Alternative corticosteroids shouldbe considered.
HMG-CoA REDUCTASE INHIBITORS
Lovastatin Interaction not studied. Initiate lovastatin and simvastatin
Simvastatin with the lowest starting dose and
Plasma concentrations of these titrate carefully while monitoringmedicinal products may be increased for safety (e.g. myopathy).
Atorvastatin when co-administered with No dose adjustment of atorvastatinlenacapavir. is required.
Pitavastatinc,e (2 mg single dose; Pitavastatin: No dose adjustment of pitavastatinsimultaneous or 3 days after AUC:↔ and rosuvastatin is required.lenacapavir) Cmax:↔(substrate of OATP)
Rosuvastatinc,e (5 mg single Rosuvastatin:dose) AUC:↑ 31%(substrate of BCRP and OATP) Cmax:↑ 57%
ANTIARRHYTHMICS
Digoxin Interaction not studied. Caution is warranted andtherapeutic concentration
Plasma concentration of digoxin may monitoring of digoxin isbe increased when co-administered recommended.with lenacapavir.
SEDATIVES/HYPNOTICS
Midazolamc,e (2.5 mg single Midazolam: Caution is warranted whendose; oral; simultaneous AUC: ↑ 259% midazolam or triazolam, isadministration) Cmax: ↑ 94% co-administered with lenacapavir.(substrate of CYP3A)1-hydroxymidazolamg:
AUC: ↓ 24%
Cmax: ↓ 46%
Midazolamc,e (2.5 mg single Midazolam:dose; oral;1 day after AUC: ↑ 308%lenacapavir) Cmax: ↑ 116%(substrate of CYP3A)1-hydroxymidazolamg:
AUC: ↓ 16%
Cmax: ↓ 48%
Triazolam Interaction not studied.
Plasma concentration of triazolammay be increased whenco-administered with lenacapavir.
Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, Cmax co-administration with Yeytuo
ANTICOAGULANTS
Direct Oral Anticoagulants Interaction not studied. Due to potential bleeding risk, dose(DOACs) adjustment of DOAC may be
Rivaroxaban Plasma concentration of DOAC may required. Consult the Summary of
Dabigatran be increased when co-administered Product Characteristics of the
Edoxaban with lenacapavir. DOAC for further information onuse in combination with moderate
CYP3A inhibitors and/or P-gpinhibitors.
ANTIFUNGALS
Voriconazolea,b,h (400 mg twice Lenacapavir: No dose adjustment of lenacapavirdaily/200 mg twice daily) AUC:↑ 41% is required.(strong CYP3A inhibitor) Cmax:↔
Itraconazole Interaction not studied.
Ketoconazole
Plasma concentration of lenacapavirmay be increased whenco-administered with itraconazole orketoconazole.
H2-RECEPTOR ANTAGONISTS
Famotidinea,b (40 mg once Famotidine: No dose adjustment of famotidinedaily, 2 hours before AUC:↑ 28% is required.lenacapavir) Cmax:↔
ORAL OR LONG-ACTING CONTRACEPTIVES
Long-acting contraceptives: Observed data does not indicate No dose adjustment of oral or long-
Medroxyprogesterone acetate clinically relevant changes in the acting contraceptives is required.
Etonogestrel exposure of long-acting
Norethisterone enanthate contraceptives.
Oral contraceptives: Interaction not studied.
Ethinylestradiol
Progestins Plasma concentrations of oralcontraceptives may be increasedwhen co-administered withlenacapavir.
GENDER AFFIRMING HORMONES (feminising or masculinising)
Estradiol Observed data does not indicate No dose adjustment of these gender
Testosterone clinically relevant changes in the affirming hormones is required.
exposure of estradiol andtestosterone.
Anti-androgens Interaction not studied.
Progestogen
Plasma concentrations of thesemedicinal products may be increasedwhen co-administered withlenacapavir.
a Fasted.b This study was conducted using lenacapavir 300 mg single dose administered orally.c Fed.d These antiretroviral medicinal products are probes for the referenced enzymes/transporters and are not to be co-administered with lenacapavir for PrEP.e This study was conducted using lenacapavir 600 mg single dose following a loading regimen of 600 mg twice daily for 2days, single 600 mg doses of lenacapavir were administered orally with each co-administered medicinal product.f Tenofovir alafenamide is converted to tenofovir in vivo.g Major active metabolite of midazolam.h This study was conducted using voriconazole 400 mg loading dose twice daily for a day, followed by 200 mgmaintenance dose twice daily.
4.6 Fertility, pregnancy and lactation
Individuals of childbearing potential
Individuals of childbearing potential should be counselled about the long-acting properties oflenacapavir injection.
If an individual plans a pregnancy, the benefits and the risks of initiating or continuing Yeytuo duringpregnancy should be discussed.
PregnancyThere are limited data (130 birth outcomes) from the use of lenacapavir in pregnant women. The ratesof adverse pregnancy outcomes in participants who received Yeytuo were similar to reportedbackground rates.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).
Yeytuo may be considered during pregnancy if the expected benefit outweighs the potential risk to thefoetus.
Breast-feedingLenacapavir is present in human milk. Lenacapavir was detected at low levels in infants who werebreastfed by individuals who became pregnant while receiving Yeytuo (see section 5.2). There isinsufficient information on the effects of lenacapavir in newborns/infants.
Yeytuo may be considered during breastfeeding if the expected benefit outweighs the potential risk tothe child.
FertilityThere are no data on the effects of lenacapavir on human male or female fertility. Animal studiesindicate no effects of lenacapavir on male or female fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Yeytuo is expected to have no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most common adverse reaction in PURPOSE 1 and PURPOSE 2 was injection site reactions(71% and 85% respectively).
Tabulated list of adverse reactionsFrequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot beestimated from the available data).
Table 3: Tabulated list of adverse reactions
Frequencya Adverse reaction
General disorders and administration site conditionsVery common injection site reactionsba Frequency based on all adverse events in PURPOSE 1 and PURPOSE 2 (see section 5.1) attributed to lenacapavir (or tothe procedure) by the investigator.b Includes injection site nodule, pain, induration, erythema, swelling, pruritus, bruising, warmth, discolouration, oedema,ulcer, haematoma, haemorrhage, and discomfort.
Description of injection-associated adverse reactions
Local injection site reactions (ISRs)
PURPOSE 1
In PURPOSE 1, 71% of participants receiving lenacapavir experienced ISRs, compared to 38% ofparticipants receiving placebo injections (and emtricitabine/tenofovir alafenamide [FTC/TAF] oremtricitabine/tenofovir disoproxil fumarate [FTC/TDF]). Most participants who received lenacapavirhad mild (Grade 1, 50%) or moderate (Grade 2, 21%) severity ISRs. Grade 3 ISRs were reported in 4(0.2%) participants, and included ulcer and nodule. Lenacapavir was discontinued due to ISRs in 4(0.2%) participants.
Nodules: Injection site nodule was reported in 66% of participants who received lenacapavir andresolved more slowly than other ISRs. The median duration of nodules was 274 (180, 407) days. Ofthe injection site nodule events associated with Day 1 lenacapavir injections, 70% had resolved withina median time of 276 days.
Other ISRs: The other ISRs reported in more than 2% of participants who received lenacapavir werepain (34%), swelling (5%), induration (4%), and pruritus (3%). The median duration of ISRs,excluding nodules and indurations, was 9 (4 to 30) days.
PURPOSE 2
In PURPOSE 2, 85% of participants receiving lenacapavir experienced ISRs, compared to 70% ofparticipants receiving placebo injections (and FTC/TDF). Most participants had mild (Grade 1, 66%)or moderate (Grade 2, 18%) severity ISRs. Grade 3 ISRs were reported in 14 (0.6%) participants, andincluded ulcer, pain, erythema, oedema, and dermatitis. Lenacapavir was discontinued due to ISRs in26 (1.2%) participants.
Nodules: Injection site nodule was reported in 65% of participants and resolved more slowly thanother ISRs. The median duration of nodules was 239 (163, 362) days. Of the injection site noduleevents associated with Day 1 lenacapavir injections, 70% had resolved within a median time of 269days.
Other ISRs: The other ISRs reported in more than 2% of participants who received lenacapavir werepain (58%), erythema (18%), induration (16%), swelling (7%), pruritus (4%), bruising (3%), andwarmth (2%). The median duration of ISRs, excluding nodules and indurations, was 4 (2 to 8) days.
Paediatric populationThe safety of lenacapavir was evaluated in 59 adolescents aged 16 to <18 years and weighing ≥35 kgin PURPOSE 1 and PURPOSE 2. The adverse reactions in adolescents were consistent with those inadults.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
If overdose occurs the individual must be monitored for signs or symptoms of adverse reactions (seesection 4.8). Treatment of overdose with Yeytuo consists of general supportive measures includingmonitoring of vital signs as well as observation of the clinical status of the individual. As lenacapaviris highly protein bound, it is unlikely to be significantly removed by dialysis.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX31
Mechanism of actionLenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to theinterface between capsid protein (CA) subunits. Lenacapavir inhibits HIV-1 replication by interferingwith multiple, essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (byinterfering with Gag/Gag-Pol functioning, reducing production of CA subunits), and capsid coreformation (by disrupting the rate of capsid subunit association, leading to malformed capsids).
Antiviral activity and selectivity in vitroThe antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes.
The EC50 and selectivity (CC50/EC50) values ranged from 30 to 190 pM and 140,000 to >1,670,000,respectively, for wild-type (WT) HIV-1 virus. The protein-adjusted EC95 for lenacapavir was 4 nM(3.87 ng per mL) in the MT-4 T-cell line for wild-type HIV-1 virus.
Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), includingsubtypes A, A1, AE, AG, B, BF, C, D, E, F, G, H.
Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.
ResistanceIn cell culture
HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. In vitroresistance selections with lenacapavir identified 7 mutations in CA: L56I, M66I, Q67H, K70N,
N74D/S, and T107N singly or in dual combination. Phenotypic susceptibility to lenacapavir wasreduced 4- to >3,226-fold, relative to WT virus.
In clinical trials
There were 2 incident infections (infections that occurred after starting lenacapavir for HIV-1 PrEP)among participants in the lenacapavir group of the PURPOSE 1 trial. Both infections occurred afterthe time of the primary analysis. Genotyping of virus in one of the participants revealed no lenacapavirresistance-associated capsid substitutions. The second participant had viral loads that were too low forgenotyping.
There were 3 incident infections among participants in the lenacapavir group of the PURPOSE 2 trial.
One of the infections occurred after the time of the primary analysis. Lenacapavir resistance-associated substitutions were detected in viruses from the 3 participants, 2 with N74D, and 1 with
Q67H/K70R.
Cross resistanceThe in vitro antiviral activity of lenacapavir was determined against a broad spectrum of HIV-1site-directed mutants and patient-derived HIV-1 isolates with resistance to the 4 main classes ofantiretroviral agents (NRTIs, NNRTIs, INSTIs and PIs; n = 58), as well as to viruses resistant tomaturation inhibitors (n = 32), and to viruses resistant to the entry inhibitors (EI) class (fostemsavir,ibalizumab, maraviroc, and enfuvirtide; n = 42). These data indicated that lenacapavir remained fullyactive against all variants tested, thereby demonstrating a non-overlapping resistance profile. Inaddition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence ofnaturally occurring Gag polymorphisms.
Effects on electrocardiogramIn a parallel-design thorough QT/QTc study, lenacapavir had no clinically relevant effect on the QTcFinterval. At supratherapeutic exposures of lenacapavir (16-fold higher than the therapeutic exposuresof lenacapavir), the predicted mean (upper 90% confidence interval) increase in QTcF interval was2.6 (4.8) msec, and there was no association (p = 0.36) between observed lenacapavir plasmaconcentrations and change in QTcF.
Clinical dataThe efficacy and safety of lenacapavir in preventing the acquisition of HIV-1 were evaluated in tworandomised, double-blind, active-controlled, multinational trials (PURPOSE 1 and PURPOSE 2).
PURPOSE 1
This study was conducted in sexually active cisgender women. Participants were randomised toreceive lenacapavir per the recommended dosing schedule (see Table 1, section 4.2; n = 2134), oncedaily FTC/TAF (n = 2136), or once daily FTC/TDF (n = 1068) in a 2:2:1 ratio.
The median age of participants was 21 years (range, 16-26); and 99.9% were Black. Baselinecharacteristics in the randomised participants were similar to the screened population.
The efficacy of lenacapavir was established by comparing the HIV-1 incidence in the lenacapavirgroup to the HIV-1 incidence in the FTC/TDF group. Incident HIV-1 infections were observed in none(0%) of the participants in the lenacapavir group compared to 16 (1.5%) participants in the FTC/TDFgroup. Lenacapavir demonstrated superiority with a 100% reduction in the risk of HIV-1 acquisitionover FTC/TDF (Table 4).
Table 4: Overall HIV-1 Infection Outcomes in PURPOSE 1
Lenacapavir FTC/TDF Rate Ratio (95% CI)n = 2134 n = 1068
Person-years 1939 949 -
HIV-1 infections 0 16 Lenacapavir/FTC/TDF:(incidence rate per (0.00) (1.69) 0.000 (0.000, 0.101)100 person-years) p < 0.0001
CI = confidence interval
PURPOSE 2
This study was conducted in sexually active cisgender men, transgender women, transgender men, andgender nonbinary individuals. Participants were randomised to receive lenacapavir per therecommended dosing schedule (see Table 1, section 4.2; n = 2179) or once daily FTC/TDF (n = 1086)in a 2:1 ratio.
The median age of participants was 29 years (range, 17-74); 33% were White; 27% were Black, 13%were Asian; 63% were Hispanic/Latine; 22% identified as gender-diverse (transgender women,transgender men, and gender nonbinary people); and 1% were over 65 years. Baseline characteristicsin the randomised participants were similar to the screened population.
The efficacy of lenacapavir was established by comparing the HIV-1 incidence in the lenacapavirgroup to the HIV-1 incidence in the FTC/TDF group. Incident HIV-1 infections were observed in 2(0.1%) participants in the lenacapavir group compared to 9 (0.8%) participants in the FTC/TDF group.
Lenacapavir demonstrated superiority with an 89% reduction over FTC/TDF (Table 5). HIV-1infections in the two participants receiving lenacapavir were diagnosed using standard serologic HIVtesting.
Table 5: Overall HIV-1 Infection Outcomes in PURPOSE 2
Lenacapavir FTC/TDF Rate Ratio (95% CI)n = 2179 n = 1086
Person-years 1938 967 -
HIV-1 infections (incidence 2 9 Lenacapavir/FTC/TDF:
rate per 100 person-years) (0.1) (0.93) 0.111 (0.024, 0.513)p = 0.00245
CI = confidence interval
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies withlenacapavir in one or more subsets of the paediatric population in prevention of HIV-1 (see section 4.2for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Subcutaneous administration
Subcutaneous administration
Absolute bioavailability of lenacapavir following subcutaneous administration was 91% based onpopulation pharmacokinetic analysis. Subcutaneously administered lenacapavir forms a drug depotwhereby lenacapavir is slowly released from the site of administration, with peak plasmaconcentrations occurring 84 days post dose.
Oral administrationLenacapavir is absorbed following oral administration with peak plasma concentrations occurringapproximately 4 hours after administration of lenacapavir. Absolute bioavailability following oraladministration of lenacapavir is low based on population pharmacokinetic analysis (approximately4 to 7%). Lenacapavir is a substrate of P-gp.
Lenacapavir AUC, Cmax and Tmax were comparable following administration of a low fat (~400 kcal,25% fat) or high fat (~1000 kcal, 50% fat) meal relative to fasted conditions. Oral lenacapavir can beadministered without regard to food.
Pharmacokinetic parametersThe population pharmacokinetic parameter estimates of lenacapavir after oral and subcutaneousadministration to adult and adolescent (weighing at least 35 kg) participants are provided in Table 6.
Similar exposures are achieved when lenacapavir is administered subcutaneously in the abdomen orthigh.
Table 6: Pharmacokinetic parameters of lenacapavir following oral and subcutaneousadministration to adult and adolescent participants receiving Yeytuo
Parameter Day 1 to end of Week 26 Steady State
Mean(%CV)a,b
AUCtau 188112 (41.0) 257332 (38.7)(h*ng/mL)
Cmax 73.8 (55.6) 82.5 (48.4)(ng/mL)
Ctrough 27.0 (58.3) 37.0 (60.7)(ng/mL)
CV = Coefficient of Variationa Simulated exposures utilising population PK analysis.b Mean lenacapavir plasma concentrations reached inhibitory quotient 4 (IQ4; 4-fold greater than the in vitro proteinadjusted 95% effective concentration) associated with significant antiviral activity by Day 2 of the required initiationdosing and were maintained above IQ4 through the dosing interval of 26 weeks.
DistributionLenacapavir steady state volume of distribution was 1657 litres based on population pharmacokineticanalysis. Lenacapavir is highly bound to plasma proteins (99.8%).
BiotransformationFollowing a single intravenous dose of radiolabelled-lenacapavir to healthy subjects, 76% of the totalradioactivity was recovered from faeces and < 1% from urine. Unchanged lenacapavir was thepredominant moiety in plasma (69%) and faeces (33%). Metabolism played a lesser role inlenacapavir elimination. Lenacapavir was metabolised via oxidation, N-dealkylation, hydrogenation,amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathioneconjugation; primarily via CYP3A and UGT1A1. No single circulating metabolite accountedfor > 10% of plasma drug-related exposure.
EliminationThe median half-life following oral and subcutaneous administration ranged from 10 to 12 days, and8 to 12 weeks, respectively. Systemic clearance of lenacapavir was 3.4 L/h based on populationpharmacokinetic analysis.
Linearity/non-linearityThe single dose pharmacokinetics of lenacapavir after oral administration are non-linear and less thandose proportional over the dose range of 50 to 1800 mg.
The single dose pharmacokinetics of lenacapavir after subcutaneous injection (309 mg/mL) are doseproportional over the dose range of 309 to 927 mg.
Other special populationsAge, sex, gender identity, race, ethnicity, and weight
Population pharmacokinetic analysis using data from trials in adults, including a limited number ofelderly participants (n = 19; ≥ 65 to 78 years), and adolescents weighing at least 35 kg did not identifyany clinically relevant differences in the exposure of lenacapavir due to age, sex assigned at birth,gender identity, race, ethnicity, or weight.
Hepatic impairmentThe pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated Phase1 trial in participants with moderate hepatic impairment (Child-Pugh Class B). Lenacapavir meanexposures (total and unbound) were 1.47- to 2.84-fold and 2.61- to 5.03-fold higher for AUCinf and
Cmax, respectively in individuals with moderate hepatic impairment (Child-Pugh B) compared toparticipants with normal hepatic function. However, this increase is not considered clinically relevantbased on lenacapavir exposure-response. The pharmacokinetics of lenacapavir have not been studiedin individuals with severe hepatic impairment (Child-Pugh C) (see section 4.2).
Renal impairmentThe pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated studyin participants with severe renal impairment (estimated creatinine clearance ≥ 15and < 30 mL/minute). Lenacapavir exposures were increased (84% and 162% for AUCinf and Cmax,respectively) in participants with severe renal impairment compared with participants with normalrenal function; however, the increase was not considered clinically relevant. The pharmacokinetics oflenacapavir have not been studied in individuals with end-stage renal disease, including those ondialysis (see section 4.2). As lenacapavir is approximately 99.8% protein bound, dialysis is notexpected to alter exposures of lenacapavir.
PregnancyNo clinically relevant changes in lenacapavir exposure during pregnancy and postpartum wereobserved compared to lenacapavir exposures in non-pregnant participants.
LactationThe median (Q1, Q3) lenacapavir concentration in human breast milk to maternal plasma ratio inparticipants (n = 102 matched pairs) who received Yeytuo was 0.52 (0.38, 0.77). The median (Q1, Q3)infant plasma concentration (n = 98) was 1.63 ng/mL (0.87, 2.85) as compared to the median (Q1, Q3)matched maternal plasma concentration (n = 96) of 65.65 ng/ml (46.00, 91.10). The median (Q1, Q3)infant-to-mother plasma ratio for lenacapavir in infants (n = 98 matched pairs) who were breastfed byparticipants receiving Yeytuo was 0.02 (0.01, 0.05).
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.
Lenacapavir was not mutagenic or clastogenic in conventional genotoxicity assays.
Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to300 mg/kg/dose once every 13 weeks, which resulted in exposures approximately 88 times theexposure in humans at the recommended human dose (RHD).
In a 2-year rat carcinogenicity study, there were lenacapavir-treatment induced subcutaneous primarysarcomas associated with fibrosis and inflammation present at the injection sites in animalsadministered 927 mg/kg/dose once every 13 weeks. 11/110 animals manifested sarcomas at the highdose where each animal had up to 16 injection sites - corresponding to an incidence of <1% totalinjection sites across animals at the high dose. Drug concentrations in the injection depot sites aredifficult to determine but systemically, the 927 mg/kg dose corresponds to 44 times the exposure inhumans at the RHD. At the no-observed-adverse-effect level (NOAEL), the 309 mg/kg/dosecorresponds to 25 times the exposure in humans at the RHD. Rats are prone to sarcoma formation atthe subcutaneous injection site, but a clinical relevance cannot be excluded considering the longduration of the drug depot in humans. There were no neoplasms associated with systemic exposure tolenacapavir at any dose.
In offspring from rat and rabbit dams treated with lenacapavir during pregnancy, there were notoxicologically significant effects on developmental endpoints.
In rats, male and female fertility was not affected at lenacapavir exposures up to 9 (male) and 6(female) times the human exposure at the RHD. In rats and rabbits, embryofoetal development was notaffected at exposures up to 20 and 159 times the human exposure, respectively, at the RHD. In rats,pre- and postnatal development was not affected at exposures up to 6 times the human exposure at the
RHD.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Macrogol (E1521)
Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years
Once the solution has been drawn into the syringes, the injections should be used immediately, from amicrobiological point of view. Chemical and physical in-use stability has been demonstrated for4 hours at 25 °C outside of the package.
If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in theoriginal outer carton in order to protect from light.
6.5 Nature and contents of container
Yeytuo injections are available in two different kits.
The withdrawal needle injection kit contains:
* 2 clear glass vials, each containing 1.5 mL solution for injection. Vials are sealed with anelastomeric butyl rubber closure and aluminium overseal with flip off cap;
* 2 withdrawal needles (18-gauge, 40 mm), 2 disposable syringes, and 2 injection safety needlesfor subcutaneous injection (22-gauge, 13 mm).
The withdrawal safety needle injection kit contains:
* 2 clear glass vials, each containing 1.5 mL solution for injection. Vials are sealed with anelastomeric butyl rubber closure and aluminium overseal with flip off cap;
* 2 withdrawal safety needles (18-gauge, 40 mm), 2 disposable syringes, and 2 injection safetyneedles for subcutaneous injection (22-gauge, 13 mm).
The Withdrawal Needle Injection Kit contains withdrawal needles that may be supplied with orwithout a safety shield. The presence or absence of a safety shield does not change how the Yeytuoinjection is prepared.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
Use aseptic technique. Visually inspect the solution in the vials for particulate matter and discolorationprior to administration. Yeytuo injection is a yellow to brown solution. Do not use Yeytuo injection ifthe solution is discoloured or if it contains particulate matter. Once the solution is withdrawn from thevials, the subcutaneous injections should be administered as soon as possible.
The injection kit components are for single use only. 18-gauge needle is for withdrawal only. Two1.5 mL injections are required for a complete dose.
Full instructions for use and handling of Yeytuo injection are provided in the package leaflet(see Instructions for Use).
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.