lenacapavir: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Sunlenca

4.1 Therapeutic indications

Applies to: Sunlenca 464 mg solution for injection

Sunlenca injection, in combination with other antiretroviral(s), is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen (see sections 4.2 and 5.1).

Applies to: Sunlenca 300 mg film-coated tablets

Sunlenca tablet, in combination with other antiretroviral(s), is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen, for oral loading prior to administration of long-acting lenacapavir injection (see sections 4.2 and 5.1).

4.2 Posology and method of administration

Applies to: Sunlenca 464 mg solution for injection

Therapy should be prescribed by a physician experienced in the management of HIV infection.

Each injection should be administered by a healthcare professional.

Prior to starting lenacapavir, the healthcare professional should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance associated with missed doses. In addition, the healthcare professional should counsel patients about the importance of adherence to an optimised background regimen (OBR) to further reduce the risk of viral rebound and potential development of resistance.

If Sunlenca is discontinued, it is essential to adopt an alternative, fully suppressive antiretroviral regimen where possible, no later than 28 weeks after the final injection of Sunlenca (see section 4.4).

Posology

Initiation
On treatment Day 1 and Day 2, the recommended dose of Sunlenca is 600 mg per day taken orally. On treatment Day 8, the recommended dose is 300 mg taken orally. Then, on treatment Day 15, the recommended dose is 927 mg administered by subcutaneous injection.

Oral tablets can be taken with or without food (see Sunlenca tablet SmPC).

Maintenance
The recommended dose is 927 mg of Sunlenca administered by subcutaneous injection once every 6 months (26 weeks) from the date of the last injection (+/- 2 weeks).

Table 1: Recommended treatment regimen for Sunlenca: initiation and maintenance dosing schedule

Treatment time

Dose of Sunlenca: initiation
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 subcutaneous injection (2 x 1.5 mL injectionsa)
Dose of Sunlenca: maintenance
Every 6 Months
(26 weeks)b
+/- 2 weeks
927 mg subcutaneous injection (2 x 1.5 mL injectionsa)

a Two injections, each at a separate site in the abdomen.
b From the date of the last injection.

Missed dose
During the maintenance period, if more than 28 weeks have elapsed since the last injection and if clinically appropriate to continue Sunlenca treatment, the regimen should be restarted from Day 1 (see table 1).

Special populations

Elderly
No dose adjustment of Sunlenca is required in elderly patients (see section 5.2).

Renal impairment
No dose adjustment of Sunlenca is required in patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥ 15 mL/min). Sunlenca has not been studied in patients with end stage renal disease (CrCl < 15 mL/min or on renal replacement therapy) (see section 5.2), therefore Sunlenca should be used with caution in these patients.

Hepatic impairment
No dose adjustment of Sunlenca is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). Sunlenca has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2), therefore Sunlenca should be used with caution in these patients.

Paediatric population
The safety and efficacy of Sunlenca in children under the age of 18 years old has not been established.
No data are available.

Method of administration

For subcutaneous use only.

Sunlenca injections must only be administered subcutaneously into the abdomen (two injections, each at a separate site) by a healthcare professional (see section 6.6). Sunlenca injections must NOT be administered 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.

Applies to: Sunlenca 300 mg film-coated tablets

Therapy should be prescribed by a physician experienced in the management of HIV infection.

Posology

Initiation of treatment with lenacapavir requires Sunlenca film-coated tablets to be taken as oral loading prior to administration of Sunlenca injection.

Table 1: Recommended treatment regimen for Sunlenca: initiation

Treatment time

Dose of Sunlenca: initiation
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 subcutaneous injection (2 x 1.5 mL injectionsa) a Two injections, each at a separate site in the abdomen.

Missed dose
If the Day 2 (600 mg) oral dose is missed by:
- less than 6 days, the patient should take 600 mg as soon as possible, and 300 mg on Day 8.
- 6 days or more, the patient should take 600 mg as soon as possible, and 300 mg on Day 15.

If the Day 8 (300 mg) oral dose is missed by:
- less than 6 days, the patient should take 300 mg as soon as possible.
- 6 days or more, the patient should take 300 mg on Day 15.

Regardless of when the Day 2 or Day 8 oral dose is being taken, subcutaneous injection should be administered on Day 15 as described in Table 1.

If the patient vomits within 3 hours of taking an oral dose of Sunlenca, another oral dose should be taken. If the patient vomits more than 3 hours after taking an oral dose of Sunlenca there is no need to take another oral dose of Sunlenca, and the scheduled dosing regimen should continue.

Special populations

Elderly
No dose adjustment of Sunlenca is required in elderly patients (see section 5.2).

Paediatric population
The safety and efficacy of Sunlenca in children under the age of 18 years old has not been established.
No data are available.

Method of administration

For oral use.

Sunlenca tablets should be taken orally with or without food (see section 5.2). The film-coated tablet should not be chewed, crushed, or split, because the effects on lenacapavir absorption have not been studied.

4.3 Contraindications

Applies to: Sunlenca 464 mg solution for injection · Sunlenca 300 mg film-coated tablets

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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).

4.8 Undesirable effects

Applies to: Sunlenca 464 mg solution for injection

Summary of the safety profile

The most common adverse reactions in heavily treatment-experienced adult participants with HIV were ISRs (76%) and nausea (6%).

Tabulated list of adverse reactions

A tabulated list of adverse reactions is presented in Table 3. Frequencies 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 be estimated from the available data).

Table 3: Tabulated list of adverse reactions

Frequencya
Adverse reaction
Immune system disorders
Not known immune reconstitution inflammatory syndrome
Gastrointestinal disorders
Common nausea
General disorders and administration site conditions
Very common injection site reactionsb a
Frequency based on all participants (Cohorts 1 and 2) in CAPELLA (see section 5.1).
b Includes injection site swelling, pain, nodule, erythema, induration, pruritus, extravasation, discomfort, mass, haematoma, oedema, and ulcer from CAPELLA; and necrosis identified from post-marketing surveillance.

Description of selected adverse reactions

Immune Reconstitution Inflammatory Syndrome
In patients with HIV with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Local injection site reactions
Through Week 156 of treatment, most participants had mild (Grade 1, 54%) or moderate (Grade 2, 17%) ISRs. Six percent (4/72) of participants experienced a severe Grade 3 ISR with a median time to resolution of 15 (range: 1 to 71) days. No participants experienced a Grade 4 ISR. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days. The median time to resolution of nodules and indurations associated with the first injections of Sunlenca was 191 (Q1, Q3: 71, 366) and 113 (Q1, Q3: 29, 224) days, respectively. After a median follow-up of 554 days, nodules associated with the first injections of Sunlenca had not resolved in 10% (7/72) of the participants. All indurations associated with the first injections of Sunlenca had resolved.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: Sunlenca 300 mg film-coated tablets

Summary of the safety profile

The most common adverse reaction in heavily treatment experienced adult participants with HIV was nausea (6%).

Tabulated list of adverse reactions
A tabulated list of adverse reactions is presented in Table 3. Frequencies 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 be estimated from the available data).

Table 3: Tabulated list of adverse reactions

Frequencya
Adverse reaction
Immune system disorders
Not known immune reconstitution inflammatory syndrome
Gastrointestinal disorders
Common nausea a
Frequency based on all participants (Cohorts 1 and 2) in CAPELLA (see section 5.1).

Description of selected adverse reactions

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Sunlenca 464 mg solution for injection

Risk of resistance following treatment discontinuation

If Sunlenca is discontinued, to minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen where possible, no later than 28 weeks after the final injection of Sunlenca.

If virologic failure is suspected, an alternative regimen should be adopted where possible.

Use of other medicinal products after discontinuation of lenacapavir

If Sunlenca is discontinued, residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods. These concentrations may affect the exposures of other medicinal products (i.e. sensitive CYP3A substrates) that are initiated within 9 months after the last subcutaneous dose of Sunlenca (see section 4.5). These concentrations are not expected to affect the exposures of other antiretroviral agents that are initiated after discontinuation of Sunlenca.

Immune Reconstitution Inflammatory Syndrome

In patients with HIV with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART.
Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Injection Site Reactions

Injection Site Reactions with Improper Administration
Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer. Sunlenca injections must only be administered subcutaneously (see section 4.2).

Slow or non-resolving injection site nodules and indurations
Administration of Sunlenca may result in local injection site reactions (ISRs), including nodules and indurations. The healthcare professional should inform patients that nodules and indurations at the injection site may take longer to resolve than other ISRs or may not resolve. In CAPELLA (see section 5.1), nodules associated with the first injections of Sunlenca had not resolved in 10% of participants after a median follow-up of 554 days, whereas all indurations had resolved (see section 4.8). The mechanism driving the persistence of injection site nodules in some participants is not fully understood but may be related to the presence of the subcutaneous drug depot and an associated

foreign body response at the injection site. Non-resolving ISRs should be subject to clinical monitoring.

Opportunistic infections

Patients should be advised that Sunlenca or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Co-administration of other medicinal products

Co-administration with medicinal products that are moderate inducers of CYP3A and P-gp (e.g. efavirenz) is not recommended (see section 4.5).

Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways), such as atazanavir/cobicistat is not recommended (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to say essentially ‘sodium-free’.

Applies to: Sunlenca 300 mg film-coated tablets

Immune Reconstitution Inflammatory Syndrome

Opportunistic infections

Co-administration of other medicinal products

Co-administration with medicinal products that are moderate inducers of CYP3A and P-gp (e.g. efavirenz) is not recommended (see section 4.5).

Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways), such as atazanavir/cobicistat is not recommended (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Sunlenca 464 mg solution for injection

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, such as rifampicin, may significantly decrease plasma concentrations of lenacapavir resulting in loss of therapeutic effect and development of resistance, therefore co-administration is contraindicated (see section 4.3). Moderate inducers of CYP3A and P-gp, such as efavirenz, may also significantly decrease plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4).

Strong inhibitors of CYP3A, P-gp and UGT1A1 together (i.e., all 3 pathways), such as atazanavir/cobicistat, may significantly increase plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4).

Strong CYP3A4 inhibitors alone (e.g. voriconazole) or strong inhibitors of CYP3A4 and P-gp together (e.g. cobicistat) do not result in a clinically meaningful increase in lenacapavir exposures.

Effect of lenacapavir on the pharmacokinetics of other medicinal products

Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if Sunlenca is 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.

Table 2: Interactions between Sunlenca and other medicinal products

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca
ANTIMYCOBACTERIALS
Rifampicina,b,c (600 mg once daily)

Lenacapavir:
AUC: ↓84%
Cmax: ↓55%
Co-administration is contraindicated (see section 4.3).
Rifabutin

Interaction not studied.

Co-administration is not recommended (see section 4.4).

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca
Co-administration of rifabutin may decrease lenacapavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
ANTICONVULSANTS
Carbamazepine
Phenytoin
Interaction not studied.

Co-administration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with lenacapavir may decrease lenacapavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Co-administration is contraindicated (see section 4.3).
Oxcarbazepine
Phenobarbital
Co-administration is not recommended (see section 4.4).

Alternative anticonvulsants should be considered.
HERBAL PRODUCTS
St. John’s wort (Hypericum perforatum)
Interaction not studied.

Co-administration of St.
John’s wort may decrease lenacapavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Co-administration is contraindicated (see section 4.3).
ANTIRETROVIRAL AGENTS
Atazanavir/cobicistatb,d,e
(300 mg/150 mg once daily)
Lenacapavir:
AUC: ↑ 321%
Cmax: ↑ 560%
Co-administration is not recommended (see section 4.4).
Efavirenzb,d,f (600 mg once daily)
Lenacapavir:
AUC:↓ 56%
Cmax:↓ 36%
Etravirine
Nevirapine
Tipranavir/ritonavir
Interaction not studied.

Co-administration of etravirine, nevirapine, or tipranavir/ritonavir may decrease lenacapavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Cobicistatb,d,g (150 mg once daily)

Lenacapavir:
AUC: ↑ 128%
Cmax:↑ 110%
No dose adjustment of lenacapavir is required.
Darunavir/cobicistatb,d,h
(800 mg/150 mg once daily)
Lenacapavir:
AUC:↑ 94%
Cmax:↑ 130%
Ritonavir
Interaction not studied.

Co-administation of ritonavir may increase lenacapavir plasma concentrations.
Tenofovir alafenamided,i,j (25 mg)
Tenofovir alafenamide:
AUC:↑ 32%
Cmax:↑ 24%

Tenofovirk:
AUC:↑ 47%
Cmax:↑ 23%
No dose adjustment of tenofovir alafenamide is required.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca
ERGOT DERIVATIVES
Dihydroergotamine
Ergotamine

Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
Caution is warranted when dihydroergotamine or ergotamine, is co-administered with Sunlenca.
PHOSPHODIESTERASE-5 (PDE-5) INHIBITORS
Sildenafil
Tadalafil
Vardenafil
Interaction not studied.

Plasma concentration of PDE-5 inhibitors may be increased when co-administered with lenacapavir.
Use of PDE-5 inhibitors for pulmonary arterial hypertension:
Co-administration with tadalafil is not recommended.

Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil: A starting dose of 25 mg is recommended.
Vardenafil: No more than 5 mg in a
24-hour period.
Tadalafil:
- For use as needed: no more than 10 mg every 72 hours
- For once daily use: dose not to exceed 2.5 mg
CORTICOSTEROIDS (systemic)
Cortisone/hydrocortisone
Dexamethasone
Interaction not studied.

Plasma concentrations of corticosteroids may be increased when co-administered with lenacapavir.

Plasma concentrations of lenacapavir may decrease when co- administered with systemic dexamethasone, which may result in loss of therapeutic effect and development of resistance.
Co-administration of Sunlenca with 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.

Caution is warranted when systemic dexamethasone is co-administered with Sunlenca, particularly for long-term use.
Alternative corticosteroids should be considered.
HMG-CoA REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g. myopathy).
Atorvastatin
No dose adjustment of atorvastatin is required.
Pitavastatind,i,l (2 mg single dose;
simultaneous or 3 days after lenacapavir)
Pitavastatin:
AUC:↔
Cmax:↔
No dose adjustment of pitavastatin and rosuvastatin is required.
Rosuvastatind,i,m (5 mg single dose)
Rosuvastatin:
AUC:↑ 31%
Cmax:↑ 57%
ANTIARRHYTHMICS
Digoxin
Interaction not studied.

Plasma concentration of digoxin may be increased when
Caution is warranted and therapeutic concentration monitoring of digoxin is recommended.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca co-administered with lenacapavir.
SEDATIVES/HYPNOTICS
Midazolamd,i,n (2.5 mg single dose;
oral; simultaneous administration)

Midazolam:
AUC: ↑ 259%
Cmax: ↑ 94%

1-hydroxymidazolamo:
AUC: ↓ 24%
Cmax: ↓ 46%
Caution is warranted when midazolam or triazolam, is co-administered with Sunlenca.
Midazolamd,i,n (2.5 mg single dose;
oral;1 day after lenacapavir)

Midazolam:
AUC: ↑ 308%
Cmax: ↑ 116%

1-hydroxymidazolamo:
AUC: ↓ 16%
Cmax: ↓ 48%
Triazolam
Interaction not studied.

Plasma concentration of triazolam may be increased when co-administered with lenacapavir.
ANTICOAGULANTS
Direct Oral Anticoagulants
(DOACs)
Rivaroxaban
Dabigatran
Edoxaban
Interaction not studied.

Plasma concentration of DOAC may be increased when co-administered with lenacapavir.
Due to potential bleeding risk, dose adjustment of DOAC may be required. Consult the Summary of Product Characteristics of the DOAC for further information on use in combination with moderate CYP3A inhibitors and/or P-gp inhibitors.
ANTIFUNGALS
Voriconazolea,b,p,q (400 mg twice daily/200 mg twice daily)

Lenacapavir:
AUC:↑ 41%
Cmax:↔
No dose adjustment of lenacapavir is required.

Itraconazole
Ketoconazole
Interaction not studied.

Plasma concentrations of ethinylestradiol and progestins may be increased when co-administered with lenacapavir.
No dose adjustment of ethinylestradiol and progestins is required.
GENDER AFFIRMING HORMONES
17β-estradiol
Anti-androgens
Progestogen
Testosterone
Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
No dose adjustment of these gender affirming hormones is required.
a
Fasted.

b This study was conducted using lenacapavir 300 mg single dose administered orally.
c
Evaluated as a strong inducer of CYP3A, and an inducer of P-gp and UGT.
d Fed.
e
Evaluated as a strong inhibitor of CYP3A, and an inhibitor UGT1A1 and P-gp.
f
Evaluated as a moderate inducer of CYP3A and an inducer of P-gp.
g Evaluated as a strong inhibitor of CYP3A and an inhibitor of P-gp.
h Evaluated as a strong inhibitor of CYP3A, and an inhibitor and inducer of P-gp.
i
This study was conducted using lenacapavir 600 mg single dose following a loading regimen of 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each co-administered medicinal product.
j
Evaluated as a P-gp substrate.
k Tenofovir alafenamide is converted to tenofovir in vivo.
l
Evaluated as an OATP substrate.
m Evaluated as an BCRP substrate.
n Evaluated as a CYP3A substrate.
o Major active metabolite of midazolam.
p Evaluated as a strong inhibitor of CYP3A.
q This study was conducted using voriconazole 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily.

Applies to: Sunlenca 300 mg film-coated tablets

Effect of other medicinal products on the pharmacokinetics of lenacapavir

Strong CYP3A4 inhibitors alone (e.g. voriconazole) or strong inhibitors of CYP3A4 and P-gp together (e.g. cobicistat) do not result in a clinically meaningful increase in lenacapavir exposures.

Effect of lenacapavir on the pharmacokinetics of other medicinal products

Table 2: Interactions between Sunlenca and other medicinal products

Lenacapavir:
AUC: ↓84%
Cmax: ↓55%
Co-administration is contraindicated (see section 4.3).
Rifabutin

Interaction not studied.

Co-administration of rifabutin may decrease lenacapavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Co-administration is not recommended (see section 4.4).
ANTICONVULSANTS
Carbamazepine
Phenytoin
Interaction not studied.

Oxcarbazepine
Phenobarbital
Co-administration is not recommended (see section 4.4).

Alternative anticonvulsants should be considered.
HERBAL PRODUCTS
St. John’s wort (Hypericum perforatum)
Interaction not studied.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca
ANTIRETROVIRAL AGENTS
Atazanavir/cobicistatb,d,e
(300 mg/150 mg once daily)
Lenacapavir:
AUC: ↑ 321%
Cmax: ↑ 560%
Co-administration is not recommended (see section 4.4).
Efavirenzb,d,f (600 mg once daily)
Lenacapavir:
AUC:↓ 56%
Cmax:↓ 36%
Etravirine
Nevirapine
Tipranavir/ritonavir
Interaction not studied.

Co-administation of ritonavir may increase lenacapavir plasma concentrations.
Tenofovir alafenamided,i,j (25 mg)
Tenofovir alafenamide:
AUC:↑ 32%
Cmax:↑ 24%

Tenofovirk:
AUC:↑ 47%
Cmax:↑ 23%
No dose adjustment of tenofovir alafenamide is required.
ERGOT DERIVATIVES
Dihydroergotamine
Ergotamine

Interaction not studied.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca
CORTICOSTEROIDS (systemic)
Cortisone/hydrocortisone
Dexamethasone

Interaction not studied.

Plasma concentrations of corticosteroids may be increased when co-administered with lenacapavir.

Plasma concentration of digoxin may be increased when co-administered with lenacapavir.
Caution is warranted and therapeutic concentration monitoring of digoxin is recommended.
SEDATIVES/HYPNOTICS
Midazolamd,i,n (2.5 mg single dose;
oral; simultaneous administration)

Midazolam:
AUC: ↑ 259%
Cmax: ↑ 94%

1-hydroxymidazolamo:
AUC: ↓ 24%
Cmax: ↓ 46%
Caution is warranted when midazolam or triazolam, is co-administered with Sunlenca.
Midazolamd,i,n (2.5 mg single dose;
oral; 1 day after lenacapavir)

Midazolam:
AUC: ↑ 308%
Cmax: ↑ 116%

1-hydroxymidazolamo:
AUC: ↓ 16%
Cmax: ↓ 48%
Triazolam
Interaction not studied.

Plasma concentration of triazolam may be increased when co-administered with lenacapavir.
ANTICOAGULANTS
Direct Oral Anticoagulants
(DOACs)
Interaction not studied.

Due to potential bleeding risk, dose adjustment of DOAC may be

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with Sunlenca
Rivaroxaban
Dabigatran
Edoxaban
Plasma concentration of DOAC may be increased when co-administered with lenacapavir.
required. Consult the Summary of
Product Characteristics of the
DOAC for further information on use in combination with moderate
CYP3A inhibitors and/or P-gp inhibitors.
ANTIFUNGALS

Voriconazolea,b,p,q (400 mg twice daily/200 mg twice daily)

Lenacapavir:
AUC:↑ 41%
Cmax:↔
No dose adjustment of lenacapavir is required.
Itraconazole
Ketoconazole
Interaction not studied.

Plasma concentration of lenacapavir may be increased when co-administered with itraconazole or ketoconazole.
H2-RECEPTOR ANTAGONISTS

Famotidinea,b (40 mg once daily, 2 hours before lenacapavir)
Famotidine:
AUC:↑ 28%
Cmax:↔
No dose adjustment of famotidine is required.
ORAL CONTRACEPTIVES
Ethinylestradiol
Progestins
Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
No dose adjustment of these gender affirming hormones is required.
a
Fasted.
b This study was conducted using lenacapavir 300 mg single dose administered orally.
c
Evaluated as a strong inducer of CYP3A, and an inducer of P-gp and UGT.
d Fed.
e
Evaluated as a strong inhibitor of CYP3A, and an inhibitor UGT1A1 and P-gp.
f
Evaluated as a moderate inducer of CYP3A and an inducer of P-gp.
g Evaluated as a strong inhibitor of CYP3A and an inhibitor of P-gp.
h Evaluated as a strong inhibitor of CYP3A, and an inhibitor and inducer of P-gp.
i
This study was conducted using lenacapavir 600 mg single dose following a loading regimen of 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each co-administered medicinal product.
j
Evaluated as a P-gp substrate.
k Tenofovir alafenamide is converted to tenofovir in vivo.
l
Evaluated as an OATP substrate.
m Evaluated as an BCRP substrate.
n Evaluated as a CYP3A substrate.
o Major active metabolite of midazolam.
p Evaluated as a strong inhibitor of CYP3A.
q This study was conducted using voriconazole 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily.

4.6 Fertility, pregnancy and lactation

Applies to: Sunlenca 464 mg solution for injection · Sunlenca 300 mg film-coated tablets

Pregnancy

There are no or limited amount of data from the use of lenacapavir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Sunlenca during pregnancy unless the clinical condition of the women requires treatment with Sunlenca.

Breast-feeding

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

It is unknown whether lenacapavir is excreted in human milk. After administration to rats during pregnancy and lactation, lenacapavir was detected at low levels in the plasma of nursing rat pups, without effects on these nursing pups.

Fertility

There are no data on the effects of lenacapavir on human male or female fertility. Animal studies indicate no effects on lenacapavir on male or female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Applies to: Sunlenca 464 mg solution for injection · Sunlenca 300 mg film-coated tablets

Sunlenca is expected to have no or negligible influence on the ability to drive and use machines.

4.9 Overdose

Applies to: Sunlenca 464 mg solution for injection · Sunlenca 300 mg film-coated tablets

If overdose occurs the patient must be monitored for signs or symptoms of adverse reactions (see section 4.8). 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 protein bound, it is unlikely to be significantly removed by dialysis.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Sunlenca 464 mg solution for injection · Sunlenca 300 mg film-coated tablets

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX31

Mechanism of action

Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (CA) subunits. Lenacapavir inhibits HIV-1 replication by interfering with multiple, essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of CA subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

Antiviral activity and selectivity in vitro

The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid 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 WT HIV-1 virus.

In a study of lenacapavir in combination with representatives from the main classes of antiretroviral agents (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs], integrase strand-transfer inhibitors [INSTIs], and protease inhibitors [PIs]), synergistic antiviral effects were observed. No antagonism was observed for these combinations.

Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes 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.

Resistance

In cell culture
HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. In vitro resistance 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 was reduced 4- to >3,226-fold, relative to WT virus. HIV-1 variants with >10-fold reduction in susceptibility to lenacapavir compared to WT virus displayed diminished replication capacity in primary human CD4+ T lymphocytes and macrophages (0.03 – 28% and 1.9 – 72% of WT virus, respectively).

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Sunlenca 464 mg solution for injection

Lenacapavir exposures (AUCtau, Cmax and Ctrough) were 29% to 84% higher in heavily treatment experienced participants with HIV-1 infection as compared to participants without HIV-1 infection based on population pharmacokinetics analysis.

Absorption

Subcutaneous administration
Lenacapavir is completely absorbed following subcutaneous administration. Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex with peak plasma concentrations occurring 84 days postdose.

Oral administration
Lenacapavir is absorbed following oral administration with peak plasma concentrations occurring approximately 4 hours after administration of Sunlenca. Absolute bioavailability following oral administration of lenacapavir is low (approximately 6 to 10%). 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 be administered without regard to food.

Pharmacokinetic parameters
Simulated steady state exposures of lenacapavir following recommended dosing regimen in heavily treatment experienced participants with HIV are provided in Table 7.

Table 7: Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration

Parameter
Mean (%CV)a
Day 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC)
Day 1 to Day 15
Day 15 to end of month 6
Steady state
Cmax
(ng/ mL)

Applies to: Sunlenca 300 mg film-coated tablets

Absorption

Pharmacokinetic parameters
Simulated steady state exposures of lenacapavir following recommended dosing regimen in heavily treatment experienced participants with HIV are provided in Table 7.

Table 7: Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration

Parameter
Mean (%CV)a
Day 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC)
Day 1 to Day 15
Day 15 to end of Month 6
Steady state
Cmax
(ng/ mL)

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. This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Yeytuo

4.1 Therapeutic indications

Applies to: Yeytuo 464 mg solution for injection

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, 4.4 and 5.1).

Applies to: Yeytuo 300 mg film-coated tablets

Yeytuo tablet 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 for:
- oral loading
- oral bridging
(see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Applies to: Yeytuo 464 mg solution for injection

Yeytuo should be prescribed by a healthcare professional experienced in the management of HIV prevention.

Each injection should be administered by a healthcare professional.

All individuals must be screened for HIV-1 prior to initiating lenacapavir, prior to each subsequent injection, and additionally as clinically appropriate (see sections 4.3 and 4.4). A combined antigen/antibody test as well as an HIV-RNA-based test should be negative. Prescribers are advised to perform both tests, even if the result of the HIV-RNA-based test will become available after initiation of lenacapavir. If a combined testing strategy including both tests is not available, testing should follow local guidelines.

Prior to starting Yeytuo, healthcare professionals should identify individuals for whom the required initiation and every 6-month continuation injection dosing schedule is appropriate, and counsel individuals about the importance of adherence to scheduled dosing visits (see section 4.4).

Posology

The 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-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
(26 weeks)c
+/- 2 weeks
927 mg subcutaneous injection (2 x 1.5 mL injectionsb)

a
The complete initiation dosing schedule, consisting of subcutaneous injections and oral tablets, is required; the efficacy of 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 dose

Anticipated delayed injections
During continuation dosing, if the scheduled 6-month injection is anticipated to be delayed by more than 2 weeks, lenacapavir tablets may be used for oral bridging on an interim basis (for up to 6 months if needed), until injections resume. Oral bridging should be initiated within 26 to 28 weeks from the last injection. The dosing schedule is 300 mg (1 tablet) taken orally once every 7 days. Resume the continuation 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 and lenacapavir tablets have not been taken for oral bridging, restart the initiation dosing schedule from Day 1 (see Table 1).

Special populations

Elderly
No dose adjustment of lenacapavir is required for elderly individuals. There are limited data available on the use of lenacapavir in individuals aged 65 years and above (see section 5.2).

Renal impairment
No dose adjustment of lenacapavir is required in individuals with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥ 15 mL/min). Lenacapavir has not been studied in individuals with end stage renal disease (CrCl < 15 mL/min or on renal replacement therapy) (see section 5.2), therefore lenacapavir should be used with caution in these individuals.

Hepatic impairment
No dose adjustment of lenacapavir is required in individuals with mild or moderate hepatic impairment (Child-Pugh Class A or B). Lenacapavir has not been studied in individuals with severe hepatic impairment (Child-Pugh Class C) (see section 5.2), therefore lenacapavir should be used with caution in these individuals.

Paediatric population
Safety and efficacy of lenacapavir in children and adolescents weighing less than 35 kg have not been established. No data are available.

Method of administration

For subcutaneous use only.

Lenacapavir injections must only be administered subcutaneously into the abdomen or thigh (two injections, with the second injection at least 5 centimetres from the first injection) by a healthcare professional (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 slowly released from the site of administration. In some individuals, this may lead to a nodule at the injection site (see sections 4.8 and 5.2).

Applies to: Yeytuo 300 mg film-coated tablets

Yeytuo should be prescribed by a healthcare professional experienced in the management of HIV prevention.

All individuals must be screened for HIV-1 prior to initiating lenacapavir and additionally as clinically appropriate (see sections 4.3 and 4.4). A combined antigen/antibody test as well as an HIV-RNA- based test should be negative. Prescribers are advised to perform both tests, even if the result of the HIV-RNA-based test will become available after initiation of lenacapavir. If a combined testing strategy including both tests is not available, testing should follow local guidelines.

Posology

The dosing schedule in adults and adolescents weighing at least 35 kg consists of a required initiation dosing (subcutaneous injections and oral tablets) (Table 1), followed by once every 6-month continuation dosing (subcutaneous injections).

Initiation
On Day 1, the required dose is 927 mg of lenacapavir administered by subcutaneous injection and 600 mg taken orally. On Day 2, the required dose is 600 mg taken orally.

Table 1: Dosing schedule for lenacapavir initiation

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) a
The complete initiation dosing schedule, consisting of subcutaneous injections and oral tablets, is required; the efficacy of 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 in the Yeytuo solution for injection SmPC).

Missed initiation dose
If the Day 1 or Day 2 oral initiation dose (600 mg) is missed, it should be taken as soon as possible.
Day 1 and Day 2 doses should not be taken 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, lenacapavir tablets may be used for oral bridging on an interim basis (for up to 6 months if needed) until injections resume. Oral bridging should be initiated within 26 to 28 weeks from the last injection. The dosing schedule is 300 mg (1 tablet) taken orally once every 7 days. Resume the continuation injection dosage within 7 days after the last oral dose.

Vomiting
If the individual vomits within 3 hours of taking an oral dose of lenacapavir, another oral dose should be taken. If the individual vomits more than 3 hours after taking an oral dose of lenacapavir there is no need to take another oral dose of lenacapavir, and the scheduled dosing regimen should continue.

Special populations

Elderly
No dose adjustment of lenacapavir is required for elderly individuals. There are limited data available on the use of lenacapavir in individuals aged 65 years and above (see section 5.2).

Paediatric population
Safety and efficacy of lenacapavir in children and adolescents weighing less than 35 kg have not been established. No data are available.

Method of administration

For oral use.

Lenacapavir tablets should be taken orally with or without food (see section 5.2). The film-coated tablet should not be chewed, or crushed, because the effects on lenacapavir absorption have not been

studied. For individuals who are unable to swallow the tablet whole, the tablet may be split in half and both halves taken one after the other, ensuring that the full dose is taken immediately.

4.3 Contraindications

Applies to: Yeytuo 464 mg solution for injection · Yeytuo 300 mg film-coated tablets

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).

4.8 Undesirable effects

Applies to: Yeytuo 464 mg solution for injection

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 reactions

Frequencies 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 be estimated from the available data).

Table 3: Tabulated list of adverse reactions

Frequencya
Adverse reaction
General disorders and administration site conditions
Very common injection site reactionsb a
Frequency based on all adverse events in PURPOSE 1 and PURPOSE 2 (see section 5.1) attributed to lenacapavir (or to the 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% of participants receiving placebo injections (and emtricitabine/tenofovir alafenamide [FTC/TAF] or emtricitabine/tenofovir disoproxil fumarate [FTC/TDF]). Most participants who received lenacapavir had 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 and resolved more slowly than other ISRs. The median duration of nodules was 274 (180, 407) days. Of the injection site nodule events associated with Day 1 lenacapavir injections, 70% had resolved within a median time of 276 days.

Other ISRs: The other ISRs reported in more than 2% of participants who received lenacapavir were pain (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% of participants 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, and included ulcer, pain, erythema, oedema, and dermatitis. Lenacapavir was discontinued due to ISRs in 26 (1.2%) participants.

Nodules: Injection site nodule was reported in 65% of participants and resolved more slowly than other ISRs. The median duration of nodules was 239 (163, 362) days. Of the injection site nodule events associated with Day 1 lenacapavir injections, 70% had resolved within a median time of 269 days.

Other ISRs: The other ISRs reported in more than 2% of participants who received lenacapavir were pain (58%), erythema (18%), induration (16%), swelling (7%), pruritus (4%), bruising (3%), and warmth (2%). The median duration of ISRs, excluding nodules and indurations, was 4 (2 to 8) days.

Paediatric population

The safety of lenacapavir was evaluated in 59 adolescents aged 16 to <18 years and weighing ≥35 kg in PURPOSE 1 and PURPOSE 2. The adverse reactions in adolescents were consistent with those in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: Yeytuo 300 mg film-coated tablets

No adverse reactions to lenacapavir taken orally were identified in adults or adolescents in PURPOSE 1 and PURPOSE 2.

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Yeytuo 464 mg solution for injection

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, and additionally 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 sexually transmitted infections (STIs). Individuals should be identified for whom the required initiation and every 6-month continuation injection dosing schedule is appropriate. Non-adherence to the required initiation 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 administration schedule, on the use of other measures to prevent STIs, and on the importance of testing for HIV-1 and other 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 protection against 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 a risk of developing resistance to lenacapavir if an individual acquires HIV-1 either before or when receiving Yeytuo, or following discontinuation of Yeytuo. To minimise this risk, it is essential to confirm HIV-1 negative status before each subsequent injection, and additionally as clinically appropriate. Yeytuo alone does not constitute a complete regimen for HIV-1 treatment and mutations have 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 treatment regimen to reduce the risk of developing resistance.

Long-acting properties

Residual concentrations of lenacapavir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer).

These concentrations may affect the exposures of other medicinal products (i.e. sensitive CYP3A and/or P-gp substrates) that are initiated within 9 months after the last subcutaneous dose of lenacapavir (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 reactions

Injection site reactions with improper administration
Improper administration (intradermal injection) has been associated with serious injection site reactions, 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 and indurations. The healthcare professional should inform patients that nodules and indurations at the injection site may take longer to resolve than other ISRs or may not resolve (see section 4.8). The mechanism driving the persistence of injection site nodules in some individuals is not fully understood but may be related to the presence of the subcutaneous drug depot and an associated foreign body response at the injection site. Non-resolving ISRs should be subject to clinical monitoring.

Co-administration of other medicinal products

Co-administration with medicinal products that are moderate inducers of CYP3A and P-gp is not recommended (see section 4.5).

Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways) is not recommended (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to say essentially ‘sodium-free’.

Applies to: Yeytuo 300 mg film-coated tablets

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, and additionally as clinically appropriate in individuals receiving lenacapavir.

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 sexually transmitted infections (STIs). Individuals should be identified for whom the required initiation and every 6-month continuation injection dosing schedule is appropriate. Nonadherence to the required initiation 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 administration schedule, on the use of other measures to prevent STIs, and on the importance of testing for HIV-1 and other STIs.

Risk of Resistance

Co-administration of other medicinal products

Co-administration with medicinal products that are moderate inducers of CYP3A and P-gp is not recommended (see section 4.5).

Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways) is not recommended (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Yeytuo 464 mg solution for injection

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 in reduced effectiveness of lenacapavir. Concomitant administration of lenacapavir with strong inducers of 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 lenacapavir with 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 significantly increase plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4).

Strong CYP3A4 inhibitors alone or strong inhibitors of CYP3A4 and P-gp together do not result in a clinically meaningful increase in lenacapavir exposure.

Effect of lenacapavir on the pharmacokinetics of other medicinal products

Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if lenacapavir is 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. Clinical drug interaction data for subcutaneous lenacapavir are not available.

Table 2: Interactions between Yeytuo and other medicinal products

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC, Cmax
Recommendation concerning co-administration with Yeytuo
ANTIMYCOBACTERIALS
Rifampicina,b
(600 mg once daily)
(strong inducer of CYP3A, and an inducer of P-gp and UGT)
Lenacapavir:
AUC: ↓84%
Cmax: ↓55%
Co-administration is contraindicated (see section 4.3).
Rifabutin
Rifapentine

Interaction not studied.

Co-administration of rifabutin or rifapentine may decrease lenacapavir plasma concentrations.
Co-administration is not recommended (see section 4.4).
ANTICONVULSANTS
Carbamazepine
Phenytoin
Interaction not studied.

Co-administration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with lenacapavir may decrease lenacapavir plasma concentrations.
Co-administration is contraindicated (see section 4.3).
Oxcarbazepine
Phenobarbital
Co-administration is not recommended (see section 4.4).

Alternative anticonvulsants should be considered.
HERBAL PRODUCTS
St. John’s wort (Hypericum perforatum)
Interaction not studied.

Co-administration of St.
John’s wort may decrease lenacapavir plasma concentrations.
Co-administration is contraindicated (see section 4.3).

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC, Cmax
Recommendation concerning co-administration with Yeytuo
ANTIRETROVIRAL AGENTS
Atazanavir/cobicistat b,c,d
(300 mg/150 mg once daily)
(strong inhibitor of CYP3A, and an inhibitor UGT1A1 and P-gp)

Lenacapavir:
AUC: ↑ 321%
Cmax: ↑ 560%
Co-administration of lenacapavir and strong inhibitors of CYP3A, P- gp, and UGT1A1 is not recommended (see section 4.4).
Efavirenz b,c,d (600 mg once daily) (moderate inducer of
CYP3A and an inducer of P-gp)
Lenacapavir:
AUC:↓ 56%
Cmax:↓ 36%
Co-administration is not recommended (see section 4.4).
Cobicistat b,c,d (150 mg once daily) (strong inhibitor of
CYP3A and an inhibitor of
P-gp)
Lenacapavir:
AUC: ↑ 128%
Cmax:↑ 110%
No dose adjustment of lenacapavir is required.
Darunavir/cobicistat b,c,d
(800 mg/150 mg once daily)
(strong inhibitor of CYP3A, and an inhibitor and inducer of
P-gp)
Lenacapavir:
AUC:↑ 94%
Cmax:↑ 130%
Tenofovir alafenamidec,e
(25 mg)
(substrate of P-gp)
Tenofovir alafenamide:
AUC:↑ 32%
Cmax:↑ 24%

Tenofovirf:
AUC:↑ 47%
Cmax:↑ 23%
No dose adjustment of tenofovir alafenamide is required.
ERGOT DERIVATIVES
Dihydroergotamine
Ergotamine

Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
Caution is warranted when dihydroergotamine or ergotamine, is co-administered with lenacapavir.
PHOSPHODIESTERASE-5 (PDE-5) INHIBITORS
Sildenafil
Tadalafil
Vardenafil
Interaction not studied.

Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil: A starting dose of 25 mg is recommended.
Vardenafil: No more than 5 mg in a
24-hour period.
Tadalafil:
• For use as needed: no more than
10 mg every 72 hours
• For once daily use: dose not to exceed 2.5 mg

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC, Cmax
Recommendation concerning co-administration with Yeytuo
CORTICOSTEROIDS (systemic)
Dexamethasone
Hydrocortisone/cortisone
Interaction not studied.

Plasma concentrations of corticosteroids may be increased when co-administered with lenacapavir.

Plasma concentrations of lenacapavir may decrease when co-administered with systemic dexamethasone.

Co-administration of lenacapavir with 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.

Caution is warranted when systemic dexamethasone is co-administered with lenacapavir, particularly for long-term use.
Alternative corticosteroids should be considered.
HMG-CoA REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g. myopathy).
Atorvastatin
No dose adjustment of atorvastatin is required.
Pitavastatinc,e (2 mg single dose;
simultaneous or 3 days after lenacapavir)
(substrate of OATP)
Pitavastatin:
AUC:↔
Cmax:↔
No dose adjustment of pitavastatin and rosuvastatin is required.
Rosuvastatinc,e (5 mg single dose)
(substrate of BCRP and OATP)
Rosuvastatin:
AUC:↑ 31%
Cmax:↑ 57%
ANTIARRHYTHMICS
Digoxin
Interaction not studied.

Plasma concentration of digoxin may be increased when co-administered with lenacapavir.
Caution is warranted and therapeutic concentration monitoring of digoxin is recommended.
SEDATIVES/HYPNOTICS
Midazolamc,e (2.5 mg single dose; oral; simultaneous administration)
(substrate of CYP3A)

Midazolam:
AUC: ↑ 259%
Cmax: ↑ 94%

1-hydroxymidazolamg:
AUC: ↓ 24%
Cmax: ↓ 46%
Caution is warranted when midazolam or triazolam, is co-administered with lenacapavir.
Midazolamc,e (2.5 mg single dose; oral;1 day after lenacapavir)
(substrate of CYP3A)

Midazolam:
AUC: ↑ 308%
Cmax: ↑ 116%

1-hydroxymidazolamg:
AUC: ↓ 16%
Cmax: ↓ 48%
Triazolam
Interaction not studied.

Plasma concentration of triazolam may be increased when co-administered with lenacapavir.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC, Cmax
Recommendation concerning co-administration with Yeytuo
ANTICOAGULANTS
Direct Oral Anticoagulants
(DOACs)
Rivaroxaban
Dabigatran
Edoxaban
Interaction not studied.

Plasma concentration of lenacapavir may be increased when co-administered with itraconazole or ketoconazole.
H2-RECEPTOR ANTAGONISTS
Famotidinea,b (40 mg once daily, 2 hours before lenacapavir)
Famotidine:
AUC:↑ 28%
Cmax:↔
No dose adjustment of famotidine is required.
ORAL OR LONG-ACTING CONTRACEPTIVES
Long-acting contraceptives:
Medroxyprogesterone acetate
Etonogestrel
Norethisterone enanthate
Observed data does not indicate clinically relevant changes in the exposure of long-acting contraceptives.
No dose adjustment of oral or long- acting contraceptives is required.
Oral contraceptives:
Ethinylestradiol
Progestins

Interaction not studied.

Plasma concentrations of oral contraceptives may be increased when co-administered with lenacapavir.
GENDER AFFIRMING HORMONES (feminising or masculinising)
Estradiol
Testosterone
Observed data does not indicate clinically relevant changes in the exposure of estradiol and testosterone.
No dose adjustment of these gender affirming hormones is required.
Anti-androgens
Progestogen

Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
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 2 days, 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 mg maintenance dose twice daily.

Applies to: Yeytuo 300 mg film-coated tablets

Effect of other medicinal products on the pharmacokinetics of lenacapavir

Strong CYP3A4 inhibitors alone or strong inhibitors of CYP3A4 and P-gp together do not result in a clinically meaningful increase in lenacapavir exposure.

Effect of lenacapavir on the pharmacokinetics of other medicinal products

Clinical drug interaction data for lenacapavir as victim are from studies with oral lenacapavir. Clinical drug interaction data for subcutaneous lenacapavir are not available.

Table 2: Interactions between Yeytuo and other medicinal products

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with lenacapavir
ANTIMYCOBACTERIALS
Rifampicina,b
(600 mg once daily)
(strong inducer of CYP3A, and an inducer of P-gp and UGT)

Lenacapavir:
AUC: ↓84%
Cmax: ↓55%
Co-administration is contraindicated (see section 4.3).

Rifabutin
Rifapentine

Interaction not studied.

Alternative anticonvulsants should be considered.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with lenacapavir
HERBAL PRODUCTS
St. John’s wort (Hypericum perforatum)
Interaction not studied.

Co-administration of St.
John’s wort may decrease lenacapavir plasma concentrations.
Co-administration is contraindicated (see section 4.3).
ANTIRETROVIRAL AGENTS
Atazanavir/cobicistat b,c,d
(300 mg/150 mg once daily)
(strong inhibitor of CYP3A, and an inhibitor UGT1A1 and P-gp.)
Lenacapavir:
AUC: ↑ 321%
Cmax: ↑ 560%
Co-administration of lenacapavir and strong inhibitors of CYP3A,
P-gp, and UGT1A1 is not recommended (see section 4.4).
Efavirenz b,c,d
(600 mg once daily)
(moderate inducer of CYP3A and an inducer of P-gp)
Lenacapavir:
AUC:↓ 56%
Cmax:↓ 36%
Co-administration is not recommended (see section 4.4).
Cobicistat b,c,d
(150 mg once daily) (strong inhibitor of CYP3A and an inhibitor of P-gp)
Lenacapavir:
AUC: ↑ 128%
Cmax:↑ 110%
No dose adjustment of lenacapavir is required.
Darunavir/cobicistat b,c,d
(800 mg/150 mg once daily)
(strong inhibitor of CYP3A, and an inhibitor and inducer of P-gp)
Lenacapavir:
AUC:↑ 94%
Cmax:↑ 130%
Tenofovir alafenamidec,e
(25 mg)
(substrate of P-gp)
Tenofovir alafenamide:
AUC:↑ 32%
Cmax:↑ 24%

Tenofovirf:
AUC:↑ 47%
Cmax:↑ 23%
No dose adjustment of tenofovir alafenamide is required.
ERGOT DERIVATIVES
Dihydroergotamine
Ergotamine
Interaction not studied.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
Caution is warranted when dihydroergotamine or ergotamine, is co-administered with lenacapavir.
PHOSPHODIESTERASE-5 (PDE-5) INHIBITORS
Sildenafil
Tadalafil
Vardenafil
Interaction not studied.

Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil: A starting dose of
25 mg is recommended.
Vardenafil: No more than 5 mg in a 24-hour period.
Tadalafil:
• For use as needed: no more than 10 mg every 72 hours
• For once daily use: dose not to exceed 2.5 mg

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with lenacapavir
CORTICOSTEROIDS (systemic)
Dexamethasone
Hydrocortisone/cortisone
Interaction not studied.

Plasma concentrations of corticosteroids may be increased when co-administered with lenacapavir.

Plasma concentrations of lenacapavir may decrease when co- administered with systemic dexamethasone.

Co-administration of lenacapavir with 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.

Plasma concentrations of these medicinal products may be increased when co-administered with lenacapavir.
Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g. myopathy).
Atorvastatin
No dose adjustment of atorvastatin is required.
Pitavastatinc,e (2 mg single dose;
simultaneous or 3 days after lenacapavir)
(substrate of OATP)
Pitavastatin:
AUC:↔
Cmax:↔
No dose adjustment of pitavastatin and rosuvastatin is required.
Rosuvastatinc,e (5 mg single dose)
(substrate of BCRP and OATP)
Rosuvastatin:
AUC:↑ 31%
Cmax:↑ 57%
ANTIARRHYTHMICS
Digoxin
Interaction not studied.

Plasma concentration of digoxin may be increased when co-administered with lenacapavir.
Caution is warranted and therapeutic concentration monitoring of digoxin is recommended.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with lenacapavir
SEDATIVES/HYPNOTICS
Midazolamc,e (2.5 mg single dose;
oral; simultaneous administration)
(substrate of CYP3A)

Midazolam:
AUC: ↑ 259%
Cmax: ↑ 94%

1-hydroxymidazolamg:
AUC: ↓ 24%
Cmax: ↓ 46%
Caution is warranted when midazolam or triazolam, is co-administered with lenacapavir.
Midazolamc,e (2.5 mg single dose;
oral;1 day after lenacapavir)
(substrate of CYP3A)

Midazolam:
AUC: ↑ 308%
Cmax: ↑ 116%

1-hydroxymidazolamg:
AUC: ↓ 16%
Cmax: ↓ 48%
Triazolam
Interaction not studied.

Plasma concentration of triazolam may be increased when co-administered with lenacapavir.
ANTICOAGULANTS
Direct Oral Anticoagulants
(DOACs)
Rivaroxaban
Dabigatran
Edoxaban
Interaction not studied.

Lenacapavir:
AUC:↑ 41%
Cmax:↔
No dose adjustment of lenacapavir is required.

Itraconazole
Ketoconazole
Interaction not studied.

Plasma concentration of lenacapavir may be increased when co-administered with itraconazole or ketoconazole.
H2-RECEPTOR ANTAGONISTS
Famotidinea,b (40 mg once daily,
2 hours before lenacapavir)
Famotidine:
AUC:↑ 28%
Cmax:↔
No dose adjustment of famotidine is required.
ORAL OR LONG-ACTING CONTRACEPTIVES
Long-acting contraceptives:
Medroxyprogesterone acetate
Etonogestrel
Norethisterone enanthate
Observed data does not indicate clinically relevant changes in the exposure of long-acting contraceptives.
No dose adjustment of oral or long-acting contraceptives is required.
Oral contraceptives:
Ethinylestradiol
Progestins
Interaction not studied.

Plasma concentrations of oral contraceptives may be increased when co-administered with lenacapavir.

Medicinal product by therapeutic areas
Effects on concentrations.
Mean percent change in AUC,
Cmax
Recommendation concerning co-administration with lenacapavir
GENDER AFFIRMING HORMONES (feminising or masculinising)
Estradiol
Testosterone
Observed data does not indicate clinically relevant changes in the exposure of estradiol and testosterone.
No dose adjustment of these gender affirming hormones is required.
Anti-androgens
Progestogen

Interaction not studied.

4.6 Fertility, pregnancy and lactation

Applies to: Yeytuo 464 mg solution for injection

Individuals of childbearing potential

Individuals of childbearing potential should be counselled about the long-acting properties of lenacapavir injection.

If an individual plans a pregnancy, the benefits and the risks of initiating or continuing Yeytuo during pregnancy should be discussed.

Pregnancy

There are limited data (130 birth outcomes) from the use of lenacapavir in pregnant women. The rates of adverse pregnancy outcomes in participants who received Yeytuo were similar to reported background 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 the foetus.

Breast-feeding

Lenacapavir is present in human milk. Lenacapavir was detected at low levels in infants who were breastfed by individuals who became pregnant while receiving Yeytuo (see section 5.2). There is insufficient information on the effects of lenacapavir in newborns/infants.

Yeytuo may be considered during breastfeeding if the expected benefit outweighs the potential risk to the child.

Fertility

There are no data on the effects of lenacapavir on human male or female fertility. Animal studies indicate no effects of lenacapavir on male or female fertility (see section 5.3).

Applies to: Yeytuo 300 mg film-coated tablets

Individuals of childbearing potential

If an individual plans a pregnancy, the benefits and the risks of initiating or continuing Yeytuo during pregnancy should be discussed.

Pregnancy

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 the foetus.

Breast-feeding

Yeytuo may be considered during breastfeeding if the expected benefit outweighs the potential risk to the child.

Fertility

There are no data on the effects of lenacapavir on human male or female fertility. Animal studies indicate no effects of lenacapavir on male or female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Applies to: Yeytuo 464 mg solution for injection · Yeytuo 300 mg film-coated tablets

Yeytuo is expected to have no or negligible influence on the ability to drive and use machines.

4.9 Overdose

Applies to: Yeytuo 464 mg solution for injection

If overdose occurs the individual must be monitored for signs or symptoms of adverse reactions (see section 4.8). Treatment of overdose with Yeytuo consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual. As lenacapavir is highly protein bound, it is unlikely to be significantly removed by dialysis.

5.
PHARMACOLOGICAL PROPERTIES

Applies to: Yeytuo 300 mg film-coated tablets

If overdose occurs the individual must be monitored for signs or symptoms of adverse reactions.
Treatment of overdose with Yeytuo consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual. As lenacapavir is highly protein bound, it is unlikely to be significantly removed by dialysis.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Yeytuo 464 mg solution for injection · Yeytuo 300 mg film-coated tablets

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX31

Mechanism of action

Antiviral activity and selectivity in vitro

Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes 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.

Resistance

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 after the time of the primary analysis. Genotyping of virus in one of the participants revealed no lenacapavir resistance-associated capsid substitutions. The second participant had viral loads that were too low for genotyping.

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 resistance

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Yeytuo 464 mg solution for injection

Absorption

Subcutaneous administration
Absolute bioavailability of lenacapavir following subcutaneous administration was 91% based on population pharmacokinetic analysis. Subcutaneously administered lenacapavir forms a drug depot whereby lenacapavir is slowly released from the site of administration, with peak plasma concentrations occurring 84 days post dose.

Oral administration
Lenacapavir is absorbed following oral administration with peak plasma concentrations occurring approximately 4 hours after administration of lenacapavir. Absolute bioavailability following oral administration of lenacapavir is low based on population pharmacokinetic analysis (approximately 4 to 7%). Lenacapavir is a substrate of P-gp.

Pharmacokinetic parameters
The population pharmacokinetic parameter estimates of lenacapavir after oral and subcutaneous administration 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 or thigh.

Table 6: Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration to adult and adolescent participants receiving Yeytuo

Parameter
Mean
(%CV)a,b
Day 1 to end of Week 26
Steady State
AUCtau
(h•ng/mL)
188112 (41.0)

257332 (38.7)

Cmax
(ng/mL)

Applies to: Yeytuo 300 mg film-coated tablets

Absorption

Pharmacokinetic parameters
The population pharmacokinetic parameter estimates of lenacapavir after oral and subcutaneous administration to adult and adolescent (weighing at least 35 kg) participants are provided in Table 5.
Similar exposures are achieved when lenacapavir is administered subcutaneously in the abdomen or thigh.

Table 5: Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration to adult and adolescent participants receiving Yeytuo

Parameter
Mean
(%CV)a,b
Day 1 to end of Week 26
Steady State
AUCtau
(h•ng/mL)
188112 (41.0)

257332 (38.7)

Cmax
(ng/mL)

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.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.