4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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'.

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, 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 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.

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.

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 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-hydroxymidazolam°:

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-hydroxymidazolam°:

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 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 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.

4.6. Fertility, pregnancy and lactation

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

Sunlenca 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 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.