Lenacapavir

Registered South African indications:

• Pre-exposure prophylaxis (PrEP) to prevent sexually acquired HIV-1 in adults and adolescents weighing at least 35kg
  - In combination with safer sex practices

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Use in individuals with unknown HIV-1 status
• Coadministration with strong inducers of CYP3A, P-gp, and UGT1A1, other than rifampicin, such as
  • Anticonvulsants: carbamazepine, phenytoin
  • Herbal products: St. John’s wort (Hypericum perforatum)

South African recommendations

Caution in the following patient groups

• End stage renal disease (CrCl < 15ml/min) or on renal replacement therapy
• Severe hepatic impairment (Child-Pugh Class C)

Prevention strategy

• Lenacapavir should only be used to prevent HIV-1 acquisition in individuals confirmed to be HIV-negative
• Confirm HIV-1 negative status prior to initiation of lenacapavir and routinely thereafter as clinically appropriate in individuals receiving lenacapavir
• Use lenacapavir to prevent HIV-1 acquisition as part of a strategy to reduce the risk of sexually transmitted infections (STIs)
• Select individuals for whom the required initiation and every 6-month maintenance injection dosing schedule is appropriate
• Non-adherence to the required initiation and maintenance dosing schedule may lead to HIV-1 acquisition
• Counsel and support individuals 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

• There is a risk of developing resistance to lenacapavir if an individual acquires HIV-1 either before or when receiving lenacapavir, or following discontinuation of lenacapavir
• Lenacapavir alone does not constitute a complete regimen for HIV-1 treatment
• 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)
• 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

Coadministration of other medicines

• Coadministration with medicinal products that are moderate inducers of CYP3A and P-gp, other than rifabutin, is not recommended
• Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways) is not recommended

Excipients

• Lenacapavir contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially ‘sodium-free’

Effects on ability to drive and use machines

• Lenacapavir is expected to have no or negligible influence on the ability to drive and use machines

Forms avail. in SA and covered in this monograph: inj, fct

South African registered indications and dosages

Pre-exposure prophylaxis (PrEP) to prevent sexually acquired HIV-1 in adults and adolescents weighing at least 35kg
- In combination with safer sex practices

Initiation - Day 1: 

• SC: 927mg (2 x 1.5ml injections), as a single dose

AND

• Oral (fct): 600mg, as a single dose

Then, Day 2:

• Oral (fct): 600mg, as a single dose

Maintenance:

• SC: 927mg (2 x 1.5ml injections), every 6 months (26 weeks)

Table: Dosing schedule for lenacapavir initiation and maintenance

Time
Dose of lenacapavir: Initiation (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)
Day 1	927mg subcutaneous injection (2 x 1.5ml injections) 600mg orally (2 x 300mg tablets)
Day 2	600mg orally (2 x 300mg tablets)
Dose of lenacapavir: Maintenance
Every 6 Months (26 weeks): From the date of the last injection (+/- 2 weeks)	927mg subcutaneous injection (2 x 1.5ml injections)

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Film coated tablets used for oral loading and oral bridging

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All individuals must be screened for HIV-1 prior to initiating lenacapavir and routinely thereafter as clinically appropriate. Individuals must have a negative HIV-1 test prior to initiating 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

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Prior to starting lenacapavir Gilead, healthcare professionals should select individuals for whom the required initiation and 6-monthly maintenance injection dosing schedule is appropriate, and counsel individuals about the importance of adherence to scheduled lenacapavir dosing visits

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Missed dose

Planned missed injections: During maintenance dosing, if an individual plans to miss a scheduled 6-month injection visit 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 300mg (1 tablet) taken orally once every 7 days. Resume the maintenance injection dosage within 7 days after the last oral dose (see table above)

Unplanned missed injections: During the maintenance 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 above)

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Method of administration

Injection: For subcutaneous use only. Lenacapavir injections must only be administered subcutaneously into the abdomen or upper buttocks (two injections, with the second injection at least 5 centimetres from the first injection) by a healthcare professional. Do NOT administer intradermally. 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. A subcutaneous drug depot forms following lenacapavir injection. In some individuals, this may lead to a nodule at the injection site

Film-coated tablet: For oral use. Lenacapavir tablets should be taken orally with or without food. The film-coated tablet should not be chewed, crushed, or split, because the effects on lenacapavir absorption have not been studied

Forms avail. in SA and covered in this monograph: inj, fct

South African registered indications and dosages

Pre-exposure prophylaxis (PrEP) to prevent sexually acquired HIV-1 in adults and adolescents weighing at least 35kg
- In combination with safer sex practices

Adolescents weighing < 35kg

• Not established for use

Adolescents weighing ≥ 35kg

• See adult dosages

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Safety and efficacy of lenacapavir has been established in adolescents weighing at least 35kg

Pregnancy

South African recommendations

• Safe; no evidence of risk in studies
• A moderate amount of data on pregnant women (369 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of lenacapavir. The rates of adverse pregnancy outcomes in participants who received lenacapavir were similar to reported background rates
• Lenacapavir exposures during each trimester of pregnancy and postpartum were comparable to those in non-pregnant participants
• Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development
• The use of lenacapavir may be considered during pregnancy, if clinically appropriate

Breastfeeding

South African recommendations

• Compatible
• Lenacapavir is present in human milk. Lenacapavir was detected at very low levels in infants who were breastfed by individuals who became pregnant while receiving lenacapavir
• No adverse effects of lenacapavir in breastfed infants have been observed
• Lenacapavir can be used during breastfeeding

Fertility

South African recommendations

• 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

South African recommendations

• Mild to severe (CrCl ≥ 15ml/min): No dose adjustment recommended
• End stage renal disease (CrCl < 15ml/min) or on renal replacement therapy: Caution; no information available
  Lenacapavir has not been studied in individuals with end stage renal disease (CrCl < 15 ml/min) or on renal replacement therapy), therefore lenacapavir should be used with caution in these individuals

South African recommendations

• Mild to moderate (Child-Pugh Class A or B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available
  Lenacapavir has not been studied in individuals with severe hepatic impairment (Child-Pugh Class C), therefore lenacapavir should be used with caution in these individuals

South African recommendations

• No dose adjustment recommended

Injection

General Disorders and Administration Site Conditions

Very common

• Injection site reactions
  • Injection site nodule
  • Pain
  • Induration
  • Erythema
  • Swelling
  • Pruritus
  • Bruising
  • Warmth
  • Discolouration
  • Oedema
  • Ulcer
  • Haematoma
  • Haemorrhage
  • Discomfort

Film-coated tablet

• None known

• Anticonvulsants
• Carbamazepine
• Phenytoin
• Anticonvulsants
• Oxcarbazepine
• Phenobarbital
• Antimycobacterials
• Rifapentine
• Strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e., all 3 pathways)
• Antiretroviral medicines
• Atazanavir/cobicistat
• Darunavir/cobicistat
• Phosphodiesterase-5 (PDE-5) inhibitors
• Tadalafil
• Antimycobacterials
• Rifampicin
• Rifabutin
• Sensitive CYP3A and/or P-gp Substrates with a narrow therapeutic index
• Ergot derivatives
• Dihydroergotamine
• Ergotamine
• Sildenafil
• Vardenafil
• Corticosteroids (systemic)
• Dexamethasone
• Hydrocortisone/cortisone
• Antidysrhythmics
• Digoxin
• Sedatives/Hypnotics
• Midazolam
• Triazolam
• Direct oral anticoagulants (DOACs)
• Rivaroxaban
• Dabigatran
• Edoxaban
• HMG-CoA Reductase Inhibitors
• Atorvastatin
• Pitavastatin
• Rosuvastatin
• Lovastatin
• Simvastatin

Other interactions

• Herbal products
• St. John's wort (Hypericum perforatum)

• HIV-1 screening

Additional observations

• Adherence

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).

Injection 464mg (per 1.5ml)

• Lenacapavir 464mg solution for injection Gilead (Gilead)

Film-coated tablet 300mg

• Lenacapavir 300mg tablet Gilead (Gilead)