Lenacapavir

Moderate inducers of CYP3A and P-gp, such as efavirenz, may also significantly decrease plasma concentrations of lenacapavir, therefore co-administration is not recommended.

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.

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.

Lenacapavir has not been studied in patients with end stage renal disease (CrCl <15 mL/min or on renal replacement therapy), therefore lenacapavir should be used with caution in these patients.

Lenacapavir has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), therefore lenacapavir should be used with caution in these patients.

Interaction not studied.

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

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.

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.

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.

Caution is warranted when midazolam or triazolam, is co-administered with lenacapavir.

Midazolam

Midazolam^d,i,n (2.5 mg single dose; oral; simultaneous administration)

Mean percent change in AUC, C_max:

Midazolam:

AUC: ↑ 259%
C_max: ↑ 94%

1-hydroxymidazolam°:

AUC: ↓ 24%
C_max: ↓ 46%

Midazolam^d,i,n (2.5 mg single dose; oral; 1 day after lenacapavir)

Mean percent change in AUC, C_max:

Midazolam:

AUC: ↑ 308%
C_max: ↑ 116%

1-hydroxymidazolam°:

AUC: ↓ 16%
C_max: ↓ 48%

^d Fed.
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.
ⁿ Evaluated as a CYP3A substrate.
^o Major active metabolite of midazolam

Triazolam

Interaction not studied.

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

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.

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.

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

In order to avoid transmission of HIV to the infant it is recommended that HIV-infected women 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.

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

Summary of the safety profile

The most common adverse reactions in heavily treatment experienced adult patients with HIV were injection site reactions (ISRs) (63%) and nausea (4%).

Tabulated list of adverse reactions

A tabulated list of adverse reactions is presented below. 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).

Tabulated list of adverse reactions:

^a Frequency based on all patients (Cohorts 1 and 2) in CAPELLA.
^b Includes injection site swelling, pain, nodule, erythema, induration, pruritus, extravasation, discomfort, mass, haematoma, oedema, and ulcer.

Description of selected adverse reactions

Immune Reconstitution Inflammatory Syndrome

In HIV infected patients 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.

Local injection site reactions

Most patients had ISRs that were mild (Grade 1, 42%) or moderate (Grade 2, 18%). Three percent of patients experienced a severe (Grade 3) ISR that resolved within 1 to 8 days. No patients experienced a Grade 4 ISR. The median duration of all ISRs excluding nodules and indurations was 6 days. The median duration of nodules and indurations was 180 and 118 days, respectively.