Interactions : אינטראקציות

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              Effects on concentrations.          Recommendation concerning therapeutic areas               Mean percent change in AUC,            co-administration with Cmax                             Sunlenca
ANTIMYCOBACTERIALS
Rifampicina,b,c (600 mg once daily)   Lenacapavir:                         Co-administration is AUC: ↓84%                            contraindicated (see section 4.3).
Cmax: ↓55%
Rifabutin                             Interaction not studied.             Co-administration is not recommended (see section 4.4).
Co-administration of rifabutin may decrease lenacapavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
ANTICONVULSANTS
Carbamazepine                         Interaction not studied.             Co-administration is Phenytoin                                                                  contraindicated (see section 4.3).
Oxcarbazepine                         Co-administration of                 Co-administration is not Phenobarbital                         carbamazepine, oxcarbazepine,        recommended (see section 4.4).
phenobarbital, or phenytoin with lenacapavir may decrease             Alternative anticonvulsants lenacapavir plasma concentrations,   should be considered.
which may result in loss of therapeutic effect and development of resistance.


Medicinal product by              Effects on concentrations.           Recommendation concerning therapeutic areas               Mean percent change in AUC,             co-administration with Cmax                              Sunlenca
HERBAL PRODUCTS
St. John’s wort (Hypericum            Interaction not studied.              Co-administration is perforatum)                                                                 contraindicated (see section 4.3).
Co-administration of St.
John’s wort may decrease lenacapavir plasma concentrations,
which may result in loss of therapeutic effect and development of resistance.
ANTIRETROVIRAL AGENTS
Atazanavir/cobicistatb,d,e            Lenacapavir:                          Co-administration is not (300 mg/150 mg once daily)            AUC: ↑ 321%                           recommended (see section 4.4).
Cmax: ↑ 560%
Efavirenzb,d,f (600 mg once daily)    Lenacapavir:
AUC:↓ 56%
Cmax:↓ 36%
Etravirine                            Interaction not studied.
Nevirapine
Tipranavir/ritonavir                  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:                          No dose adjustment of AUC: ↑ 128%                           lenacapavir is required.
Cmax:↑ 110%
Darunavir/cobicistatb,d,h             Lenacapavir:
(800 mg/150 mg once daily)            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:                No dose adjustment of tenofovir AUC:↑ 32%                             alafenamide is required.
Cmax:↑ 24%

Tenofovirk:
AUC:↑ 47%
Cmax:↑ 23%
ERGOT DERIVATIVES
Dihydroergotamine                     Interaction not studied.              Caution is warranted when Ergotamine                                                                  dihydroergotamine or ergotamine, Plasma concentrations of these                    is co-administered with Sunlenca.
medicinal products may be increased when co-administered with lenacapavir.
PHOSPHODIESTERASE-5 (PDE-5) INHIBITORS
Sildenafil                Interaction not studied.                          Use of PDE-5 inhibitors for Tadalafil                                                                   pulmonary arterial hypertension: Vardenafil                Plasma concentration of PDE-5                     Co-administration with tadalafil is inhibitors may be increased when                  not recommended.
co-administered with lenacapavir.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil: A starting dose of
25 mg is recommended.
Medicinal product by             Effects on concentrations.          Recommendation concerning therapeutic areas              Mean percent change in AUC,             co-administration with Cmax                               Sunlenca
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)
Dexamethasone                       Interaction not studied.            Co-administration of Sunlenca Hydrocortisone/cortisone                                                with corticosteroids whose Plasma concentrations of            exposures are significantly corticosteroids may be increased    increased by CYP3A inhibitors when co-administered with           can increase the risk for Cushing's lenacapavir.                        syndrome and adrenal suppression. Initiate with the lowest starting dose and titrate
Plasma concentrations of            carefully while monitoring for lenacapavir may decrease when       safety.
co-administered with systemic dexamethasone, which may result     Caution is warranted when in loss of therapeutic effect and   systemic dexamethasone is development of resistance.          co-administered with Sunlenca,
particularly for long-term use.
Alternative corticosteroids should be considered.
HMG-CoA REDUCTASE INHIBITORS
Lovastatin                           Interaction not studied.           Initiate lovastatin and simvastatin Simvastatin                                                             with the lowest starting dose and Plasma concentrations of these     titrate carefully while monitoring medicinal products may be          for safety (e.g. myopathy).
Atorvastatin                         increased when co-administered     No dose adjustment of with lenacapavir.                  atorvastatin is required.
Pitavastatind,i,l (2 mg single dose; Pitavastatin:                      No dose adjustment of simultaneous or 3 days after         AUC:↔                              pitavastatin and rosuvastatin is lenacapavir)                         Cmax:↔                             required.
Rosuvastatind,i,m (5 mg single       Rosuvastatin: dose)                                AUC:↑ 31%
Cmax:↑ 57%
ANTIARRHYTHMICS
Digoxin                              Interaction not studied.           Caution is warranted and therapeutic concentration
Plasma concentration of digoxin     monitoring of digoxin is may be increased when               recommended.
co-administered with lenacapavir.


Medicinal product by                 Effects on concentrations.              Recommendation concerning therapeutic areas                  Mean percent change in AUC,                co-administration with Cmax                                 Sunlenca
SEDATIVES/HYPNOTICS
Midazolamd,i,n (2.5 mg single dose;     Midazolam:                               Caution is warranted when oral; simultaneous administration)      AUC: ↑ 259%                              midazolam or triazolam, is Cmax: ↑ 94%                              co-administered with Sunlenca.

1-hydroxymidazolamo:
AUC: ↓ 24%
Cmax: ↓ 46%
Midazolamd,i,n (2.5 mg single           Midazolam: dose; oral;1 day after lenacapavir)     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              Interaction not studied.                 Due to potential bleeding risk, (DOACs)                                                                          dose adjustment of DOAC may be Rivaroxaban                             Plasma concentration of DOAC             required. Consult the Summary of Dabigatran                              may be increased when                    Product Characteristics of the Edoxaban                                co-administered with lenacapavir.        DOAC for further information on use in combination with moderate
CYP3A inhibitor and/or P-gp inhibitors.
ANTIFUNGALS
Voriconazolea,b,p,q (400 mg twice       Lenacapavir:                             No dose adjustment of daily/200 mg twice daily)               AUC:↑ 41%                                lenacapavir is required.
Cmax:↔
Itraconazole                            Interaction not studied.
Ketoconazole
Plasma concentration of lenacapavir may be increased when co-administered with itraconazole or ketoconazole.
H2-RECEPTOR ANTAGONISTS
Famotidinea,b (40 mg once daily, 2      Famotidine:                              No dose adjustment of famotidine hours before lenacapavir)               AUC:↑ 28%                                is required.
Cmax:↔
ORAL CONTRACEPTIVES
Ethinylestradiol                        Interaction not studied.                 No dose adjustment of Progestins                                                                       ethinylestradiol and progestins is Plasma concentrations of                                  required.
ethinylestradiol and progestins may be increased when co-administered with lenacapavir.
GENDER AFFIRMING HORMONES
17β-estradiol          Interaction not studied.                                  No dose adjustment of these Anti-androgens                                                                   gender affirming hormones is Progestogen            Plasma concentrations of these                            required.
Testosterone           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 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.