Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
Descovy should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

Emtricitabine

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low.
Co-administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.
Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Medicinal products that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. Medicinal products that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Descovy and development of resistance. Co-administration of Descovy with other medicinal products that inhibit P-gp and BCRP activity (e.g., cobicistat, ritonavir, ciclosporin) is expected to increase the absorption and plasma concentration of tenofovir alafenamide.
Based on data from an in vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.



Other interactions

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide is an inhibitor of other UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro.

Interactions between the components of Descovy and potential co-administered medicinal products are listed in Table 2 (increase is indicated as “↑”, decrease as “ ”, no change as “ ”). The interactions described are based on studies conducted with Descovy, or the components of Descovy as individual agents and/or in combination, or are potential drug-drug interactions that may occur with Descovy.

Table 2: Interactions between the individual components of Descovy and other medicinal products

Medicinal product by        Effects on medicinal product levels.        Recommendation concerning therapeutic areas1           Mean percent change in AUC,              co-administration with Descovy Cmax, Cmin2
ANTI-INFECTIVES
Antifungals
Ketoconazole                    Interaction not studied with either of     The recommended dose of Descovy Itraconazole                    the components of Descovy.                 is 200/10 mg once daily.

Co-administration of ketoconazole or itraconazole, which are potent P-gp inhibitors, is expected to increase plasma concentrations of tenofovir alafenamide.
Fluconazole                     Interaction not studied with either of     Dose Descovy according to the Isavuconazole                   the components of Descovy.                 concomitant antiretroviral (see section 4.2).
Co-administration of fluconazole or isavuconazole may increase plasma concentrations of tenofovir alafenamide.
Antimycobacterials
Rifabutin                       Interaction not studied with either of     Co-administration of Descovy and Rifampicin                      the components of Descovy.                 rifabutin rifampicin, or rifapentine Rifapentine                                                                is not recommended.
Co-administration of rifampicin,
rifabutin, and rifapentine, all of which are P-gp inducers, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.



Medicinal product by          Effects on medicinal product levels.     Recommendation concerning therapeutic areas1             Mean percent change in AUC,           co-administration with Descovy Cmax, Cmin2
Anti-hepatitis C virus medicinal products
Ledipasvir (90 mg once daily)/    Ledipasvir:                             No dose adjustment of ledipasvir or sofosbuvir (400 mg once daily),   AUC: ↑ 79%                              sofosbuvir is required. Dose emtricitabine (200 mg once        Cmax: ↑ 65%                             Descovy according to the daily)/ tenofovir alafenamide     Cmin: ↑ 93%                             concomitant antiretroviral (see (10 mg once daily) 3                                                      section 4.2).
Sofosbuvir:
AUC: ↑ 47%
Cmax: ↑ 29%

Sofosbuvir metabolite GS-331007:
AUC: ↑ 48%
Cmax:
Cmin: ↑ 66%

Emtricitabine:
AUC:
Cmax:
Cmin:
Tenofovir alafenamide:
AUC:
Cmax:
Ledipasvir (90 mg once daily)/    Ledipasvir:                             No dose adjustment of ledipasvir or sofosbuvir (400 mg once daily),   AUC:                                    sofosbuvir is required. Dose emtricitabine (200 mg once        Cmax:                                   Descovy according to the daily)/ tenofovir alafenamide     Cmin:                                   concomitant antiretroviral (see (25 mg once daily) 4                                                      section 4.2).
Sofosbuvir:
AUC:
Cmax:

Sofosbuvir metabolite GS-331007:
AUC:
Cmax:
Cmin:

Emtricitabine:
AUC:
Cmax:
Cmin:
Tenofovir alafenamide:
AUC: ↑ 32%
Cmax:



Medicinal product by          Effects on medicinal product levels.     Recommendation concerning therapeutic areas1             Mean percent change in AUC,           co-administration with Descovy Cmax, Cmin2
Sofosbuvir (400 mg once daily)/    Sofosbuvir:                            No dose adjustment of velpatasvir (100 mg once daily),   AUC: ↑ 37%                             sofosbuvir,velpatasvir or emtricitabine (200 mg once         Cmax:                                  voxilaprevir is required. Dose daily)/ tenofovir alafenamide                                             Descovy according to the (10 mg once daily)3                Sofosbuvir metabolite GS-331007:       concomitant antiretroviral (see AUC: ↑ 48%                             section 4.2).
Cmax:
Cmin: ↑ 58%

Velpatasvir:
AUC: ↑ 50%
Cmax: ↑ 30%
Cmin: ↑ 60%

Emtricitabine:
AUC:
Cmax:
Cmin:
Tenofovir alafenamide:
AUC:
Cmax: 20%
Sofosbuvir/velpatasvir/            Sofosbuvir: voxilaprevir                       AUC:
(400 mg/100 mg/100 mg+100 mg       Cmax: ↑ 27% once daily)7/ emtricitabine (200 mg once         Sofosbuvir metabolite GS-331007: daily)/ tenofovir alafenamide      AUC: ↑ 43%
(10 mg once daily)3                Cmax:

Velpatasvir:
AUC:
Cmin: ↑ 46%
Cmax:

Voxilaprevir:
AUC: ↑ 171%
Cmin: ↑ 350%
Cmax: ↑ 92%
Emtricitabine:
AUC:
Cmin:
Cmax:

Tenofovir alafenamide:
AUC:
Cmax: 21%



Medicinal product by          Effects on medicinal product levels.     Recommendation concerning therapeutic areas1             Mean percent change in AUC,           co-administration with Descovy Cmax, Cmin2
Sofosbuvir/velpatasvir/            Sofosbuvir:                            No dose adjustment of sofosbuvir, voxilaprevir                       AUC:                                   velpatasvir or voxilaprevir is (400 mg/100 mg/100 mg+100 mg       Cmax:                                  required. Dose Descovy according once daily)7/                                                             to the concomitant antiretroviral emtricitabine   (200 mg  once      Sofosbuvir metabolite GS-331007:       (see section 4.2).
daily)/ tenofovir alafenamide      AUC:
(25 mg once daily)4                Cmin:

Velpatasvir:
AUC:
Cmin:
Cmax:

Voxilaprevir:
AUC:
Cmin:
Cmax:
Emtricitabine:
AUC:
Cmin:
Cmax:

Tenofovir alafenamide:
AUC: ↑ 52%
Cmax: ↑ 32%
ANTIRETROVIRALS
HIV protease inhibitors
Atazanavir/cobicistat              Tenofovir alafenamide:                 The recommended dose of Descovy (300 mg/150 mg once daily),        AUC: ↑ 75%                             is 200/10 mg once daily.
tenofovir alafenamide (10 mg)      Cmax: ↑ 80%

Atazanavir:
AUC:
Cmax:
Cmin:
Atazanavir/ritonavir (300/100 mg   Tenofovir alafenamide:                 The recommended dose of Descovy once daily), tenofovir             AUC: ↑ 91%                             is 200/10 mg once daily.
alafenamide (10 mg)                Cmax: ↑ 77%

Atazanavir:
AUC:
Cmax:
Cmin:
Darunavir/cobicistat (800/150 mg   Tenofovir alafenamide:                 The recommended dose of Descovy once daily), tenofovir             AUC:                                   is 200/10 mg once daily.
alafenamide (25 mg once daily)5    Cmax:

Tenofovir:
AUC: ↑ 224%
Cmax: ↑ 216%
Cmin: ↑ 221%

Darunavir:
AUC:
Cmax:
Cmin:


Medicinal product by          Effects on medicinal product levels.       Recommendation concerning therapeutic areas1             Mean percent change in AUC,             co-administration with Descovy Cmax, Cmin2
Darunavir/ritonavir (800/100 mg    Tenofovir alafenamide:                   The recommended dose of Descovy once daily), tenofovir             AUC:                                     is 200/10 mg once daily.
alafenamide (10 mg once daily)     Cmax:

Tenofovir:
AUC: ↑ 105%
Cmax: ↑ 142%

Darunavir:
AUC:
Cmax:
Cmin:
Lopinavir/ritonavir (800/200 mg    Tenofovir alafenamide:                   The recommended dose of Descovy once daily), tenofovir             AUC: ↑ 47%                               is 200/10 mg once daily.
alafenamide (10 mg once daily)     Cmax: ↑ 119%

Lopinavir:
AUC:
Cmax:
Cmin:
Tipranavir/ritonavir               Interaction not studied with either of   Co-administration with Descovy is the components of Descovy.               not recommended.

Tipranavir/ritonavir results in P-gp induction. Tenofovir alafenamide exposure is expected to decrease when tipranavir/ritonavir is used in combination with Descovy.
Other protease inhibitors          Effect is unknown.                       There are no data available to make dosing recommendations for co-administration with other protease inhibitors.
Other HIV antiretrovirals
Dolutegravir (50 mg once daily),   Tenofovir alafenamide:                   The recommended dose of Descovy tenofovir alafenamide (10 mg       AUC:                                     is 200/25 mg once daily.
once daily)3                       Cmax:

Dolutegravir:
AUC:
Cmax:
Cmin:
Rilpivirine (25 mg once daily),    Tenofovir alafenamide:                   The recommended dose of Descovy tenofovir alafenamide (25 mg       AUC:                                     is 200/25 mg once daily.
once daily)                        Cmax:

Rilpivirine:
AUC:
Cmax:
Cmin:
Efavirenz (600 mg once daily),     Tenofovir alafenamide:                   The recommended dose of Descovy tenofovir alafenamide (40 mg       AUC: 14%                                 is 200/25 mg once daily.
once daily)4                       Cmax: 22%



Medicinal product by        Effects on medicinal product levels.         Recommendation concerning therapeutic areas1            Mean percent change in AUC,              co-administration with Descovy Cmax, Cmin2
Maraviroc                        Interaction not studied with either of     The recommended dose of Descovy Nevirapine                       the components of Descovy.                 is 200/25 mg once daily.
Raltegravir
Tenofovir alafenamide exposure is not expected to be affected by maraviroc, nevirapine or raltegravir, nor is it expected to affect the metabolic and excretion pathways relevant to maraviroc,
nevirapine or raltegravir.
ANTICONVULSANTS
Oxcarbazepine                    Interaction not studied with either of     Co-administration of Descovy and Phenobarbital                    the components of Descovy.                 oxcarbazepine, phenobarbital or Phenytoin                                                                   phenytoin is not recommended.
Co-administration of oxcarbazepine,
phenobarbital, or phenytoin, all of which are P-gp inducers, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Carbamazepine (titrated from     Tenofovir alafenamide:                     Co-administration of Descovy and 100 mg to 300 mg twice a day),   AUC: 55%                                   carbamazepine is not emtricitabine/tenofovir          Cmax: 57%                                  recommended.
alafenamide (200 mg/25 mg once daily)5, 6                       Co-administration of carbamazepine,
a P-gp inducer, decreases tenofovir alafenamide plasma concentrations,
which may result in loss of therapeutic effect and development of resistance.
ANTIDEPRESSANTS
Sertraline (50 mg once daily),   Tenofovir alafenamide:                     No dose adjustment of sertraline is tenofovir alafenamide (10 mg     AUC:                                       required. Dose Descovy according once daily)3                     Cmax:                                      to the concomitant antiretroviral (see section 4.2).
Sertraline:
AUC: ↑ 9%
Cmax: ↑ 14%
HERBAL PRODUCTS
St. John’s wort (Hypericum       Interaction not studied with either of     Co-administration of Descovy with perforatum)                      the components of Descovy.                 St. John’s wort is not recommended.
Co-administration of St. John’s wort,
a P-gp inducer, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
IMMUNOSUPPRESSANTS
Ciclosporin                      Interaction not studied with either of     The recommended dose of Descovy the components of Descovy.                 is 200/10 mg once daily.

Co-administration of ciclosporin, a potent P-gp inhibitor, is expected to increase plasma concentrations of tenofovir alafenamide.


Medicinal product by              Effects on medicinal product levels.         Recommendation concerning therapeutic areas1                 Mean percent change in AUC,               co-administration with Descovy Cmax, Cmin2
ORAL CONTRACEPTIVES
Norgestimate                          Norelgestromin:                             No dose adjustment of (0.180/0.215/0.250 mg once            AUC:                                        norgestimate/ethinylestradiol is daily), ethinylestradiol (0.025 mg    Cmin:                                       required. Dose Descovy according once daily),                          Cmax:                                       to the concomitant antiretroviral emtricitabine/tenofovir                                                           (see section 4.2).
alafenamide (200/25 mg once           Norgestrel: daily)5                               AUC:
Cmin:
Cmax:

Ethinylestradiol:
AUC:
Cmin:
Cmax:
SEDATIVES/HYPNOTICS
Orally administered midazolam         Midazolam:                                  No dose adjustment of midazolam (2.5 mg single dose), tenofovir       AUC:                                        is required. Dose Descovy alafenamide (25 mg once daily)        Cmax:                                       according to the concomitant Intravenously administered            Midazolam:                                  antiretroviral (see section 4.2).
midazolam (1 mg single dose),         AUC: tenofovir alafenamide (25 mg          Cmax: once daily)
1     When doses are provided, they are the doses used in clinical drug-drug interaction studies.
2     When data are available from drug-drug interaction studies.
3     Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination tablet.
4     Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablet.
5     Study conducted with Descovy.
6     Emtricitabine/tenofovir alafenamide was taken with food in this study.
7     Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposurers expected in HCV-infected patients.