Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
This medicinal product should not be co-administered with medicinal products containing tenofovir disoproxil, tenofovir alafenamide or adefovir dipivoxil.

Medicinal products that may affect tenofovir alafenamide

Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinal products that are P-gp inducers (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital or St. John’s wort) are expected to decrease plasma concentrations of tenofovir alafenamide, which may lead to loss of therapeutic effect of Vemlidy. Co-administration of such medicinal products with tenofovir alafenamide is not recommended.

Co-administration of tenofovir alafenamide with medicinal products that inhibit P-gp and BCRP may increase plasma concentrations of tenofovir alafenamide. Co-administration of strong inhibitors of P-gp with tenofovir alafenamide is not recommended.

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/or OATP1B3.

Effect of tenofovir alafenamide on other medicinal products

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 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.

Drug interaction information for Vemlidy with potential concomitant medicinal products is summarised in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”; twice daily as “b.i.d.”, single dose as “s.d.”, once daily as “q.d.”). The drug interactions described are based on studies conducted with tenofovir alafenamide, or are potential drug interactions that may occur with Vemlidy.

Table 1: Interactions Between Vemlidy and Other Medicinal Products

Medicinal product by         Effects on drug levels.a,b   Recommendation concerning co-administration therapeutic areas            Mean ratio (90%              with Vemlidy confidence interval) for
AUC, Cmax, Cmin
ANTICONVULSANTS
Carbamazepine                Tenofovir alafenamide        Co-administration is not recommended.
(300 mg orally, b.i.d.)      ↓ Cmax 0.43 (0.36, 0.51)
↓ AUC 0.45 (0.40, 0.51)
Tenofovir alafenamidec
(25 mg orally, s.d.)         Tenofovir
↓ Cmax 0.70 (0.65, 0.74)
↔ AUC 0.77 (0.74, 0.81)
Oxcarbazepine                Interaction not studied.     Co-administration is not recommended.
Phenobarbital                Expected:
↓ Tenofovir alafenamide
Phenytoin                    Interaction not studied.     Co-administration is not recommended.
Expected:
↓ Tenofovir alafenamide
Midazolamd                   Midazolam                    No dose adjustment of midazolam (administered (2.5 mg orally, s.d.)        ↔ Cmax 1.02 (0.92, 1.13)     orally or intravenously) is required.
↔ AUC 1.13 (1.04, 1.23)
Tenofovir alafenamidec
(25 mg orally, q.d.)
Midazolamd                   Midazolam
(1 mg intravenously, s.d.)   ↔ Cmax 0.99 (0.89, 1.11)
↔ AUC 1.08 (1.04, 1.14)
Tenofovir alafenamidec
(25 mg orally, q.d.)
ANTIDEPRESSANTS
Sertraline                   Tenofovir alafenamide        No dose adjustment of Vemlidy or sertraline is (50 mg orally, s.d.)         ↔ Cmax 1.00 (0.86, 1.16)     required.
↔ AUC 0.96 (0.89, 1.03)
Tenofovir alafenamidee
(10 mg orally, q.d.)         Tenofovir
↔ Cmax 1.10 (1.00, 1.21)
↔ AUC 1.02 (1.00, 1.04)
↔ Cmin 1.01 (0.99, 1.03)
Sertraline                   Sertraline
(50 mg orally, s.d.)         ↔ Cmax 1.14 (0.94, 1.38)
↔ AUC 0.93 (0.77, 1.13)
Tenofovir alafenamidee
(10 mg orally, q.d.)
ANTIFUNGALS


Medicinal product by        Effects on drug levels.a,b   Recommendation concerning co-administration therapeutic areas           Mean ratio (90%              with Vemlidy confidence interval) for
AUC, Cmax, Cmin
Itraconazole                Interaction not studied.     Co-administration is not recommended.
Ketoconazole                Expected:
↑ Tenofovir alafenamide
ANTIMYCOBACTERIALS
Rifampicin                  Interaction not studied.     Co-administration is not recommended.
Rifapentine                 Expected:
↓ Tenofovir alafenamide
Rifabutin                   Interaction not studied.     Co-administration is not recommended.
Expected:
↓ Tenofovir alafenamide
HCV ANTIVIRAL AGENTS
Sofosbuvir (400 mg orally,  Interaction not studied.     No dose adjustment of Vemlidy or sofosbuvir is q.d.)                       Expected:                    required.
↔ Sofosbuvir
↔ GS-331007
Ledipasvir/sofosbuvir       Ledipasvir                   No dose adjustment of Vemlidy or (90 mg/400 mg orally, q.d.) ↔ Cmax 1.01 (0.97, 1.05)     ledipasvir/sofosbuvir is required.
↔ AUC 1.02 (0.97, 1.06)
Tenofovir alafenamidef      ↔ Cmin 1.02 (0.98, 1.07)
(25 mg orally, q.d.)
Sofosbuvir
↔ Cmax 0.96 (0.89, 1.04)
↔ AUC 1.05 (1.01, 1.09)

GS-331007g
↔ Cmax 1.08 (1.05, 1.11)
↔ AUC 1.08 (1.06, 1.10)
↔ Cmin 1.10 (1.07, 1.12)

Tenofovir alafenamide
↔ Cmax 1.03 (0.94, 1.14)
↔ AUC 1.32 (1.25, 1.40)
Tenofovir
↑ Cmax 1.62 (1.56, 1.68)
↑ AUC 1.75 (1.69, 1.81)
↑ Cmin 1.85 (1.78, 1.92)
Sofosbuvir/velpatasvir      Interaction not studied.     No dose adjustment of Vemlidy or (400 mg/100 mg orally,      Expected:                    sofosbuvir/velpatasvir is required.
q.d.)                       ↔ Sofosbuvir
↔ GS-331007
↔ Velpatasvir
↑ Tenofovir alafenamide



Medicinal product by       Effects on drug levels.a,b   Recommendation concerning co-administration therapeutic areas          Mean ratio (90%              with Vemlidy confidence interval) for
AUC, Cmax, Cmin
Sofosbuvir/velpatasvir/    Sofosbuvir                   No dose adjustment of Vemlidy or voxilaprevir               ↔ Cmax 0.95 (0.86, 1.05)     sofosbuvir/velpatasvir/voxilaprevir is required.
(400 mg/100 mg/            ↔ AUC 1.01 (0.97, 1.06)
100 mg + 100 mgi orally,
q.d.)                      GS-331007g
↔ Cmax 1.02 (0.98, 1.06)
Tenofovir alafenamidef     ↔ AUC 1.04 (1.01, 1.06)
(25 mg orally, q.d.)
Velpatasvir
↔ Cmax 1.05 (0.96, 1.16)
↔ AUC 1.01 (0.94, 1.07)
↔ Cmin 1.01 (0.95, 1.09)

Voxilaprevir
↔ Cmax 0.96 (0.84, 1.11)
↔ AUC 0.94 (0.84, 1.05)
↔ Cmin 1.02 (0.92, 1.12)

Tenofovir alafenamide
↑ Cmax 1.32 (1.17, 1.48)
↑ AUC 1.52 (1.43, 1.61)
HIV ANTIRETROVIRAL AGENTS – PROTEASE INHIBITORS
Atazanavir/cobicistat  Tenofovir alafenamide    Co-administration is not recommended.
(300 mg/150 mg orally, ↑ Cmax 1.80 (1.48, 2.18) q.d.)                  ↑ AUC 1.75 (1.55, 1.98)
Tenofovir alafenamidec     Tenofovir
(10 mg orally, q.d.)       ↑ Cmax 3.16 (3.00, 3.33)
↑ AUC 3.47 (3.29, 3.67)
↑ Cmin 3.73 (3.54, 3.93)

Atazanavir
↔ Cmax 0.98 (0.94, 1.02)
↔ AUC 1.06 (1.01, 1.11)
↔ Cmin 1.18 (1.06, 1.31)

Cobicistat
↔ Cmax 0.96 (0.92, 1.00)
↔ AUC 1.05 (1.00, 1.09)
↑ Cmin 1.35 (1.21, 1.51)
Atazanavir/ritonavir       Tenofovir alafenamide        Co-administration is not recommended.
(300 mg/100 mg orally,     ↑ Cmax 1.77 (1.28, 2.44) q.d.)                      ↑ AUC 1.91 (1.55, 2.35)
Tenofovir alafenamidec     Tenofovir
(10 mg orally, s.d.)       ↑ Cmax 2.12 (1.86, 2.43)
↑ AUC 2.62 (2.14, 3.20)

Atazanavir
↔ Cmax 0.98 (0.89, 1.07)
↔ AUC 0.99 (0.96, 1.01)
↔ Cmin 1.00 (0.96, 1.04)



Medicinal product by       Effects on drug levels.a,b   Recommendation concerning co-administration therapeutic areas          Mean ratio (90%              with Vemlidy confidence interval) for
AUC, Cmax, Cmin
Darunavir/cobicistat       Tenofovir alafenamide        Co-administration is not recommended.
(800 mg/150 mg orally,     ↔ Cmax 0.93 (0.72, 1.21) q.d.)                      ↔ AUC 0.98 (0.80, 1.19)

Tenofovir alafenamidec     Tenofovir
(25 mg orally, q.d.)       ↑ Cmax 3.16 (3.00, 3.33)
↑ AUC 3.24 (3.02, 3.47)
↑ Cmin 3.21 (2.90, 3.54)

Darunavir
↔ Cmax 1.02 (0.96, 1.09)
↔ AUC 0.99 (0.92, 1.07)
↔ Cmin 0.97 (0.82, 1.15)
Cobicistat
↔ Cmax 1.06 (1.00, 1.12)
↔ AUC 1.09 (1.03, 1.15)
↔ Cmin 1.11 (0.98, 1.25)
Darunavir/ritonavir        Tenofovir alafenamide        Co-administration is not recommended.
(800 mg/100 mg orally,     ↑ Cmax 1.42 (0.96, 2.09) q.d.)                      ↔ AUC 1.06 (0.84, 1.35)

Tenofovir alafenamidec     Tenofovir
(10 mg orally, s.d.)       ↑ Cmax 2.42 (1.98, 2.95)
↑ AUC 2.05 (1.54, 2.72)

Darunavir
↔ Cmax 0.99 (0.91, 1.08)
↔ AUC 1.01 (0.96, 1.06)
↔ Cmin 1.13 (0.95, 1.34)
Lopinavir/ritonavir        Tenofovir alafenamide        Co-administration is not recommended.
(800 mg/200 mg orally,     ↑ Cmax 2.19 (1.72, 2.79) q.d.)                      ↑ AUC 1.47 (1.17, 1.85)
Tenofovir alafenamidec     Tenofovir
(10 mg orally, s.d.)       ↑ Cmax 3.75 (3.19, 4.39)
↑ AUC 4.16 (3.50, 4.96)

Lopinavir
↔ Cmax 1.00 (0.95, 1.06)
↔ AUC 1.00 (0.92, 1.09)
↔ Cmin 0.98 (0.85, 1.12)
Tipranavir/ritonavir   Interaction not studied. Co-administration is not recommended.
Expected:
↓ Tenofovir alafenamide
HIV ANTIRETROVIRAL AGENTS – INTEGRASE INHIBITORS
Dolutegravir           Tenofovir alafenamide    No dose adjustment of Vemlidy or dolutegravir is (50 mg orally, q.d.)   ↑ Cmax 1.24 (0.88, 1.74) required.
↑ AUC 1.19 (0.96, 1.48)
Tenofovir alafenamidec
(10 mg orally, s.d.)   Tenofovir
↔ Cmax 1.10 (0.96, 1.25)
↑ AUC 1.25 (1.06, 1.47)

Dolutegravir
↔ Cmax 1.15 (1.04, 1.27)
↔ AUC 1.02 (0.97, 1.08)
↔ Cmin 1.05 (0.97, 1.13)

Medicinal product by   Effects on drug levels.a,b Recommendation concerning co-administration therapeutic areas      Mean ratio (90%            with Vemlidy confidence interval) for
AUC, Cmax, Cmin
Raltegravir            Interaction not studied.   No dose adjustment of Vemlidy or raltegravir is Expected:                  required.
↔ Tenofovir alafenamide
↔ Raltegravir
HIV ANTIRETROVIRAL AGENTS – NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Efavirenz              Tenofovir alafenamide      No dose adjustment of Vemlidy or efavirenz is (600 mg orally, q.d.)  ↓ Cmax 0.78 (0.58, 1.05)   required.
↔ AUC 0.86 (0.72, 1.02)
Tenofovir alafenamideh
(40 mg orally, q.d.)   Tenofovir
↓ Cmax 0.75 (0.67, 0.86)
↔ AUC 0.80 (0.73, 0.87)
↔ Cmin 0.82 (0.75, 0.89)

Expected:
↔ Efavirenz
Nevirapine                         Interaction not studied.          No dose adjustment of Vemlidy or nevirapine is Expected:                         required.
↔ Tenofovir alafenamide
↔ Nevirapine
Rilpivirine                        Tenofovir alafenamide             No dose adjustment of Vemlidy or rilpivirine is (25 mg orally, q.d.)               ↔ Cmax 1.01 (0.84, 1.22)          required.
↔ AUC 1.01 (0.94, 1.09)
Tenofovir alafenamide
(25 mg orally, q.d.)               Tenofovir
↔ Cmax 1.13 (1.02, 1.23)
↔ AUC 1.11 (1.07, 1.14)
↔ Cmin 1.18 (1.13, 1.23)

Rilpivirine
↔ Cmax 0.93 (0.87, 0.99)
↔ AUC 1.01 (0.96, 1.06)
↔ Cmin 1.13 (1.04, 1.23)
HIV ANTIRETROVIRAL AGENTS – CCR5 RECEPTOR ANTAGONIST
Maraviroc               Interaction not studied. No dose adjustment of Vemlidy or maraviroc is Expected:                required.
↔ Tenofovir alafenamide
↔ Maraviroc
HERBAL SUPPLEMENTS
St. John’s wort         Interaction not studied. Co-administration is not recommended.
(Hypericum perforatum)  Expected:
↓ Tenofovir alafenamide
ORAL CONTRACEPTIVES
Norgestimate            Norelgestromin           No dose adjustment of Vemlidy or (0.180 mg/0.215 mg/     ↔ Cmax 1.17 (1.07, 1.26) norgestimate/ethinyl estradiol is required.
0.250 mg orally, q.d.)  ↔ AUC 1.12 (1.07, 1.17)
↔ Cmin 1.16 (1.08, 1.24)
Ethinylestradiol
(0.025 mg orally, q.d.) Norgestrel
↔ Cmax 1.10 (1.02, 1.18)
Tenofovir alafenamidec  ↔ AUC 1.09 (1.01, 1.18)
(25 mg orally, q.d.)    ↔ Cmin 1.11 (1.03, 1.20)

Ethinylestradiol
↔ Cmax 1.22 (1.15, 1.29)
↔ AUC 1.11 (1.07, 1.16)
↔ Cmin 1.02 (0.93, 1.12) a. All interaction studies are conducted in healthy volunteers

b. All No Effect Boundaries are 70%-143%.
c. Study conducted with emtricitabine/tenofovir alafenamide fixed-dose combination tablet d. A sensitive CYP3A4 substrate e. Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination tablet f. Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablet g. The predominant circulating nucleoside metabolite of sofosbuvir h. Study conducted with tenofovir alafenamide 40 mg and emtricitabine 200 mg i. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.