Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
As Vosevi contains sofosbuvir, velpatasvir and voxilaprevir, any interactions that have been identified with these active substances individually may occur with Vosevi.

Pharmacokinetic interactions

Potential for Vosevi to affect other medicinal products
Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Vosevi with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. Medicinal products that are sensitive substrates of these transporters and for which elevated plasma levels are associated with serious events are contraindicated (see Table 2).
Dabigatran etexilate (P-gp substrate) and rosuvastatin (OATP1B and BCRP substrate) are contraindicated (see section 4.3 and Table 2).

Potential for other medicinal products to affect Vosevi

Sofosbuvir, velpatasvir and voxilaprevir are substrates of drug transporters P-gp and BCRP.
Velpatasvir and voxilaprevir are substrates of drug transporters OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8 and CYP3A4 and of voxilaprevir primarily by CYP3A4 was observed.

Medicinal products that may decrease plasma exposure of Vosevi
Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) may decrease plasma concentrations of sofosbuvir, velpatasvir and/or voxilaprevir leading to reduced therapeutic effect of Vosevi. The use of such medicinal products with Vosevi is contraindicated (see section 4.3 and Table 2).

Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir, velpatasvir and/or voxilaprevir plasma concentrations leading to reduced therapeutic effect of Vosevi. Co-administration with such medicinal products is not recommended with Vosevi (see section 4.4 and Table 2).

Medicinal products that may increase plasma exposure of Vosevi
Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir, velpatasvir or voxilaprevir plasma concentrations. Medicinal products that inhibit OATP1B, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir or voxilaprevir.
The use of strong inhibitors of OATP1B (e.g. ciclosporin) with Vosevi is not recommended (see section 4.4 and Table 2). Clinically significant medicinal product interactions with Vosevi mediated by P-gp, BCRP and CYP inhibitors are not expected. Vosevi may be co-administered with P-gp, BCRP and CYP inhibitors.

Pharmacodynamic interactions

Patients treated with vitamin K antagonists
As liver function may change during treatment with Vosevi, close monitoring of International Normalised Ratio (INR) values is recommended.

Impact of DAA therapy on medicinal products metabolized by the liver

The pharmacokinetics of medicinal products that are metabolized by the liver (e.g.
immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV.

Patients treated with ethinylestradiol-containing medicinal products

Concomitant use with ethinylestradiol-containing medicinal products may increase the risk of alanine aminotransferase (ALT) elevations and is contraindicated (see section 4.3 and Table 2).

Interactions between Vosevi and other medicinal products

Table 2 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined interaction boundaries). The medicinal product interactions described are based on studies conducted with either sofosbuvir/velpatasvir/voxilaprevir, its components (sofosbuvir, velpatasvir, and/or voxilaprevir), or are predicted medicinal product interactions that may occur with Vosevi. The table is not all-inclusive.

Table 2: Interactions between Vosevi and other medicinal products
Medicinal product by         Effects on medicinal product levels.
therapeutic                  Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                   Recommendation concerning of interaction               Active                 Cmax   AUC     Cmin    co-administration with Vosevi ACID REDUCING AGENTS
Antacids e.g. Aluminium or            Interaction not studied.                      It is recommended to separate magnesium hydroxide;         Expected:                                     antacid and Vosevi calcium carbonate            ↔ Sofosbuvir                                  administration by 4 hours.
↓ Velpatasvir
(Increase in gastric pH      ↔ Voxilaprevir decreases velpatasvir solubility)
H2-receptor antagonists
Famotidine                   Observed:                                     H2-receptor antagonists may be (40 mg single dose) +        Sofosbuvir             ↔      ↔               administered simultaneously sofosbuvir/velpatasvir/                                                    with or staggered from Vosevi at voxilaprevir                                                               a dose that does not exceed doses (400/100/100 mg single                                                     comparable with famotidine dose)c                       Velpatasvir            ↔      ↔               40 mg twice daily.

Famotidine dosed simultaneously with
Vosevi
Voxilaprevir        ↔        ↔
Cimetidined
Nizatidined


Medicinal product by        Effects on medicinal product levels.
therapeutic                 Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                 Recommendation concerning of interaction              Active              Cmax     AUC      Cmin   co-administration with Vosevi Ranitidined

(Increase in gastric pH decreases velpatasvir solubility)

Famotidine                  Observed:
(40 mg single dose) +       Sofosbuvir          ↔        ↔ sofosbuvir/velpatasvir/ voxilaprevir (400/100/
100 mg single dose)c
Velpatasvir         ↔        ↔
Famotidine dosed 12 hours prior to Vosevi
(Increase in gastric pH
Voxilaprevir        ↔        ↔ decreases velpatasvir solubility)

Proton pump inhibitors
Omeprazole                  Observed:                                    Proton pump inhibitors may be (20 mg once daily) +        Sofosbuvir          ↓        ↓               administered with Vosevi at a sofosbuvir/velpatasvir/                         0.77     0.73            dose that does not exceed doses voxilaprevir (400/100/                          (0.65,   (0.67,          comparable with omeprazole 100 mg single dose)c                            0.91)    0.79)           20 mg.
Velpatasvir         ↓        ↓
Omeprazole dosed 2 hours                        0.43     0.46 prior to Vosevi                                 (0.38,   (0.41,
0.49)    0.52)
Lansoprazoled
Rabeprazoled
Pantoprazoled
Voxilaprevir        ↓        ↔
Esomeprazoled
0.76
(0.69,
(Increase in gastric pH
0.85) decreases velpatasvir solubility)

Omeprazole                  Observed:
(20 mg once daily) +        Sofosbuvir          ↔        ↔ sofosbuvir/velpatasvir/ voxilaprevir (400/100/
100 mg single dose)c
Velpatasvir         ↓        ↓
Omeprazole dosed 4 hours
0.49     0.49 after Vosevi
(0.43,   (0.43,
0.55)    0.55)
(Increase in gastric pH
Voxilaprevir        ↔        ↔ decreases velpatasvir solubility)


Medicinal product by       Effects on medicinal product levels.
therapeutic                Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                      Recommendation concerning of interaction             Active                 Cmax     AUC       Cmin     co-administration with Vosevi ANTIARRHYTHMICS
Amiodarone                 Effect on amiodarone, voxilaprevir, velpatasvir,   Coadministration of amiodarone and sofosbuvir concentrations unknown.             with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia.
Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with
Vosevi (see sections 4.4 and 4.8).
Digoxin                    Interaction only studied with velpatasvir.         Co-administration of Vosevi Expected:                                          with digoxin may increase the ↔ Sofosbuvir                                       concentration of digoxin.
↔ Voxilaprevir                                     Caution is warranted and Digoxin (0.25 mg single    Effect on velpatasvir exposure not studied         therapeutic concentration dose)e + velpatasvir       Expected:                                          monitoring of digoxin is (100 mg single dose)       ↔ Velpatasvir                                      recommended.

(Inhibition of P-gp)       Observed:
Digoxin                ↑        ↑
1.88     1.34
(1.71,   (1.13,
2.08)    1.60)
ANTICOAGULANTS
Dabigatran etexilate       Effect on sofosbuvir, velpatasvir and              Vosevi is contraindicated with (75 mg single dose) +      voxilaprevir concentrations not studied            dabigatran etexilate (see sofosbuvir/velpatasvir/    Expected:                                          section 4.3).
voxilaprevir (400/100/     ↔ Sofosbuvir
100 mg single dose) +      ↔ Velpatasvir voxilaprevir (100 mg       ↔ Voxilaprevir single dose)f              Observed:
Dabigatran             ↑        ↑
(Inhibition of P-gp)                              2.87     2.61
(2.61,   (2.41,
3.15)    2.82)
Edoxaban                   Interaction not studied.                           Co-administration of Vosevi Expected:                                          with edoxaban is not (Inhibition of OATP1B1)    ↑ Edoxaban (active metabolite)                     recommended. Should direct Xa ↔ Sofosbuvir                                       inhibitor use be deemed ↔ Velpatasvir                                      necessary, apixaban or ↔ Voxilaprevir                                     rivaroxaban may be considered.
Vitamin K antagonists      Interaction not studied.                           Close monitoring of INR is recommended when Vosevi is
(Liver function changes                                                       co-administered with all vitamin during treatment with                                                         K antagonists.
Vosevi).
ANTICONVULSANTS
Phenytoin                  Interaction not studied.                           Vosevi is contraindicated with Phenobarbital              Expected:                                          phenobarbital and phenytoin (see ↓ Sofosbuvir                                       section 4.3).
↓ Velpatasvir

Medicinal product by       Effects on medicinal product levels.
therapeutic                Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                  Recommendation concerning of interaction             Active                Cmax      AUC     Cmin   co-administration with Vosevi ↓ Voxilaprevir
(Induction of P-gp and
CYPs)
Carbamazepine              Interaction not studied.                       Vosevi is contraindicated with Expected:                                      carbamazepine (see section 4.3).
(Induction of P-gp and     ↓ Velpatasvir
CYPs)                      ↓ Voxilaprevir
Observed:
Sofosbuvir             ↓        ↓
0.52     0.52
(0.43,   (0.46
0.62)    ,
0.59)


Medicinal product by          Effects on medicinal product levels.
therapeutic                   Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                       Recommendation concerning of interaction                Active                Cmax      AUC       Cmin   co-administration with Vosevi ANTIFUNGALS
Ketoconazole                  Interaction only studied with velpatasvir        No dose adjustment of Vosevi or Expected:                                        ketoconazole is required.
(Inhibition of P-gp and       ↔ Sofosbuvir
CYP3A)                        ↑ Voxilaprevir
Ketoconazole (200 mg          Effect on ketoconazole exposure not studied.
twice daily) + velpatasvir    Expected:
(100 mg single dose)f         ↔ Ketoconazole
Observed:
Itraconazoled                 Velpatasvir            ↑        ↑
Posaconazoled                                        1.29     1.71
Isavuconazoled                                       (1.02,   (1.35,
1.64)    2.18)

(Inhibition of P-gp and
CYP3A)
Voriconazole                  Interaction only studied with voxilaprevir.      No dose adjustment of Vosevi or Expected:                                        voriconazole is required.
(Inhibition of CYP3A)         ↔ Sofosbuvir
↑ Velpatasvir
Voriconazole (200 mg          Observed: twice daily) + voxilaprevir   Voxilaprevir          ↔         ↑
(100 mg single dose)f                                         1.84
(1.66,
2.03)
ANTIMYCOBACTERIALS
Rifampicin (single dose)   Interaction only studied with velpatasvir and       Vosevi is contraindicated with voxilaprevir.                                       rifampicin (see section 4.3).
(Inhibition of OATP1B)
Expected:
↔ Rifampicin
↔ Sofosbuvir
Rifampicin (600 mg single  Observed: dose) + velpatasvir        Velpatasvir           ↑         ↑
(100 mg single dose)f                            1.28      1.46
(1.05,    (1.17,
1.56)     1.83)
Rifampicin (600 mg single  Voxilaprevir          ↑         ↑ dose) + voxilaprevir                             11.10     7.91
(100 mg single dose)f                            (8.23,    (6.20,
14.98)    10.09)
Rifampicin (multiple dose) Effect on rifampicin exposure not studied.

(Induction of P-gp and        Expected:
CYPs)                         ↔ Rifampicin
Rifampicin (600 mg once       Observed: daily) + sofosbuvir           Sofosbuvir           ↓          ↓
(400 mg single dose)f                              0.23       0.28
(0.19,     (0.24,
0.29)      0.32)

Medicinal product by         Effects on medicinal product levels.
therapeutic                  Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                        Recommendation concerning of interaction               Active                Cmax     AUC       Cmin      co-administration with Vosevi Rifampicin (600 mg once      Velpatasvir          ↓         ↓ daily) + velpatasvir                              0.29      0.18
(100 mg single dose)f                             (0.23,    (0.15,
0.37)     0.22)
Rifampicin (600 mg once      Voxilaprevir         ↔         ↓ daily) + voxilaprevir                                       0.27
(100 mg single dose)f                                       (0.23,
0.31)
Rifabutin              Interaction not studied.                            Vosevi is contraindicated with Expected:                                           rifabutin (see section 4.3).
↓ Velpatasvir
↓ Voxilaprevir
(Induction of P-gp and Observed:              ↓       ↓
CYPs)                  Sofosbuvir             0.64    0.76
(0.53 (0.63,
,       0.91)
0.77)
Rifapentine            Interaction not studied.                            Co-administration of Vosevi Expected:                                           with rifapentine is not (Induction of P-gp and ↓ Sofosbuvir                                        recommended (see section 4.4).
CYPs)                  ↓ Velpatasvir
↓ Voxilaprevir
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Tenofovir disoproxil   Vosevi has been shown to increase tenofovir exposure (P-gp inhibition). There was fumarate               an increase in tenofovir exposure (AUC and Cmax) of around 40% during co- treatment with Vosevi and darunavir + ritonavir + tenofovir disoproxil (Inhibition of P-gp)   fumarate/emtricitabine.

Patients receiving tenofovir disoproxil fumarate and Vosevi concomitantly should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. Refer to the tenofovir disoproxil fumarate-containing product’s Summary of Product Characteristics for recommendations on renal monitoring (see section 4.4).
Efavirenz/emtricitabine/     Interaction only studied with                       Co-administration of Vosevi tenofovir disoproxil         sofosbuvir/velpatasvir                              with fumarate (600/200/300 mg     Expected:                                           efavirenz/emtricitabine/tenofovir once daily)g + sofosbuvir/   ↓ Voxilaprevir                                      disoproxil fumarate is not velpatasvir (400/100 mg      Observed:                                           recommended (see section 4.4).
once daily)f, h              Efavirenz              ↔         ↔        ↔ Sofosbuvir             ↑         ↔
(Induction of CYPs)                                 1.38
(1.14,
1.67)
Velpatasvir            ↓         ↓        ↓
0.53      0.47     0.43
(0.43,    (0.39,   (0.36,
0.64)     0.57)    0.52)


Medicinal product by           Effects on medicinal product levels.
therapeutic                    Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                      Recommendation concerning of interaction                 Active              Cmax     AUC      Cmin     co-administration with Vosevi Emtricitabine/rilpivirine/     Observed:                                      No dose adjustment of Vosevi or tenofovir alafenamide          Rilpivirine         ↔        ↔        ↔        emtricitabine/rilpivirine/tenofovi (200/25/25 mg once daily)i     Sofosbuvir          ↔        ↔                 r alafenamide is required.
+ sofosbuvir/velpatasvir/      Velpatasvir         ↔        ↔        ↔ voxilaprevir (400/100/         Voxilaprevir        ↔        ↔        ↔ 100 mg once daily) + voxilaprevir
(100 mg once daily)f
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with    Effect on atazanavir and ritonavir exposure not    Co-administration of Vosevi ritonavir (300 + 100 mg    studied.                                           with atazanavir is expected to single dose) + sofosbuvir/                                                    increase the concentration of voxilaprevir. Co-administration velpatasvir/voxilaprevir   Expected: of Vosevi with atazanavir-
(400/100/100 mg single     ↔ Atazanavir                                       containing regimens is not dose)f                     ↔ Ritonavir                                        recommended.
Observed:
(Inhibition of OATP1B,     Sofosbuvir            ↑         ↑
P-gp and CYP3A)                                  1.29      1.40
(1.09,    (1.25,
1.52)     1.57)
Velpatasvir           ↑         ↑
1.29      1.93
(1.07,    (1.58,
1.56)     2.36)

Voxilaprevir        ↑        ↑
4.42     4.31
(3.65,   (3.76,
5.35)    4.93)

Darunavir boosted with         Observed:                                      No dose adjustment of Vosevi, ritonavir (800 + 100 mg        Darunavir           ↔        ↔        ↓        darunavir (ritonavir boosted) or once daily) + emtricitabine/                                         0.66     emtricitabine/tenofovir tenofovir disoproxil                                                 (0.58,   disoproxil fumarate is required.
fumarate (200/300 mg once                                            0.74) daily)j + sofosbuvir/          Ritonavir           ↑        ↑        ↔ velpatasvir/voxilaprevir                           1.60     1.45
(400/100/100 mg once                               (1.47,   (1.35,
daily) + voxilaprevir                              1.75)    1.57)
(100 mg once daily)f           Sofosbuvir          ↓        ↔
0.70
(Inhibition of OATP1B,                             (0.62,
P-gp, and CYP3A)                                   0.78)
Velpatasvir         ↔        ↔        ↔
Voxilaprevir        ↑        ↑        ↑
1.72     2.43     4.00
(1.51,   (2.15,   (3.44,
1.97)    2.75)    4.65)


Medicinal product by        Effects on medicinal product levels.
therapeutic                 Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                      Recommendation concerning of interaction              Active                 Cmax     AUC      Cmin     co-administration with Vosevi Lopinavir                   Interaction not studied.                          Co-administration of Vosevi Expected:                                         with lopinavir-containing (Inhibition of OATP1B)      ↔ Lopinavir                                       regimens is not recommended.
↔ Sofosbuvir
↔ Velpatasvir
↑ Voxilaprevir


HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir (400 mg twice Interaction only studied with                       No dose adjustment of Vosevi, daily)k + emtricitabine/  sofosbuvir/velpatasvir                              raltegravir or tenofovir disoproxil      Expected:                                           emtricitabine/tenofovir disoproxil fumarate is required.
fumarate (200/300 mg once ↔ Voxilaprevir daily)j + sofosbuvir/     Observed: velpatasvir (400/100 mg   Raltegravir            ↔      ↔            ↓ once daily)f, h                                                      0.79 (0.42,
1.48)
Sofosbuvir            ↔         ↔
Velpatasvir           ↔         ↔        ↔
Elvitegravir/cobicistat/    Observed:                                         No dose adjustment of Vosevi or emtricitabine/tenofovir     Elvitegravir          ↔         ↔        ↑        elvitegravir/cobicistat/ alafenamide fumarate                                                 1.32     emtricitabine/tenofovir (150/150/200/10 mg once                                              (1.17,   alafenamide fumarate is required.
daily)l +                                                            1.49) sofosbuvir/velpatasvir/     Cobicistat            ↔         ↑        ↑ voxilaprevir (400/100/                                      1.50     3.50 100 mg once daily) +                                        (1.44,   (3.01, voxilaprevir (100 mg once                                   1.58)    4.07) daily)f                     Tenofovir             ↓         ↔
0.79
(Inhibition of OATP1B,                            (0.68,
P-gp/BCRP and CYP3A)                              0.92)
Sofosbuvir            ↑         ↔
1.27
(1.09,
1.48)
Velpatasvir           ↔         ↔        ↑
1.46
(1.30,
1.64)
Voxilaprevir           ↑        ↑        ↑
1.92     2.71     4.50
(1.63,   (2.30,   (3.68,
2.26)    3.19)    5.50)
Dolutegravir (50 mg once    Interaction only studied with                     No dose adjustment of Vosevi or daily) + sofosbuvir/        sofosbuvir/velpatasvir                            dolutegravir is required.
velpatasvir (400/100 mg     Expected: once daily)h                ↔ Voxilaprevir
Observed:
Dolutegravir           ↔        ↔        ↔

Medicinal product by         Effects on medicinal product levels.
therapeutic                  Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                           Recommendation concerning of interaction               Active                 Cmax      AUC        Cmin      co-administration with Vosevi Sofosbuvir             ↔         ↔
Velpatasvir            ↔         ↔          ↔

HERBAL SUPPLEMENTS
St. John’s wort            Interaction not studied.                                Vosevi is contraindicated with Expected:                                               St. John’s wort (see section 4.3).
(Induction of P-gp and     ↓ Sofosbuvir
CYPs)                      ↓ Velpatasvir
↓ Voxilaprevir
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin               Interaction only studied with sofosbuvir/               Atorvastatin may be velpatasvir.                                            administered with Vosevi at a Expected:                                               dose that does not exceed ↔ Voxilaprevir                                          atorvastatin 20 mg.
Atorvastatin (40 mg single Observed:       ↑         ↑ dose) + sofosbuvir/        atorvastatin    1.7       1.5 velpatasvir (400/100 mg                    (1.5,     (1.5,
once daily) f                              1.9)      1.6)
Rosuvastatin                 Effect on sofosbuvir, velpatasvir and                 Vosevi is contraindicated with voxilaprevir not studied.                             rosuvastatin (see section 4.3).
Expected:
↔ Sofosbuvir
↔ Velpatasvir
↔ Voxilaprevir
Rosuvastatin (10 mg single   Observed: dose) + sofosbuvir/          Rosuvastatin           ↑        ↑ velpatasvir/voxilaprevir                            18.9     7.4
(400/100/100 mg once                                (16.2,   (6.7,
daily) + voxilaprevir                               22.0)    8.2)
(100 mg once daily)f

(Inhibition of OATP1B and
BCRP)
Pravastatin                  Effect on sofosbuvir, velpatasvir and                 Pravastatin may be administered voxilaprevir not studied.                             with Vosevi at a dose that does Expected:                                             not exceed pravastatin 40 mg.
↔ Sofosbuvir
↔ Velpatasvir
↔ Voxilaprevir
Pravastatin (40 mg single    Observed: dose) + sofosbuvir/          Pravastatin            ↑        ↑ velpatasvir/voxilaprevir                            1.89     2.16
(400/100/100 mg once                                (1.53,   (1.79,
daily) + voxilaprevir                               2.34)    2.60)
(100 mg once daily)f

(Inhibition of OATP1B)
Other statins                Effect on fluvastatin, lovastatin, pitavastatin and   Interactions cannot be excluded simvastatin not studied.                              with other HMG-CoA reductase (Inhibition of OATP1B)                                                             inhibitors. Co-administration 
Medicinal product by         Effects on medicinal product levels.
therapeutic                  Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                    Recommendation concerning of interaction               Active               Cmax     AUC      Cmin    co-administration with Vosevi with Vosevi is not recommended.
NARCOTIC ANALGESICS
Methadone                  Interaction only studied with sofosbuvir         No dose adjustment of Vosevi or Expected:                                        methadone is required.
↔ Velpatasvir
↔ Voxilaprevir
Methadone                  Observed:
(Methadone maintenance     R-methadone            ↔        ↔         ↔ therapy [30 to 130 mg      S-methadone            ↔        ↔         ↔ daily]) + sofosbuvir       Sofosbuvir             ↔        ↑
(400 mg once daily)f                                       1.30
(1.00,
1.69)
IMMUNOSUPPRESSANTS
Ciclosporin                Observed:                                        Co-administration of Vosevi (600 mg single dose)f +    Ciclosporin            ↔        ↔                with ciclosporin is not sofosbuvir (400 mg single  Sofosbuvir             ↑        ↑                recommended (see section 4.4).
dose)e                                            2.54     4.53
(1.87,   (3.26,
(Inhibition of OATP1B or                          3.45)    6.30)
P-gp or BCRP)
Ciclosporin                Ciclosporin            ↔        ↓
(600 mg single dose)e +                                    0.88 velpatasvir (100 mg single                                 (0.78,
dose)f                                                     1.0)
Velpatasvir            ↑        ↑
1.56     2.03
(1.22,   (1.51,
2.01)    2.71)
Ciclosporin                Ciclosporin            ↔        ↔
(600 mg single dose)e +    Voxilaprevir           ↑        ↑ voxilaprevir (100 mg                              19.0     9.4 f single dose)                                      (14.1,   (7.4,
25.6)    12.0)
Tacrolimus                 Effect on velpatasvir or voxilaprevir exposure   No dose adjustment of Vosevi or not studied.                                     tacrolimus is required at Expected:                                        initiation of co-administration.
↔ Velpatasvir                                    Afterwards, close monitoring and ↔ Voxilaprevir                                   potential dose adjustment of Tacrolimus (5 mg single    Observed:                                        tacrolimus may be required.
dose)e + sofosbuvir        Tacrolimus             ↓        ↑
(400 mg single dose)f                             0.73     1.09
(0.59,   (0.84,
0.90)    1.40)
Sofosbuvir             ↓        ↑
0.97     1.13
(0.65,   (0.81,
1.43)    1.57)


Medicinal product by      Effects on medicinal product levels.
therapeutic               Mean ratio (90% confidence interval)a,b areas/Possible mechanism                                                                Recommendation concerning of interaction            Active                 Cmax   AUC     Cmin                    co-administration with Vosevi HORMONAL CONTRACEPTIVES
Oral norgestimate/ethinyl Observed:                                                     Vosevi is contraindicated with estradiol (norgestimate   Norelgestromin         ↔      ↔       ↔                       ethinylestradiol-containing 0.180 mg/0.215 mg/0.25 m                                                                medicinal products (see g/ethinyl estradiol                                                                     section 4.3). Alternative 0.025 mg) +                                                                             methods of contraception (e.g.
sofosbuvir/velpatasvir/                                                                 progestin only contraception or Norgestrel             ↔      ↔       ↔ voxilaprevir (400/100/                                                                  non-hormonal methods) should Ethinyl estradiol      ↔      ↔       ↔
100 mg once daily) +                                                                    be considered.
voxilaprevir (100 mg once daily)f
STIMULANTS
Modafinil                 Interaction not studied.                                      Co-administration of Vosevi Expected:                                                     with modafinil is not (Induction of P-gp and    ↔ Modafinil                                                   recommended (see section 4.4).
CYPs)                     ↓ Sofosbuvir
↓ Velpatasvir
↓ Voxilaprevir a. Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00.
b. All interaction studies conducted in healthy volunteers.
c. Lack of pharmacokinetics interaction lower bound 70%.
d. These are medicinal products within class where similar interactions could be predicted.
e. Bioequivalence/Equivalence boundary 80-125%.
f. Lack of pharmacokinetics interaction bounds 70-143%.
g. Administered as efavirenz, emtricitabine and tenofovir DF fixed-dose combination.
h. Administered as sofosbuvir, velpatasvir fixed-dose combination.
i. Administered as emtricitabine, rilpivirine, and tenofovir alafenamide fixed-dose combination.
j. Administered as emtricitabine, tenofovir disoproxil fumarate fixed-dose combination.
k. Lack of pharmacokinetics interaction bounds 50-200%.
l. Administered as elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fixed-dose combination.