Interactions : אינטראקציות

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

Potential for Epclusa to affect other medicinal products

Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Epclusa with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. See Table 3 for examples of interactions with sensitive substrates of P-gp (digoxin), BCRP (rosuvastatin), and OATP (pravastatin).

Potential for other medicinal products to affect Epclusa

Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. Velpatasvir is also a substrate of drug transporter OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8 and CYP3A4 was observed. Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital and phenytoin, rifampicin, rifabutin and St. John’s wort) may decrease plasma concentrations of sofosbuvir or velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinal products with Epclusa is contraindicated (see section 4.3). Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of Epclusa. Co-administration with such medicinal products is not recommended with Epclusa (see section 4.4). Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir or velpatasvir plasma concentrations. Medicinal products that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Clinically significant medicinal product interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Epclusa may be co-administered with P-gp, BCRP, OATP and CYP inhibitors.

Patients treated with vitamin K antagonists

As liver function may change during treatment with Epclusa, a 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 medicinal products such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV.


Interactions between Epclusa and other medicinal products

Table 3 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 or velpatasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with sofosbuvir/velpatasvir. The table is not all-inclusive.

Table 3: Interactions between Epclusa and other medicinal products
Effects on medicinal product levels.
Medicinal product by       Mean ratio (90% confidence therapeutic areas/Possible interval)a,b                               Recommendation concerning Mechanism of Interaction   Active        Cmax      AUC      Cmin      co-administration with Epclusa ACID REDUCING AGENTS
Velpatasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease the concentration of velpatasvir.
Antacids e.g. Aluminium or            Interaction not studied.                 It is recommended to separate magnesium hydroxide;         Expected.                                antacid and Epclusa calcium carbonate               Sofosbuvir                            administration by 4 hours.
Velpatasvir
(Increase in gastric pH)
H2-receptor antagonists
Famotidine                   Sofosbuvir                               H2-receptor antagonists may be (40 mg single dose)/                                                  administered simultaneously with sofosbuvir/ velpatasvir                                               or staggered from Epclusa at a (400/ 100 mg single dose)c                                            dose that does not exceed doses comparable to famotidine 40 mg
Famotidine dosed             Velpatasvir                              twice daily.
simultaneously with                          0.80           0.81
Epclusad                                     (0.70,         (0.71,
0.91)          0.91)
Cimetidinee
Nizatidinee
Ranitidinee

(Increase in gastric pH)
Famotidine                   Sofosbuvir
(40 mg single dose)/                         0.77           0.80 sofosbuvir/ velpatasvir                      (0.68,         (0.73,
(400/ 100 mg single dose)c                   0.87)          0.88)

Famotidine dosed 12 hours    Velpatasvir prior to Epclusad
(Increase in gastric pH)


Effects on medicinal product levels.
Medicinal product by          Mean ratio (90% confidence therapeutic areas/Possible    interval)a,b                                 Recommendation concerning Mechanism of Interaction      Active        Cmax      AUC      Cmin        co-administration with Epclusa Proton pump inhibitors
Omeprazole                    Sofosbuvir                                   Co-administration with proton (20 mg once daily)/                           0.66           0.71          pump inhibitors is not sofosbuvir/ velpatasvir                       (0.55,         (0.60,        recommended. If it is considered (400/ 100 mg single dose                      0.78)          0.83)         necessary to co-administer, then fasted)c                                                                   Epclusa should be administered with food and taken 4 hours
Omeprazole dosed              Velpatasvir                                  before proton pump inhibitor at simultaneously with                           0.63           0.64          max doses comparable to Epclusad                                      (0.50,         (0.52,        omeprazole 20 mg.
0.78)          0.79)
Lansoprazolee
Rabeprazolee
Pantoprazolee
Esomeprazolee

(Increase in gastric pH)
Omeprazole                    Sofosbuvir
(20 mg once daily)/                           0.79 sofosbuvir/ velpatasvir                       (0.68,
(400/ 100 mg single dose                      0.92) fed)c

Omeprazole dosed 4 hours      Velpatasvir after Epclusad                                0.67           0.74
(0.58,         (0.63,
(Increase in gastric pH)                      0.78)          0.86)
ANTIARRHYTHMICS
Amiodarone                    Effect on amiodarone, velpatasvir, and       Co-administration of amiodarone 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
Epclusa (see sections 4.4 and 4.8).
Digoxin                       Interaction only studied with velpatasvir.   Co-administration of Epclusa with Expected:                                    digoxin may increase the Sofosbuvir                                concentration of digoxin. Caution Digoxin (0.25 mg single       Effect on velpatasvir exposure not studied   is warranted and therapeutic dose)f/ velpatasvir (100 mg   Expected:                                    concentration monitoring of single dose)                     Velpatasvir                               digoxin is recommended when co-administered with Epclusa.
(Inhibition of P-gp)
Observed:
Digoxin         ↑              ↑
1.9            1.3
(1.7,          (1.1,
2.1)           1.6)
ANTICOAGULANTS
Dabigatran etexilate          Interaction not studied.                     Clinical monitoring, looking for Expected:                                    signs of bleeding and anaemia, is ↑ Dabigatran                                 recommended when dabigatran Sofosbuvir                                etexilate is co-administered with Velpatasvir                               Epclusa. A coagulation test helps (Inhibition of P-gp)                                                       to identify patients with an increased bleeding risk due to increased dabigatran exposure.
Effects on medicinal product levels.
Medicinal product by         Mean ratio (90% confidence therapeutic areas/Possible   interval)a,b                                Recommendation concerning Mechanism of Interaction     Active           Cmax   AUC      Cmin       co-administration with Epclusa Vitamin K antagonists        Interaction not studied                     Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Epclusa.
ANTICONVULSANTS
Phenytoin                    Interaction not studied.                    Epclusa is contraindicated with Phenobarbital                Expected:                                   phenobarbital and phenytoin (see Sofosbuvir                                section 4.3).
(Induction of P-gp and         Velpatasvir
CYPs)
Carbamazepine                Interaction not studied.                    Epclusa is contraindicated with Expected:                                   carbamazepine (see section 4.3).
Velpatasvir

(Induction of P-gp and       Observed:        0.52            0.52
CYPs)                        Sofosbuvir      (0.43,         (0.46,
0.62)          0.59)

Oxcarbazepine                Interaction not studied.                    Co-administration of Epclusa with Expected:                                   oxcarbazepine is expected to Sofosbuvir                                decrease the concentration of (Induction of P-gp and         Velpatasvir                               sofosbuvir and velpatasvir, CYPs)                                                                    leading to reduced therapeutic effect of Epclusa.
Co-administration is not recommended (see section 4.4).
ANTIFUNGALS
Ketoconazole                 Interaction only studied with velpatasvir   No dose adjustment of Epclusa or Expected:                                   ketoconazole is required.
Sofosbuvir
Ketoconazole (200 mg         Effect on ketoconazole exposure not twice daily)/ velpatasvir    studied.
(100 mg single dose)d        Expected:
Ketoconazole
Observed:
Velpatasvir     ↑         ↑
(Inhibition of P-gp and                      1.3       1.7
CYPs)                                        (1.0,     (1.4,
1.6)      2.2)
Itraconazolee
Voriconazolee
Posaconazolee
Isavuconazolee


Effects on medicinal product levels.
Medicinal product by          Mean ratio (90% confidence therapeutic areas/Possible    interval)a,b                                  Recommendation concerning Mechanism of Interaction      Active        Cmax      AUC      Cmin         co-administration with Epclusa ANTIMYCOBACTERIALS
Rifampicin (600 mg once       Effect on rifampicin exposure not studied.    Epclusa is contraindicated with daily)/ sofosbuvir (400 mg                                                  rifampicin (see section 4.3).
single dose)d                 Expected:
Rifampicin
Observed:
(Induction of P-gp and        Sofosbuvir
CYPs)                                         0.23     0.28
(0.19,   (0.24,
0.29)    0.32)
Rifampicin (600 mg once       Effect on rifampicin exposure not studied.
daily)/ velpatasvir (100 mg single dose)                  Expected:
Rifampicin
Observed:
Velpatasvir
0.29          0.18
(Induction of P-gp and                         (0.23,        (0.15,
CYPs)                                          0.37)         0.22)
Rifabutin                     Interaction not studied.                      Epclusa is contraindicated with Expected:                                     rifabutin (see section 4.3).
Velpatasvir

(Induction of P-gp and        Observed:
CYPs)                         Sofosbuvir      0.64           0.76
(0.53,         (0.63,
0.77)          0.91)
Rifapentine                   Interaction not studied.             Co-administration of Epclusa with Expected:                            rifapentine is expected to decrease Sofosbuvir                         the concentration of sofosbuvir
Velpatasvir                        and velpatasvir, leading to
(Induction of P-gp and                                             reduced therapeutic effect of CYPs)                                                              Epclusa. Co-administration is not recommended (see section 4.4).
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Tenofovir disoproxil   Epclusa has been shown to increase tenofovir exposure (P-gp-inhibition). The fumarate               increase in tenofovir exposure (AUC and Cmax) was around 40-80% during co- treatment with Epclusa and tenofovir disoproxil fumarate/emtricitabine as part of various HIV regimens.

Patients receiving tenofovir disoproxil fumarate and Epclusa concomitantly should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. Refer to the tenofovir disoproxil fumarate-containing product’s Prescribing Information for recommendations on renal monitoring (see section 4.4).
Efavirenz/ emtricitabine/     Efavirenz                                     Co-administration of Epclusa with tenofovir disoproxil          Sofosbuvir       ↑                            efavirenz/ emtricitabine/ tenofovir fumarate                                       1.4                          disoproxil fumarate is expected to (600/ 200/ 300 mg once                         (1.1,                        decrease the concentration of daily)/ sofosbuvir/                            1.7)                         velpatasvir. Co-administration of velpatasvir (400/ 100 mg      Velpatasvir                                   Epclusa with efavirenz-containing once daily)c, d                                0.53     0.47      0.43      regimens is not recommended (0.43,   (0.39,    (0.36,    (see section 4.4).
0.64)    0.57)     0.52)


Effects on medicinal product levels.
Medicinal product by        Mean ratio (90% confidence therapeutic areas/Possible interval)a,b                                      Recommendation concerning Mechanism of Interaction    Active        Cmax      AUC      Cmin            co-administration with Epclusa Emtricitabine/ rilpivirine/ Rilpivirine                                      No dose adjustment of Epclusa or tenofovir disoproxil        Sofosbuvir                                       emtricitabine/ rilpivirine/ fumarate                    Velpatasvir                                      tenofovir disoproxil fumarate is (200/ 25/ 300 mg once                                                        required.
daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with     Atazanavir                       ↑               No dose adjustment of Epclusa, ritonavir (300/ 100 mg once                                  1.4             atazanavir (ritonavir boosted) or daily) + emtricitabine/                                      (1.2,           emtricitabine/ tenofovir disoproxil tenofovir disoproxil                                         1.6)            fumarate is required.
fumarate (200/ 300 mg once Ritonavir                         ↑ daily)/ sofosbuvir/                                          1.3 velpatasvir (400/ 100 mg                                     (1.5,
once daily)c, d                                              1.4)
Sofosbuvir

Velpatasvir   ↑             ↑        ↑
1.6           2.4      4.0
(1.4,         (2.2,    (3.6,
1.7)          2.6)     4.5)
Darunavir boosted with         Darunavir                                     No dose adjustment of Epclusa, ritonavir (800/ 100 mg once    Ritonavir                                     darunavir (ritonavir boosted) or daily) + emtricitabine/        Sofosbuvir                                    emtricitabine/ tenofovir disoproxil tenofovir disoproxil                         0.62          0.72              fumarate is required.
fumarate (200/ 300 mg once                   (0.54,        (0.66,
daily)/ sofosbuvir/                          0.71)         0.80) velpatasvir (400/ 100 mg       Velpatasvir once daily)c, d                              0.76
(0.65,
0.89)
Lopinavir boosted with         Lopinavir                                     No dose adjustment of Epclusa, ritonavir (4x200 mg/ 50 mg     Ritonavir                                     lopinavir (ritonavir boosted) or once daily) + emtricitabine/   Sofosbuvir                                    emtricitabine/ tenofovir disoproxil tenofovir disoproxil                         0.59          0.7               fumarate is required.
fumarate (200/ 300 mg once                   (0.49         (0.6,
daily)/ sofosbuvir/                          0.71)         0.8) velpatasvir (400/ 100 mg       Velpatasvir                          ↑ once daily)c, d                        0.70                         1.6 (0.59,                       (1.4,
0.83)                        1.9)
HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir (400 mg twice  Raltegravir                                       No dose adjustment of Epclusa, daily)g + emtricitabine/                                            0.79     raltegravir or emtricitabine/ tenofovir disoproxil                                                (0.42,   tenofovir disoproxil fumarate is fumarate (200/ 300 mg once                                          1.5)     required.
daily)/ sofosbuvir/        Sofosbuvir velpatasvir (400/ 100 mg   Velpatasvir once daily)c, d


Effects on medicinal product levels.
Medicinal product by         Mean ratio (90% confidence therapeutic areas/Possible   interval)a,b                               Recommendation concerning Mechanism of Interaction     Active        Cmax      AUC      Cmin      co-administration with Epclusa Elvitegravir/ cobicistat/    Elvitegravir                               No dose adjustment of Epclusa or emtricitabine/ tenofovir     Cobicistat                       ↑         elvitegravir/ cobicistat/ alafenamide fumarate                                          2.0       emtricitabine/ tenofovir (150/ 150/ 200/ 10 mg once                                    (1.7,     alafenamide fumarate is required.
daily)/ sofosbuvir/                                           2.5) velpatasvir (400/ 100 mg     Tenofovir once daily)c, d              alafenamide
Sofosbuvir              ↑
1.4
(1.2,
1.5)
Velpatasvir   ↑         ↑        ↑
1.3       1.5      1.6
(1.2,     (1.4,    (1.4,
1.5)      1.7)     1.8)
Elvitegravir/ cobicistat/    Elvitegravir                               No dose adjustment of Epclusa or emtricitabine/ tenofovir     Cobicistat                       ↑         elvitegravir/ cobicistat/ disoproxil fumarate                                           1.7       emtricitabine/ tenofovir disoproxil (150/ 150/ 200/ 300 mg                                        (1.5,     fumarate is required.
once daily)/ sofosbuvir/                                      1.9) velpatasvir (400/ 100 mg     Sofosbuvir once daily)c, d              Velpatasvir                      ↑
1.4
(1.2,
1.5)
Dolutegravir (50 mg once     Dolutegravir                               No dose adjustment of Epclusa or daily)/ sofosbuvir/          Sofosbuvir                                 dolutegravir is required.
velpatasvir (400/ 100 mg once daily)                  Velpatasvir

HERBAL SUPPLEMENTS
St. John’s wort              Interaction not studied.                   Epclusa is contraindicated with Expected:                                  St. John’s wort (see section 4.3).
Sofosbuvir
Velpatasvir
(Induction of P-gp and
CYPs)
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin (40 mg single Observed:       ↑         ↑                  No dose adjustment of Epclusa or dose) + sofosbuvir /       Atorvastatin 1.7          1.5                atorvastatin is required.
velpatasvir (400/ 100 mg                   (1.5,     (1.5,
once daily)d                               1.9)      1.6)
Rosuvastatin               Interaction only studied with velpatasvir    Co-administration of Epclusa with Expected:                                    rosuvastatin increases the Sofosbuvir                                concentration of rosuvastatin, Rosuvastatin (10 mg single Observed:                                    which is associated with increased dose)/ velpatasvir (100 mg Rosuvastatin ↑            ↑                  risk of myopathy, including once daily)d                               2.6       2.7                rhabdomyolysis. Rosuvastatin, at (2.3,     (2.5,              a dose that does not exceed
2.9)      2.9)               10 mg, may be administered with
Effect on velpatasvir exposure not studied   Epclusa.
(Inhibition of OATP1B and  Expected:
BCRP)                         Velpatasvir


Effects on medicinal product levels.
Medicinal product by          Mean ratio (90% confidence therapeutic areas/Possible    interval)a,b                                 Recommendation concerning Mechanism of Interaction      Active          Cmax      AUC       Cmin     co-administration with Epclusa Pravastatin                   Interaction only studied with velpatasvir    No dose adjustment of Epclusa or Expected:                                    pravastatin is required.
Sofosbuvir
Pravastatin (40 mg single     Observed: dose)/ velpatasvir (100 mg    Pravastatin     ↑         ↑ once daily)d                                  1.3       1.4
(1.1,     (1.2,
1.5)      1.5)
(Inhibition of OATP1B)        Effect on velpatasvir exposure not studied Expected:
Velpatasvir
Other statins                 Expected:                                    Interactions cannot be excluded ↑ Statins                                    with other HMG-CoA reductase inhibitors. When co-administered with Epclusa, careful monitoring for statin adverse reactions should be undertaken and a reduced dose of statins should be considered if required.
NARCOTIC ANALGESICS
Methadone                     R-methadon                                   No dose adjustment of Epclusa or (Methadone maintenance        e                                            methadone is required.
therapy [30 to 130 mg daily])/ sofosbuvir (400 mg   S-methadon once daily)d                  e

Sofosbuvir                ↑
1.3
(1.0,
1.7)
Methadone                     Interaction only studied with sofosbuvir Expected:
Velpatasvir
IMMUNOSUPPRESSANTS
Ciclosporin               Ciclosporin                                      No dose adjustment of Epclusa or (600 mg single dose)/                                                      ciclosporin is required at initiation sofosbuvir (400 mg single Sofosbuvir         ↑            ↑                of co-administration. Afterwards, dose)f                                       2.5          4.5              close monitoring and potential (1.9,        (3.3,            dose adjustment of ciclosporin
3.5)         6.3)             may be required.
Ciclosporin                   Ciclosporin
(600 mg single dose)f/                                    0.88 velpatasvir (100 mg single                                (0.78,
dose)d                                                    1.0)
Velpatasvir    ↑            ↑
1.6          2.0
(1.2,        (1.5,
2.0)         2.7)


Effects on medicinal product levels.
Medicinal product by                Mean ratio (90% confidence therapeutic areas/Possible          interval)a,b                                    Recommendation concerning Mechanism of Interaction            Active          Cmax     AUC       Cmin         co-administration with Epclusa Tacrolimus                          Tacrolimus               ↑                      No dose adjustment of Epclusa or (5 mg single dose)f/                                0.73     1.1                    tacrolimus is required at initiation sofosbuvir (400 mg single                           (0.59,   (0.84,                 of co-administration. Afterwards, dose)d                                              0.90)    1.4)                   close monitoring and potential Sofosbuvir               ↑                      dose adjustment of tacrolimus 0.97     1.1                    may be required.
(0.65,   (0.81,
1.4)     1.6)
Tacrolimus                          Effect on velpatasvir exposure not studied.
Expected:
Velpatasvir
ORAL CONTRACEPTIVES
Norgestimate/ ethinyl      Norelgestro                                              No dose adjustment of oral estradiol (norgestimate    min                                                      contraceptives is required.
0.180 mg/ 0.215 mg/
0.25 mg/ ethinyl estradiol
0.025 mg)/ sofosbuvir
(400 mg once daily)d
Norgestrel                             ↑        ↑
1.2      1.2
(0.98,   (1.0,
1.5)     1.5)
Ethinyl estradiol
Norgestimate/ ethinyl               Norelgestro estradiol (norgestimate             min
0.180 mg/ 0.215 mg/                 Norgestrel
0.25 mg/ ethinyl estradiol
0.025 mg)/ velpatasvir              Ethinyl          ↑
(100 mg once daily)d                estradiol        1.4                   0.83 (1.2,                 (0.65,
1.7)                  1.1) 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     Administered as Epclusa.
d     Lack of pharmacokinetics interaction bounds 70-143%.
e     These are medicinal products within class where similar interactions could be predicted.
f     Bioequivalence/Equivalence boundary 80-125%.
g     Lack of pharmacokinetics interaction bounds 50-200%.