Interactions : אינטראקציות

4.5.      Interaction with other medicinal products and other forms of interaction
Potential for Maviret to affect other medicinal products

Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Co-administration with Maviret may increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatran etexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). See Table 3 for specific recommendations on interactions with sensitive substrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment may be needed.

Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridine glucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Maviret.

Both glecaprevir and pibrentasvir inhibit the bile salt export pump (BSEP) in vitro.

Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4, UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected.


MAV API APR 22_CL                                                                             Page 4 of 25 Patients treated with vitamin K antagonists

As liver function may change during treatment with Maviret, a close monitoring of International Normalised Ratio (INR) values is recommended.

Potential for other medicinal products to affect Maviret

Use with strong P-gp/CYP3A inducers
Medicinal products that are strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St.
John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) could significantly decrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effect of Maviret or loss of virologic response. Co-administration of such medicinal products with Maviret is contraindicated (see section 4.3).

Co-administration of Maviret with medicinal products that are moderate inducers P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended (see section 4.4).

Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Maviret with medicinal products that inhibit P-gp and BCRP (e.g. ciclosporin, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow elimination of glecaprevir and pibrentasvir and thereby increase plasma exposure of the antivirals. Medicinal products that inhibit OATP1B1/3 (e.g. elvitegravir, ciclosporin, darunavir, lopinavir) increase systemic concentrations of glecaprevir.

Established and other potential medicinal product interactions

Table 3 provides the least-squares mean Ratio (90% Confidence Interval) effect on concentration of Maviret and some common concomitant medicinal products. The direction of the arrow indicates the direction of the change in exposures (Cmax, AUC, and Cmin) in glecaprevir, pibrentasvir, and the co- administered medicinal product (↑ = increase (more than 25%), ↓ = decrease (more than 20%), ↔ = no change (equal to or less than 20% decrease or 25% increase)). This is not an exclusive list. All interaction studies were performed in adults.

Table 3: Interactions between Maviret and other medicinal products

Medicinal product by therapeutic      Effect on areas/possible    medicinal        Cmax                  AUC         Cmin       Clinical comments mechanism of    product levels interaction
ANGIOTENSIN-II RECEPTOR BLOCKERS
Losartan          ↑ losartan          2.51                   1.56        --       No dose adjustment 50 mg single dose                 (2.00, 3.15)           (1.28, 1.89)             is required.
↑ losartan          2.18                    ↔          -- carboxylic      (1.88, 2.53) acid
Valsartan         ↑ valsartan         1.36                   1.31        --       No dose adjustment 80 mg single dose                 (1.17, 1.58)           (1.16, 1.49)             is required.

(Inhibition of
OATP1B1/3)


MAV API APR 22_CL                                                                           Page 5 of 25 ANTIARRHYTHMICS
Digoxin            ↑ digoxin                 1.72           1.48            --        Caution and 0.5 mg single dose                       (1.45, 2.04)   (1.40, 1.57)                  therapeutic concentration
(Inhibition of P-gp)                                                                  monitoring of digoxin is recommended.
ANTICOAGULANTS
Dabigatran etexilate ↑ dabigatran            2.05           2.38            --        Co-administration 150 mg single dose                       (1.72, 2.44)   (2.11, 2.70)                  is contraindicated (see section 4.3).
(Inhibition of P-gp)
ANTICONVULSANTS
Carbamazepine        ↓ glecaprevir          0.33            0.34            --        Co-administration  200 mg twice daily                      (0.27, 0.41)    (0.28, 0.40)                  may lead to reduced
↓ pibrentasvir         0.50            0.49            --        therapeutic effect of (Induction of P-                        (0.42, 0.59)    (0.43, 0.55)                  Maviret and is gp/CYP3A)                                                                             contraindicated (see Phenytoin,           Not studied.                                                     section 4.3).
phenobarbital,       Expected: ↓ glecaprevir and ↓ pibrentasvir primidone

ANTIMYCOBACTERIALS
Rifampicin         ↑ glecaprevir      6.52                  8.55                      Co-administration 600 mg single dose                (5.06, 8.41)          (7.01, 10.4)        --        is contraindicated ↔ pibrentasvir      ↔                     ↔              --        (see section 4.3).
(Inhibition of
OATP1B1/3)
Rifampicin 600 mg  ↓ glecaprevir      0.14                  0.12            -- once dailya                       (0.11, 0.19)          (0.09, 0.15)
↓ pibrentasvir     0.17                  0.13            --
(Induction of P-                  (0.14, 0.20)          (0.11, 0.15) gp/BCRP/CYP3A)
ETHINYL-OESTRADIOL-CONTAINING PRODUCTS
Ethinyloestradiol  ↑ EE               1.31                  1.28           1.38       Co-administration (EE)/Norgestimate                 (1.24, 1.38)          (1.23, 1.32)   (1.25, 1.52)   of Maviret with 35 µg/250 µg once  ↑                   ↔                    1.44           1.45       ethinyloestradiol- daily              norelgestromin                       (1.34, 1.54)   (1.33, 1.58)   containing products ↑ norgestrel       1.54                  1.63           1.75       is contraindicated (1.34, 1.76)          (1.50, 1.76)   (1.62, 1.89)   due to the risk of EE/Levonorgestrel  ↑ EE               1.30                  1.40           1.56       ALT elevations (see  20 µg/100 µg once                 (1.18, 1.44)          (1.33, 1.48)   (1.41, 1.72)   section 4.3).
daily              ↑ norgestrel       1.37                  1.68           1.77       No dose adjustment (1.23, 1.52)          (1.57, 1.80)   (1.58, 1.98)   is required with levonorgestrel,
norethidrone or norgestimate as contraceptive progestagen.
HERBAL PRODUCTS
St. John’s wort Not studied.                                                          Co-administration (Hypericum      Expected: ↓ glecaprevir and ↓ pibrentasvir                            may lead to reduced perforatum)                                                                           therapeutic effect of Maviret and is
(Induction of P-                                                                      contraindicated (see gp/CYP3A)                                                                             section 4.3).
HIV-ANTIVIRAL AGENTS
Atazanavir +     ↑ glecaprevir              ≥4.06          ≥6.53          ≥14.3       Co-administration ritonavir                                (3.15, 5.23)   (5.24, 8.14)   (9.85, 20.7)   with atazanavir is 300/100 mg once  ↑ pibrentasvir             ≥1.29          ≥1.64          ≥2.29       contraindicated due dailyb                                   (1.15, 1.45)   (1.48, 1.82)   (1.95, 2.68)   to the risk of ALT 

MAV API APR 22_CL                                                                              Page 6 of 25 elevations (see section 4.3).
Darunavir +             ↑ glecaprevir           3.09            4.97             8.24       Co-administration ritonavir                                   (2.26, 4.20)    (3.62, 6.84)     (4.40, 15.4)   with darunavir is 800/100 mg once         ↔ pibrentasvir           ↔               ↔               1.66       not recommended.
daily                                                                        (1.25, 2.21) Efavirenz/emtricitab    ↑ tenofovir              ↔               1.29            1.38       Co-administration ine/tenofovir                                                (1.23, 1.35)    (1.31, 1.46)   with efavirenz may disoproxil fumarate     The effect of efavirenz/emtricitabine/tenofovir disoproxil          lead to reduced 600/200/300 mg          fumarate on glecaprevir and pibrentasvir was not directly           therapeutic effect of once daily              quantified within this study, but glecaprevir and pibrentasvir      Maviret and is not exposures were significantly lower than historical controls.        recommended. No clinically significant interactions are expected with tenofovir disoproxil fumarate.
Elvitegravir/cobicist   ↔ tenofovir              ↔               ↔               ↔          No dose adjustment at/emtricitabine/       ↑ glecaprevir           2.50            3.05            4.58        is required.
tenofovir                                   (2.08, 3.00)    (2.55, 3.64)    (3.15, 6.65) alafenamide             ↑ pibrentasvir           ↔              1.57            1.89 (1.39, 1.76)    (1.63, 2.19)
(P-gp, BCRP, and
OATP inhibition by cobicistat, OATP inhibition by elvitegravir)
Lopinavir/ritonavir     ↑ glecaprevir           2.55            4.38            18.6        Co-administration  400/100 mg twice                            (1.84, 3.52)    (3.02, 6.36)    (10.4, 33.5)    is not daily                   ↑ pibrentasvir          1.40            2.46            5.24        recommended.
(1.17, 1.67)    (2.07, 2.92)    (4.18, 6.58)
Raltegravir             ↑ raltegravir           1.34            1.47            2.64        No dose adjustment  400 mg twice daily                          (0.89, 1.98)    (1.15, 1.87)    (1.42, 4.91)    is required.

(Inhibition of
UGT1A1)
HCV-ANTIVIRAL AGENTS
Sofosbuvir         ↑ sofosbuvir       1.66                      2.25              --        No dose adjustment  400 mg single dose                (1.23, 2.22)              (1.86, 2.72)                    is required.
↑ GS-331007         ↔                         ↔              1.85 (P-gp/BCRP                                                                  (1.67, 2.04) inhibition)        ↔ glecaprevir       ↔                         ↔               ↔ ↔ pibrentasvir      ↔                         ↔               ↔ HMG-COA REDUCTASE INHIBITORS
Atorvastatin       ↑ atorvastatin     22.0                      8.28              --        Co-administration 10 mg once daily                  (16.4, 29.5)              (6.06, 11.3)                    with atorvastatin and simvastatin is
(Inhibition of                                                                              contraindicated (see OATP1B1/3, P-gp,                                                                            section 4.3).
BCRP, CYP3A)
Simvastatin             ↑ simvastatin           1.99            2.32              -- 5 mg once daily                             (1.60, 2.48)    (1.93, 2.79) ↑ simvastatin           10.7            4.48              --
(Inhibition of          acid                (7.88, 14.6)    (3.11, 6.46) OATP1B1/3, P-gp,
BCRP)
Lovastatin              ↑ lovastatin            ↔               1.70              --        Co-administration 10 mg once daily                                            (1.40, 2.06)                    is not ↑ lovastatin            5.73            4.10              --        recommended. If (Inhibition of          acid                (4.65, 7.07)    (3.45, 4.87)                    used, lovastatin should not exceed a

MAV API APR 22_CL                                                                                    Page 7 of 25 OATP1B1/3, P-gp,                                                                       dose of 20 mg/day BCRP)                                                                                  and patients should be monitored.
Pravastatin          ↑ pravastatin          2.23             2.30            --        Caution is 10 mg once daily                        (1.87, 2.65)     (1.91, 2.76)                  recommended.
Pravastatin dose
(Inhibition of                                                                         should not exceed OATP1B1/3)                                                                             20 mg per day and Rosuvastatin         ↑ rosuvastatin         5.62             2.15            --        rosuvastatin dose 5 mg once daily                         (4.80, 6.59)     (1.88, 2.46)                  should not exceed 5 mg per day.
(Inhibition of
OATP1B1/3,
BCRP)
Fluvastatin,         Not studied.                                                      Interactions with Pitavastatin         Expected: ↑ fluvastatin and ↑ pitavastatin                        fluvastatin and pitavastatin are likely and caution is recommended during the combination. A low dose of the statin is recommended at the initiation of the
DAA treatment.
IMMUNOSUPPRESSANTS
Ciclosporin        ↑ glecaprevirc           1.30             1.37           1.34       Maviret is not 100 mg single dose                      (0.95, 1.78)     (1.13, 1.66)   (1.12, 1.60)   recommended for ↑ pibrentasvir            ↔                ↔             1.26       use in patients (1.15, 1.37)   requiring stable
Ciclosporin          ↑ glecaprevir          4.51             5.08            --        ciclosporin doses  400 mg single dose                      (3.63, 6.05)     (4.11, 6.29)                  > 100 mg per day.
↑ pibrentasvir          ↔               1.93            --        If the combination (1.78, 2.09)                  is unavoidable, use can be considered if the benefit outweighs the risk with a close clinical monitoring.
Tacrolimus           ↑ tacrolimus           1.50             1.45            --        The combination of 1 mg single dose                        (1.24, 1.82)     (1.24, 1.70)                  Maviret with ↔ glecaprevir           ↔                ↔             ↔          tacrolimus should (CYP3A4 and P-gp     ↔ pibrentasvir          ↔                ↔             ↔          be used with inhibition)                                                                            caution. Increase of tacrolimus exposure is expected.
Therefore, a therapeutic drug monitoring of tacrolimus is recommended and a dose adjustment of tacrolimus made accordingly.
PROTON PUMP INHIBITORS
Omeprazole           ↓ glecaprevir         0.78             0.71             --  20 mg once daily                       (0.60, 1.00)     (0.58, 0.86)                   No dose adjustment
↔ pibrentasvir         ↔                ↔               --        is required.
(Increase gastric pH value)
Omeprazole           ↓ glecaprevir         0.36             0.49             -- (0.21, 0.59)     (0.35, 0.68)


MAV API APR 22_CL                                                                               Page 8 of 25   40 mg once daily (1 ↔ pibrentasvir             ↔             ↔                -- hour before breakfast)
Omeprazole          ↓ glecaprevir            0.54            0.51             --   40 mg once daily                         (0.44, 0.65)    (0.45, 0.59)
(evening without    ↔ pibrentasvir            ↔               ↔               -- food)
VITAMIN K ANTAGONISTS
Vitamin K           Not studied.                                                        Close monitoring of antagonists                                                                             INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with
Maviret.
DAA=direct acting antiviral a. Effect of rifampicin on glecaprevir and pibrentasvir 24 hours after final rifampicin dose.
b. Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported.
c. HCV-infected transplant recipients who received a median ciclosporin dose of 100 mg per day had increased glecaprevir exposures to 2.4-fold of those not receiving ciclosporin.

Additional drug-drug interaction studies were performed with the following medical products and showed no clinically significant interactions with Maviret: abacavir, amlodipine, buprenorphine, caffeine, dextromethorphan, dolutegravir, emtricitabine, felodipine, lamivudine, lamotrigine, methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, rilpivirine, tenofovir alafenamide and tolbutamide.