Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with Harvoni.

Potential for Harvoni to affect other medicinal products

Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters.

Potential for other medicinal products to affect Harvoni

Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not.
Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected.
Patients treated with vitamin K antagonists

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

Impact of DAA therapy on drugs metabolized by the liver

The pharmacokinetics of drugs 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 virus.

Interactions between Harvoni 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 equivalence boundaries). The medicinal product interactions described are based on studies conducted with either ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive.

Table 3: Interactions between Harvoni and other medicinal products

Medicinal product by
Effects on medicinal product levels.                Recommendation concerning Mean ratio (90% confidence interval) therapeutic areas                                                     co-administration with for AUC, Cmax, Cmina, b                              Harvoni
ACID REDUCING AGENTS
Ledipasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease concentration of ledipasvir.
Antacids e.g. Aluminium or          Interaction not studied.                   It is recommended to separate magnesium hydroxide;       Expected:                                  antacid and Harvoni calcium carbonate          ↓ Ledipasvir                               administration by 4 hours.
↔ Sofosbuvir
↔ GS-331007

(Increase in gastric pH)
H2-receptor antagonists
Famotidine                 Ledipasvir                                 H2-receptor antagonists may be (40 mg single dose)/       ↓ Cmax 0.80 (0.69, 0.93)                   administered simultaneously ledipasvir (90 mg single   ↔ AUC 0.89 (0.76, 1.06)                    with or staggered from Harvoni dose)c/ sofosbuvir                                                    at a dose that does not exceed (400 mg single dose)c, d   Sofosbuvir                                 doses comparable to famotidine ↑ Cmax 1.15 (0.88, 1.50)                   40 mg twice daily.
Famotidine dosed           ↔ AUC 1.11 (1.00, 1.24) simultaneously with
Harvonid                   GS-331007
↔ Cmax 1.06 (0.97, 1.14)
↔ AUC 1.06 (1.02, 1.11)
Cimetidinee
Nizatidinee                (Increase in gastric pH)
Ranitidinee
Medicinal product by        Effects on medicinal product levels.   Recommendation concerning therapeutic areas       Mean ratio (90% confidence interval)       co-administration with for AUC, Cmax, Cmina, b                 Harvoni
Famotidine                 Ledipasvir
(40 mg single dose)/       ↓ Cmax 0.83 (0.69, 1.00) ledipasvir (90 mg single   ↔ AUC 0.98 (0.80, 1.20) dose)c/ sofosbuvir
(400 mg single dose)c, d   Sofosbuvir
↔ Cmax 1.00 (0.76, 1.32)
Famotidine dosed           ↔ AUC 0.95 (0.82, 1.10)
12 hours prior to
Harvonid                   GS-331007
↔ Cmax 1.13 (1.07, 1.20)
↔ AUC 1.06 (1.01, 1.12)

(Increase in gastric pH)
Proton pump inhibitors
Omeprazole                 Ledipasvir                               Proton pump inhibitor doses (20 mg once daily)/        ↓ Cmax 0.89 (0.61, 1.30)                 comparable to omeprazole ledipasvir (90 mg single   ↓ AUC 0.96 (0.66, 1.39)                  20 mg can be administered dose)c/ sofosbuvir                                                  simultaneously with Harvoni.
(400 mg single dose)c      Sofosbuvir                               Proton pump inhibitors should ↔ Cmax 1.12 (0.88, 1.42)                 not be taken before Harvoni.
Omeprazole dosed           ↔ AUC 1.00 (0.80, 1.25) simultaneously with
Harvoni                    GS-331007
↔ Cmax 1.14 (1.01, 1.29)
Lansoprazolee              ↔ AUC 1.03 (0.96, 1.12)
Rabeprazolee
Pantoprazolee              (Increase in gastric pH)
Esomeprazolee
ANTIARRHYTHMICS
Amiodarone                 Effect on amiodarone, sofosbuvir and     Coadministration of amiodarone ledipasvir 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
Harvoni (see sections 4.4 and
4.8).
Digoxin                    Interaction not studied.                 Co-administration of Harvoni Expected:                                with digoxin may increase the ↑ Digoxin                                concentration of digoxin.
↔ Ledipasvir                             Caution is warranted and
↔ Sofosbuvir                             therapeutic concentration
↔ GS-331007                              monitoring of digoxin is recommended when
(Inhibition of P-gp)                     co-administered with Harvoni.
Medicinal product by    Effects on medicinal product levels.   Recommendation concerning therapeutic areas     Mean ratio (90% confidence interval)     co-administration with for AUC, Cmax, Cmina, b                 Harvoni
ANTICOAGULANTS
Dabigatran etexilate    Interaction not studied.               Clinical monitoring, looking for Expected:                              signs of bleeding and anaemia, ↑ Dabigatran                           is recommended when
↔ Ledipasvir                           dabigatran etexilate is
↔ Sofosbuvir                           co-administered with Harvoni.
↔ GS-331007                            A coagulation test helps to identify patients with an
(Inhibition of P-gp)                   increased bleeding risk due to increased dabigatran exposure.
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 Harvoni.
ANTICONVULSANTS
Phenobarbital           Interaction not studied.               Harvoni is contraindicated with Phenytoin               Expected:                              phenobarbital and phenytoin ↓ Ledipasvir                           (see section 4.3).
↓ Sofosbuvir
↔ GS-331007

(Induction of P-gp)
Carbamazepine           Interaction not studied                Harvoni is contraindicated with Expected:                              carbamazepine (see section 4.3).
↓ Ledipasvir

Observed:
Sofosbuvir
↓ Cmax 0.52 (0.43, 0.62)
↓ AUC 0.52 (0.46, 0.59)
Cmin (NA)

GS-331007
↔ Cmax 1.04 (0.97, 1.11)
↔ AUC 0.99 (0.94, 1.04)
Cmin (NA)
(Induction of P-gp)
Oxcarbazepine           Interaction not studied.               Co-administration of Harvoni Expected:                              with oxcarbazepine is expected ↓ Ledipasvir                           to decrease the concentration of ↓ Sofosbuvir                           ledipasvir and sofosbuvir
↔ GS-331007                            leading to reduced therapeutic effect of Harvoni. Such
(Induction of P-gp)                    co-administration is not recommended (see section 4.4).
Medicinal product by     Effects on medicinal product levels.   Recommendation concerning therapeutic areas     Mean ratio (90% confidence interval)      co-administration with for AUC, Cmax, Cmina, b                Harvoni
ANTIMYCOBACTERIALS
Rifampicin (600 mg      Interaction not studied.                 Harvoni is contraindicated with once daily)/ ledipasvir Expected:                                rifampicin (see section 4.3).
(90 mg single dose) d
Rifampicin
↔ Cmax
↔ AUC
↔ Cmin

Observed:
Ledipasvir
↓ Cmax 0.65 (0.56, 0.76)
↓ AUC 0.41 (0.36, 0.48)

(Induction of P-gp)
Rifampicin (600 mg        Interaction not studied.
once daily)/ sofosbuvir   Expected:
(400 mg single dose)d     Rifampicin
↔ Cmax
↔ AUC
↔ Cmin
Observed:
Sofosbuvir
↓ Cmax 0.23 (0.19, 0.29)
↓ AUC 0.28 (0.24, 0.32)

GS-331007
↔ Cmax 1.23 (1.14, 1.34)
↔ AUC 0.95 (0.88, 1.03)

(Induction of P-gp)
Rifabutin                 Interaction not studied.               Harvoni is contraindicated with Expected:                              rifabutin (see section 4.3).
↓ Ledipasvir

Observed:
Sofosbuvir
↓ Cmax 0.64 (0.53, 0.77)
↓ AUC 0.76 (0.63, 0.91)
Cmin (NA)

GS-331007
↔ Cmax 1.15 (1.03, 1.27)
↔ AUC 1.03 (0.95, 1.12)
Cmin (NA)
(Induction of P-gp)
Medicinal product by       Effects on medicinal product levels.    Recommendation concerning therapeutic areas       Mean ratio (90% confidence interval)        co-administration with for AUC, Cmax, Cmina, b                     Harvoni
Rifapentine              Interaction not studied.                 Co-administration of Harvoni Expected:                                with rifapentine is expected to ↓ Ledipasvir                             decrease the concentration of ↓ Sofosbuvir                             ledipasvir and sofosbuvir, ↔ GS-331007                              leading to reduced therapeutic (Induction of P-gp)                      effect of Harvoni. Such co-administration is not recommended.
SEDATIVES/HYPNOTICS
Midazolam (2.5 mg        Observed:                                No dose adjustment of Harvoni single                   Midazolam                                or midazolam is required.
dose)/ ledipasvir (90 mg ↔ Cmax 1.07 (1.00, 1.14) single dose)             ↔ AUC 0.99 (0.95, 1.04)
(Inhibition of CYP3A)

Midazolam
Ledipasvir (90 mg once   ↔ Cmax 0.95 (0.87, 1.04) daily)                   ↔ AUC 0.89 (0.84, 0.95)
(Induction of CYP3A)

Expected:
↔ Sofosbuvir
↔ GS-331007
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Efavirenz/ emtricitabine/ Efavirenz                No dose adjustment of Harvoni tenofovir disoproxil      ↔ Cmax 0.87 (0.79, 0.97) or efavirenz/ emtricitabine/ fumarate                  ↔ AUC 0.90 (0.84, 0.96)  tenofovir disoproxil fumarate is (600 mg/ 200 mg/          ↔ Cmin 0.91 (0.83, 0.99) required.
300 mg/ once daily)/ ledipasvir (90 mg once    Emtricitabine daily)c/ sofosbuvir       ↔ Cmax 1.08 (0.97, 1.21)
(400 mg once daily)c, d   ↔ AUC 1.05 (0.98, 1.11)
↔ Cmin 1.04 (0.98, 1.11)

Tenofovir
↑ Cmax 1.79 (1.56, 2.04)
↑ AUC 1.98 (1.77, 2.23)
↑ Cmin 2.63 (2.32, 2.97)

Ledipasvir
↓ Cmax 0.66 (0.59, 0.75)
↓ AUC 0.66 (0.59, 0.75)
↓ Cmin 0.66 (0.57, 0.76)
Sofosbuvir
↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.94 (0.81, 1.10)

GS-331007
↔ Cmax 0.86 (0.76, 0.96)
↔ AUC 0.90 (0.83, 0.97)
↔ Cmin 1.07 (1.02, 1.13)
Medicinal product by        Effects on medicinal product levels.    Recommendation concerning therapeutic areas        Mean ratio (90% confidence interval)        co-administration with for AUC, Cmax, Cmina, b                    Harvoni
Emtricitabine/              Emtricitabine                           No dose adjustment of Harvoni rilpivirine/ tenofovir      ↔ Cmax 1.02 (0.98, 1.06)                or emtricitabine/ rilpivirine/ disoproxil fumarate         ↔ AUC 1.05 (1.02, 1.08)                 tenofovir disoproxil fumarate is (200 mg/ 25 mg/ 300 mg      ↔ Cmin 1.06 (0.97, 1.15)                required.
once daily)/ ledipasvir
(90 mg once daily)c/        Rilpivirine sofosbuvir (400 mg once     ↔ Cmax 0.97 (0.88, 1.07) daily)c, d                  ↔ AUC 1.02 (0.94, 1.11)
↔ Cmin 1.12 (1.03, 1.21)

Tenofovir
↔ Cmax 1.32 (1.25, 1.39)
↑ AUC 1.40 (1.31, 1.50)
↑ Cmin 1.91 (1.74, 2.10)

Ledipasvir
↔ Cmax 1.01 (0.95, 1.07)
↔ AUC 1.08 (1.02, 1.15)
↔ Cmin 1.16 (1.08, 1.25)
Sofosbuvir
↔ Cmax 1.05 (0.93, 1.20)
↔ AUC 1.10 (1.01, 1.21)

GS-331007
↔ Cmax 1.06 (1.01, 1.11)
↔ AUC 1.15 (1.11, 1.19)
↔ Cmin 1.18 (1.13, 1.24)
Abacavir/ lamivudine        Abacavir                                No dose adjustment of Harvoni (600 mg/ 300 mg once        ↔ Cmax 0.92 (0.87, 0.97)                or abacavir/ lamivudine is daily)/ ledipasvir (90 mg   ↔ AUC 0.90 (0.85, 0.94)                 required.
once daily)c/ sofosbuvir
(400 mg once daily)c, d     Lamivudine
↔ Cmax 0.93 (0.87, 1.00)
↔ AUC 0.94 (0.90, 0.98)
↔ Cmin 1.12 (1.05, 1.20)

Ledipasvir
↔ Cmax 1.10 (1.01, 1.19)
↔ AUC 1.18 (1.10, 1.28)
↔ Cmin 1.26 (1.17, 1.36)

Sofosbuvir
↔ Cmax 1.08 (0.85, 1.35)
↔ AUC 1.21 (1.09, 1.35)
GS-331007
↔ Cmax 1.00 (0.94, 1.07)
↔ AUC 1.05 (1.01, 1.09)
↔ Cmin 1.08 (1.01, 1.14)
Medicinal product by        Effects on medicinal product levels.   Recommendation concerning therapeutic areas       Mean ratio (90% confidence interval)       co-administration with for AUC, Cmax, Cmina, b                Harvoni
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with Atazanavir                                 No dose adjustment of Harvoni ritonavir                 ↔ Cmax 1.07 (1.00, 1.15)                 or atazanavir (ritonavir boosted) (300 mg/ 100 mg once      ↔ AUC 1.33 (1.25, 1.42)                  is required.
daily)/ ledipasvir (90 mg ↑ Cmin 1.75 (1.58, 1.93) once daily)c/ sofosbuvir                                           For the combination of (400 mg once daily)c, d   Ledipasvir                               tenofovir/emtricitabine + ↑ Cmax 1.98 (1.78, 2.20)                 atazanavir/ritonavir, please see ↑ AUC 2.13 (1.89, 2.40)                  below.
↑ Cmin 2.36 (2.08, 2.67)

Sofosbuvir
↔ Cmax 0.96 (0.88, 1.05)
↔ AUC 1.08 (1.02, 1.15)

GS-331007
↔ Cmax 1.13 (1.08, 1.19)
↔ AUC 1.23 (1.18, 1.29)
↔ Cmin 1.28 (1.21, 1.36)
Atazanavir boosted with   Atazanavir                               When given with tenofovir ritonavir (300 mg/        ↔ Cmax 1.07 (0.99, 1.14)                 disoproxil fumarate used in 100 mg once               ↔ AUC 1.27 (1.18, 1.37)                  conjunction with daily) + emtricitabine/   ↑ Cmin 1.63 (1.45, 1.84)                 atazanavir/ritonavir, Harvoni tenofovir disoproxil                                               increased the concentration of fumarate (200 mg/         Ritonavir                                tenofovir.
300 mg once daily)/       ↔ Cmax 0.86 (0.79, 0.93) ledipasvir (90 mg once    ↔ AUC 0.97 (0.89, 1.05)                  The safety of tenofovir daily)c/ sofosbuvir       ↑ Cmin 1.45 (1.27, 1.64)                 disoproxil fumarate in the (400 mg once daily)c, d                                            setting of Harvoni and a Emtricitabine                            pharmacokinetic enhancer (e.g.
Dosed simultaneouslyf     ↔ Cmax 0.98 (0.94, 1.02)                 ritonavir or cobicistat) has not ↔ AUC 1.00 (0.97, 1.04)                  been established.
↔ Cmin 1.04 (0.96, 1.12)
The combination should be used
Tenofovir                                with caution with frequent renal ↑ Cmax 1.47 (1.37, 1.58)                 monitoring, if other alternatives ↔ AUC 1.35 (1.29, 1.42)                  are not available (see
↑ Cmin 1.47 (1.38, 1.57)                 section 4.4).

Ledipasvir                               Atazanavir concentrations are ↑ Cmax 1.68 (1.54, 1.84)                 also increased, with a risk for an ↑ AUC 1.96 (1.74, 2.21)                  increase in bilirubin
↑ Cmin 2.18 (1.91, 2.50)                 levels/icterus. That risk is even higher if ribavirin is used as part
Sofosbuvir                               of the HCV treatment.
↔ Cmax 1.01 (0.88, 1.15)
↔ AUC 1.11 (1.02, 1.21)

GS-331007
↔ Cmax 1.17 (1.12, 1.23)
↔ AUC 1.31 (1.25, 1.36)
↑ Cmin 1.42 (1.34, 1.49)
Medicinal product by        Effects on medicinal product levels.    Recommendation concerning therapeutic areas        Mean ratio (90% confidence interval)         co-administration with for AUC, Cmax, Cmina, b                      Harvoni
Darunavir boosted with      Darunavir                               No dose adjustment of Harvoni ritonavir                   ↔ Cmax 1.02 (0.88, 1.19)                or darunavir (ritonavir boosted) (800 mg/ 100 mg once        ↔ AUC 0.96 (0.84, 1.11)                 is required.
daily)/ ledipasvir (90 mg   ↔ Cmin 0.97 (0.86, 1.10) once daily)d                                                        For the combination of Ledipasvir                              tenofovir/emtricitabine +
↑ Cmax 1.45 (1.34, 1.56)                darunavir/ritonavir, please see ↑ AUC 1.39 (1.28, 1.49)                 below.
↑ Cmin 1.39 (1.29, 1.51)
Darunavir boosted with      Darunavir ritonavir                   ↔ Cmax 0.97 (0.94, 1.01)
(800 mg/ 100 mg once        ↔ AUC 0.97 (0.94, 1.00) daily)/ sofosbuvir          ↔ Cmin 0.86 (0.78, 0.96)
(400 mg once daily)
Sofosbuvir
↑ Cmax 1.45 (1.10, 1.92)
↑ AUC 1.34 (1.12, 1.59)

GS-331007
↔ Cmax 0.97 (0.90, 1.05)
↔ AUC 1.24 (1.18, 1.30)
Darunavir boosted with      Darunavir                               When given with ritonavir (800 mg/          ↔ Cmax 1.01 (0.96, 1.06)                darunavir/ritonavir used in 100 mg once                 ↔ AUC 1.04 (0.99, 1.08)                 conjunction with tenofovir daily) + emtricitabine/     ↔ Cmin 1.08 (0.98, 1.20)                disoproxil fumarate, Harvoni tenofovir disoproxil                                                increased the concentration of fumarate (200 mg/           Ritonavir                               tenofovir.
300 mg once daily)/         ↔ Cmax 1.17 (1.01, 1.35) ledipasvir (90 mg once      ↔ AUC 1.25 (1.15, 1.36)                 The safety of tenofovir daily)c/ sofosbuvir         ↑ Cmin 1.48 (1.34, 1.63)                disoproxil fumarate in the (400 mg once daily)c, d                                             setting of Harvoni and a Emtricitabine                           pharmacokinetic enhancer (e.g.
Dosed simultaneouslyf       ↔ Cmax 1.02 (0.96, 1.08)                ritonavir or cobicistat) has not ↔ AUC 1.04 (1.00, 1.08)                 been established.
↔ Cmin 1.03 (0.97, 1.10)
The combination should be used
Tenofovir                               with caution with frequent renal ↑ Cmax 1.64 (1.54, 1.74)                monitoring, if other alternatives ↑ AUC 1.50 (1.42, 1.59)                 are not available (see
↑ Cmin 1.59 (1.49, 1.70)                section 4.4).

Ledipasvir
↔ Cmax 1.11 (0.99, 1.24)
↔ AUC 1.12 (1.00, 1.25)
↔ Cmin 1.17 (1.04, 1.31)

Sofosbuvir
↓ Cmax 0.63 (0.52, 0.75)
↓ AUC 0.73 (0.65, 0.82)
GS-331007
↔ Cmax 1.10 (1.04, 1.16)
↔ AUC 1.20 (1.16, 1.24)
↔ Cmin 1.26 (1.20, 1.32)
Medicinal product by         Effects on medicinal product levels.    Recommendation concerning therapeutic areas         Mean ratio (90% confidence interval)        co-administration with for AUC, Cmax, Cmina, b                     Harvoni
Lopinavir boosted with     Interaction not studied.                 When given with ritonavir + emtricitabine/ Expected:                                lopinavir/ritonavir used in tenofovir disoproxil       ↑ Lopinavir                              conjunction with tenofovir fumarate                   ↑ Ritonavir                              disoproxil fumarate, Harvoni is expected to increase the
↔ Emtricitabine                           concentration of tenofovir.
↑ Tenofovir
The safety of tenofovir
↑ Ledipasvir                              disoproxil fumarate in the ↔ Sofosbuvir                              setting of Harvoni and a
↔ GS-331007                               pharmacokinetic enhancer (e.g.
ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Tipranavir boosted with   Interaction not studied.                  Co-administration of Harvoni ritonavir                 Expected:                                 with tipranavir (ritonavir ↓ Ledipasvir                              boosted) is expected to decrease ↓ Sofosbuvir                              the concentration of ledipasvir, ↔ GS-331007                               leading to reduced therapeutic effect of Harvoni.
(Induction of P-gp)                       Co-administration is not recommended.
HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir            Raltegravir                                  No dose adjustment of Harvoni (400 mg twice daily)/  ↓ Cmax 0.82 (0.66, 1.02)                     or raltegravir is required.
ledipasvir (90 mg once ↔ AUC 0.85 (0.70, 1.02) daily)d                ↑ Cmin 1.15 (0.90, 1.46)

Ledipasvir
↔ Cmax 0.92 (0.85, 1.00)
↔ AUC 0.91 (0.84, 1.00)
↔ Cmin 0.89 (0.81, 0.98)
Raltegravir               Raltegravir
(400 mg twice daily)/     ↓ Cmax 0.57 (0.44, 0.75) sofosbuvir (400 mg once   ↓ AUC 0.73 (0.59, 0.91) daily)d                   ↔ Cmin 0.95 (0.81, 1.12)

Sofosbuvir
↔ Cmax 0.87 (0.71, 1.08)
↔ AUC 0.95 (0.82, 1.09)
GS-331007
↔ Cmax 1.09 (0.99, 1.19)
↔ AUC 1.02 (0.97, 1.08)
Medicinal product by         Effects on medicinal product levels.    Recommendation concerning therapeutic areas         Mean ratio (90% confidence interval)        co-administration with for AUC, Cmax, Cmina, b                     Harvoni
Elvitegravir/ cobicistat/   Interaction not studied.                 When given with elvitegravir/ emtricitabine/ tenofovir    Expected:                                cobicistat/ emtricitabine/ disoproxil fumarate         ↔ Emtricitabine                          tenofovir disoproxil fumarate, (150 mg/ 150 mg/            ↑ Tenofovir                              Harvoni is expected to increase 200 mg/ 300 mg once                                                  the concentration of tenofovir.
daily)/ ledipasvir (90 mg   Observed: once daily)c/ sofosbuvir    Elvitegravir                             The safety of tenofovir (400 mg once daily)c        ↔ Cmax 0.88 (0.82, 0.95)                 disoproxil fumarate in the ↔ AUC 1.02 (0.95, 1.09)                  setting of Harvoni and a
↑ Cmin 1.36 (1.23, 1.49)                 pharmacokinetic enhancer (e.g.
ritonavir or cobicistat) has not
Cobicistat                               been established.
↔ Cmax 1.25 (1.18, 1.32)
↑ AUC 1.59 (1.49, 1.70)                  The combination should be used ↑ Cmin 4.25 (3.47, 5.22)                 with caution with frequent renal monitoring, if other alternatives
Ledipasvir                               are not available (see
↑ Cmax 1.63 (1.51, 1.75)                 section 4.4).
↑ AUC 1.78 (1.64, 1.94)
↑ Cmin 1.91 (1.76, 2.08)

Sofosbuvir
↑ Cmax 1.33 (1.14, 1.56)
↑ AUC 1.36 (1.21, 1.52)

GS-331007
↑ Cmax 1.33 (1.22, 1.44)
↑ AUC 1.44 (1.41, 1.48)
↑ Cmin 1.53 (1.47, 1.59)
Dolutegravir     Interaction not studied.                            No dose adjustment required.
Expected:
↔ Dolutegravir
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
HERBAL SUPPLEMENTS
St. John’s wort  Interaction not studied.                            Harvoni is contraindicated with Expected:                                           St. John’s wort (see section 4.3).
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007

(Induction of P-gp)
Medicinal product by
Effects on medicinal product levels.        Recommendation concerning Mean ratio (90% confidence interval) therapeutic areas                                              co-administration with for AUC, Cmax, Cmina, b                      Harvoni
HMG-CoA REDUCTASE INHIBITORS
Rosuvastating     ↑ Rosuvastatin                                Co-administration of Harvoni with rosuvastatin may
(Inhibition of drug transporters OATP   significantly increase the and BCRP)                               concentration of rosuvastatin (several fold-increase in AUC) which is associated with increased risk of myopathy,
including rhabdomyolysis.
Co-administration of Harvoni with rosuvastatin is contraindicated (see section 4.3).
Pravastating            ↑ Pravastatin                           Co-administration of Harvoni with pravastatin may significantly increase the concentration of pravastatin which is associated with increased risk of myopathy.
Clinical and biochemical control is recommended in these patients and a dose adjustment may be needed (see section 4.4).
Other statins           Expected:                               Interactions cannot be excluded ↑ Statins                               with other HMG-CoA reductase inhibitors. When co-administered with Harvoni, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken
(see section 4.4).
NARCOTIC ANALGESICS
Methadone               Interaction not studied.                No dose adjustment of Harvoni Expected:                               or methadone is required.
↔ Ledipasvir
Methadone               R-methadone
(Methadone              ↔ Cmax 0.99 (0.85, 1.16) maintenance therapy     ↔ AUC 1.01 (0.85, 1.21)
[30 to 130 mg/ daily])/ ↔ Cmin 0.94 (0.77, 1.14) sofosbuvir (400 mg once daily)d                 S-methadone
↔ Cmax 0.95 (0.79, 1.13)
↔ AUC 0.95 (0.77, 1.17)
↔ Cmin 0.95 (0.74, 1.22)

Sofosbuvir
↓ Cmax 0.95 (0.68, 1.33)
↑ AUC 1.30 (1.00, 1.69)

GS-331007
↓ Cmax 0.73 (0.65, 0.83)
↔ AUC 1.04 (0.89, 1.22)
Medicinal product by   Effects on medicinal product levels.   Recommendation concerning therapeutic areas   Mean ratio (90% confidence interval)      co-administration with for AUC, Cmax, Cmina, b                Harvoni
IMMUNOSUPPRESSANTS
Ciclosporing          Interaction not studied.                 No dose adjustment of Harvoni Expected:                                or ciclosporin is required at ↑ Ledipasvir                             initiation of co-administration.
↔ Ciclosporin                            Afterwards, close monitoring Ciclosporin           Ciclosporin                              and potential dose adjustment of (600 mg single dose)/ ↔ Cmax 1.06 (0.94, 1.18)                 ciclosporin may be required.
sofosbuvir (400 mg    ↔ AUC 0.98 (0.85, 1.14) single dose) h

Sofosbuvir
↑ Cmax 2.54 (1.87, 3.45)
↑ AUC 4.53 (3.26, 6.30)

GS-331007
↓ Cmax 0.60 (0.53, 0.69)
↔ AUC 1.04 (0.90, 1.20)
Tacrolimus              Interaction not studied.               No dose adjustment of Harvoni Expected:                              or tacrolimus is required at
↔ Ledipasvir                           initiation of co-administration.
Tacrolimus              Tacrolimus                             Afterwards, close monitoring (5 mg single dose)/     ↓ Cmax 0.73 (0.59, 0.90)               and potential dose adjustment of sofosbuvir (400 mg      ↑ AUC 1.09 (0.84, 1.40)                tacrolimus may be required.
single dose)h
Sofosbuvir
↓ Cmax 0.97 (0.65, 1.43)
↑ AUC 1.13 (0.81, 1.57)

GS-331007
↔ Cmax 0.97 (0.83, 1.14)
↔ AUC 1.00 (0.87, 1.13)
ORAL CONTRACEPTIVES
Norgestimate/ ethinyl   Norelgestromin                         No dose adjustment of oral estradiol (norgestimate ↔ Cmax 1.02 (0.89, 1.16)               contraceptives is required.
0.180 mg/ 0.215 mg/     ↔ AUC 1.03 (0.90, 1.18)
0.25 mg/ ethinyl        ↔ Cmin 1.09 (0.91, 1.31) estradiol 0.025 mg)/ ledipasvir (90 mg once  Norgestrel daily)d                 ↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.99 (0.82, 1.20)
↔ Cmin 1.00 (0.81, 1.23)

Ethinyl estradiol
↑ Cmax 1.40 (1.18, 1.66)
↔ AUC 1.20 (1.04, 1.39)
↔ Cmin 0.98 (0.79, 1.22)
Medicinal product by       Effects on medicinal product levels.       Recommendation concerning therapeutic areas       Mean ratio (90% confidence interval)          co-administration with for AUC, Cmax, Cmina, b                     Harvoni
Norgestimate/ ethinyl     Norelgestromin estradiol (norgestimate   ↔ Cmax 1.07 (0.94, 1.22)
0.180 mg/ 0.215 mg/       ↔ AUC 1.06 (0.92, 1.21)
0.25 mg/ ethinyl          ↔ Cmin 1.07 (0.89, 1.28) estradiol 0.025 mg)/ sofosbuvir (400 mg once   Norgestrel daily)d                   ↔ Cmax 1.18 (0.99, 1.41)
↑ AUC 1.19 (0.98, 1.45)
↑ Cmin 1.23 (1.00, 1.51)

Ethinyl estradiol
↔ Cmax 1.15 (0.97, 1.36)
↔ AUC 1.09 (0.94, 1.26)
↔ Cmin 0.99 (0.80, 1.23) 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 Harvoni.
d     Lack of pharmacokinetics interaction bounds 70-143%.
e     These are drugs within class where similar interactions could be predicted.
f     Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results.
g     This study was conducted in the presence of another two direct-acting antiviral agents.
h     Bioequivalence/Equivalence boundary 80-125%.