Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
As Truvada contains emtricitabine and tenofovir disoproxil, any interactions that have been identified with these agents individually may occur with Truvada. Interaction studies have only been performed in adults.

The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil were administered together versus each medicinal product dosed alone.

In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP450 mediated interactions involving emtricitabine and tenofovir disoproxil with other medicinal products is low.

Concomitant use not recommended

Truvada should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide or other cytidine analogues, such as lamivudine (see section 4.4). Truvada should not be administered concomitantly with adefovir dipivoxil.

Didanosine: The co-administration of Truvada and didanosine is not recommended (see section 4.4 and Table 2).

Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Truvada with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of Truvada should be avoided with concurrent or recent use of a nephrotoxic medicinal product.
Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

Other interactions

Interactions between Truvada or its individual component(s) and other medicinal products are listed in Table 2 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.” and once daily as “q.d.”). If available, 90% confidence intervals are shown in parentheses.


Table 2: Interactions between Truvada or its individual component(s) and other medicinal products

Medicinal product by                Effects on drug levels        Recommendation concerning therapeutic areas             Mean percent change in AUC,      co-administration with Truvada Cmax, Cmin with 90% confidence   (emtricitabine 200 mg, tenofovir intervals if available            disoproxil 245 mg)
(mechanism)
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors
Atazanavir/Ritonavir/Tenofovir       Atazanavir:                      No dose adjustment is disoproxil                           AUC: ↓ 25% (↓ 42 to ↓ 3)         recommended. The increased (300 mg q.d./100 mg q.d./245 mg      Cmax: ↓ 28% (↓ 50 to ↑ 5)        exposure of tenofovir could q.d.)                                Cmin: ↓ 26% (↓ 46 to ↑ 10)       potentiate tenofovir associated adverse events, including renal
Tenofovir:                       disorders. Renal function should
AUC: ↑ 37%                       be closely monitored (see
Cmax: ↑ 34%                      section 4.4).
Cmin: ↑ 29%
Atazanavir/Ritonavir/Emtricitabine   Interaction not studied.
Darunavir/Ritonavir/Tenofovir        Darunavir:                       No dose adjustment is disoproxil                           AUC: ↔                           recommended. The increased (300 mg q.d./100 mg q.d./245 mg      Cmin: ↔                          exposure of tenofovir could q.d.)                                                                 potentiate tenofovir associated Tenofovir:                       adverse events, including renal
AUC: ↑ 22%                       disorders. Renal function should
Cmin: ↑ 37%                      be closely monitored (see
Darunavir/Ritonavir/Emtricitabine    Interaction not studied.         section 4.4).
Lopinavir/Ritonavir/Tenofovir        Lopinavir/Ritonavir:             No dose adjustment is disoproxil                           AUC: ↔                           recommended. The increased (400 mg b.i.d./100 mg b.i.d/245 mg   Cmax: ↔                          exposure of tenofovir could q.d.)                                Cmin: ↔                          potentiate tenofovir associated adverse events, including renal
Tenofovir:                       disorders. Renal function should
AUC: ↑ 32% (↑ 25 to ↑ 38)        be closely monitored (see
Cmax: ↔                          section 4.4).
Cmin: ↑ 51% (↑ 37 to ↑ 66)
Lopinavir/Ritonavir/Emtricitabine    Interaction not studied.


Medicinal product by             Effects on drug levels           Recommendation concerning therapeutic areas          Mean percent change in AUC,         co-administration with Truvada Cmax, Cmin with 90% confidence      (emtricitabine 200 mg, tenofovir intervals if available               disoproxil 245 mg)
(mechanism)
NRTIs
Didanosine/Tenofovir disoproxil   Co-administration of tenofovir      Co-administration of Truvada and disoproxil and didanosine results   didanosine is not recommended in a 40-60% increase in systemic    (see section 4.4).
exposure to didanosine.
Didanosine/Emtricitabine          Interaction not studied.            Increased systemic exposure to didanosine may increase didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal,
have been reported.
Co-administration of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count,
possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of
250 mg didanosine co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.
Lamivudine/Tenofovir disoproxil   Lamivudine:                         Lamivudine and Truvada should AUC: ↓ 3% (↓ 8% to ↑ 15)            not be administered concomitantly Cmax: ↓ 24% (↓ 44 to ↓ 12)          (see section 4.4).
Cmin: NC

Tenofovir:
AUC: ↓ 4% (↓ 15 to ↑ 8)
Cmax: ↑ 102% (↓ 96 to ↑ 108)
Cmin: NC
Efavirenz/Tenofovir disoproxil    Efavirenz:                          No dose adjustment of efavirenz is AUC: ↓ 4% (↓ 7 to ↓ 1)              required.
Cmax: ↓ 4% (↓ 9 to ↑ 2)
Cmin: NC

Tenofovir:
AUC: ↓ 1% (↓ 8 to ↑ 6)
Cmax: ↑ 7% (↓ 6 to ↑ 22)
Cmin: NC


Medicinal product by               Effects on drug levels        Recommendation concerning therapeutic areas            Mean percent change in AUC,      co-administration with Truvada Cmax, Cmin with 90% confidence   (emtricitabine 200 mg, tenofovir intervals if available            disoproxil 245 mg)
(mechanism)
ANTI-INFECTIVES
Hepatitis B virus (HBV) antiviral agents
Adefovir dipivoxil/Tenofovir        Adefovir dipivoxil:              Adefovir dipivoxil and Truvada disoproxil                          AUC: ↓ 11% (↓ 14 to ↓ 7)         should not be administered Cmax: ↓ 7% (↓ 13 to ↓ 0)         concomitantly (see section 4.4).
Cmin: NC

Tenofovir:
AUC: ↓ 2% (↓ 5 to ↑ 0)
Cmax: ↓ 1% (↓ 7 to ↑ 6)
Cmin: NC
Hepatitis C virus (HCV) antiviral agents
Ledipasvir/Sofosbuvir               Ledipasvir:                      Increased plasma concentrations (90 mg/400 mg q.d.) +               AUC: ↑ 96% (↑ 74 to ↑ 121)       of tenofovir resulting from Atazanavir/Ritonavir                Cmax: ↑ 68% (↑ 54 to ↑ 84)       co-administration of tenofovir (300 mg q.d./100 mg q.d.) +         Cmin: ↑ 118% (↑ 91 to ↑ 150)     disoproxil, ledipasvir/sofosbuvir Emtricitabine/Tenofovir disoproxil                                   and atazanavir/ritonavir may (200 mg/245 mg q.d.)1               Sofosbuvir:                      increase adverse reactions related AUC: ↔                           to tenofovir disoproxil, including Cmax: ↔                          renal disorders. The safety of tenofovir disoproxil when used
GS-3310072:                      with ledipasvir/sofosbuvir and a
AUC: ↔                           pharmacokinetic enhancer (e.g.
Cmax: ↔                          ritonavir or cobicistat) has not
Cmin: ↑ 42% (↑ 34 to ↑ 49)       been established.

Atazanavir:                      The combination should be used
AUC: ↔                           with caution with frequent renal
Cmax: ↔                          monitoring, if other alternatives
Cmin: ↑ 63% (↑ 45 to ↑ 84)       are not available (see section 4.4).

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 45% (↑ 27 to ↑ 64)
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↑ 47% (↑ 37 to ↑ 58)
Cmin: ↑ 47% (↑ 38 to ↑ 57)


Medicinal product by                Effects on drug levels        Recommendation concerning therapeutic areas             Mean percent change in AUC,      co-administration with Truvada Cmax, Cmin with 90% confidence   (emtricitabine 200 mg, tenofovir intervals if available            disoproxil 245 mg)
(mechanism)
Ledipasvir/Sofosbuvir                Ledipasvir:                      Increased plasma concentrations (90 mg/400 mg q.d.) +                AUC: ↔                           of tenofovir resulting from Darunavir/Ritonavir                  Cmax: ↔                          co-administration of tenofovir (800 mg q.d./100 mg q.d.) +          Cmin: ↔                          disoproxil, ledipasvir/sofosbuvir Emtricitabine/Tenofovir disoproxil                                    and darunavir/ritonavir may (200 mg/245 mg q.d.)1                Sofosbuvir:                      increase adverse reactions related AUC: ↓ 27% (↓ 35 to ↓ 18)        to tenofovir disoproxil, including Cmax: ↓ 37% (↓ 48 to ↓ 25)       renal disorders. The safety of tenofovir disoproxil when used
GS-3310072:                      with ledipasvir/sofosbuvir and a
AUC: ↔                           pharmacokinetic enhancer (e.g.
Cmax: ↔                          ritonavir or cobicistat) has not
Cmin: ↔                          been established.

Darunavir:                       The combination should be used
AUC: ↔                           with caution with frequent renal
Cmax: ↔                          monitoring, if other alternatives
Cmin: ↔                          are not available (see section 4.4).

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 48% (↑ 34 to ↑ 63)
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 50% (↑ 42 to ↑ 59)
Cmax: ↑ 64% (↑ 54 to ↑ 74)
Cmin: ↑ 59% (↑ 49 to ↑ 70)


Medicinal product by               Effects on drug levels        Recommendation concerning therapeutic areas            Mean percent change in AUC,      co-administration with Truvada Cmax, Cmin with 90% confidence   (emtricitabine 200 mg, tenofovir intervals if available            disoproxil 245 mg)
(mechanism)
Ledipasvir/Sofosbuvir               Ledipasvir:                      No dose adjustment is (90 mg/400 mg q.d.) +               AUC: ↓ 34% (↓ 41 to ↓ 25)        recommended. The increased Efavirenz/Emtricitabine/Tenofovir   Cmax: ↓ 34% (↓ 41 to ↑ 25)       exposure of tenofovir could disoproxil                          Cmin: ↓ 34% (↓ 43 to ↑ 24)       potentiate adverse reactions (600 mg/200 mg/245 mg q.d.)                                          associated with tenofovir Sofosbuvir:                      disoproxil, including renal
AUC: ↔                           disorders. Renal function should
Cmax: ↔                          be closely monitored (see section 4.4).
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 98% (↑ 77 to ↑ 123)
Cmax: ↑ 79% (↑ 56 to ↑ 104)
Cmin: ↑ 163% (↑ 137 to ↑ 197)
Ledipasvir/Sofosbuvir               Ledipasvir:                      No dose adjustment is (90 mg/400 mg q.d.) +               AUC: ↔                           recommended. The increased Emtricitabine/Rilpivirine/          Cmax: ↔                          exposure of tenofovir could Tenofovir disoproxil                Cmin: ↔                          potentiate adverse reactions (200 mg/25 mg/245 mg q.d.)                                           associated with tenofovir Sofosbuvir:                      disoproxil, including renal
AUC: ↔                           disorders. Renal function should
Cmax: ↔                          be closely monitored (see section 4.4).
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Rilpivirine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40% (↑ 31 to ↑ 50)
Cmax: ↔
Cmin: ↑ 91% (↑ 74 to ↑ 110)


Medicinal product by                Effects on drug levels      Recommendation concerning therapeutic areas             Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available           disoproxil 245 mg)
(mechanism)
Ledipasvir/Sofosbuvir                Sofosbuvir:                    No dose adjustment is required.
(90 mg/400 mg q.d.) +                AUC: ↔                         The increased exposure of Dolutegravir (50 mg q.d.) +          Cmax: ↔                        tenofovir could potentiate adverse Emtricitabine/Tenofovir disoproxil                                  reactions associated with tenofovir (200 mg/245 mg q.d.)                 GS-3310072                     disoproxil, including renal AUC: ↔                         disorders. Renal function should
Cmax: ↔                        be closely monitored (see section
Cmin: ↔                        4.4).

Ledipasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔

Dolutegravir
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 65% (↑ 59 to ↑ 71)
Cmax: ↑ 61% (↑ 51 to ↑ 72)
Cmin: ↑ 115% (↑ 105 to ↑ 126)


Medicinal product by                Effects on drug levels       Recommendation concerning therapeutic areas             Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available           disoproxil 245 mg)
(mechanism)
Sofosbuvir/Velpatasvir               Sofosbuvir:                    Increased plasma concentrations (400 mg/100 mg q.d.) +               AUC: ↔                         of tenofovir resulting from Atazanavir/Ritonavir                 Cmax: ↔                        co-administration of tenofovir (300 mg q.d./100 mg q.d.) +                                         disoproxil, sofosbuvir/velpatasvir Emtricitabine/Tenofovir disoproxil   GS-3310072:                    and atazanavir/ritonavir may (200 mg/245 mg q.d.)                 AUC: ↔                         increase adverse reactions related Cmax: ↔                        to tenofovir disoproxil, including
Cmin: ↑ 42% (↑ 37 to ↑ 49)     renal disorders. The safety of tenofovir disoproxil when used
Velpatasvir:                   with sofosbuvir/velpatasvir and a
AUC: ↑ 142% (↑ 123 to ↑ 164)   pharmacokinetic enhancer (e.g.
Cmax: ↑ 55% (↑ 41 to ↑ 71)     ritonavir or cobicistat) has not Cmin: ↑ 301% (↑ 257 to ↑ 350)  been established.

Atazanavir:                      The combination should be used
AUC: ↔                           with caution with frequent renal
Cmax: ↔                          monitoring (see section 4.4).
Cmin: ↑ 39% (↑ 20 to ↑ 61)

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 29% (↑ 15 to ↑ 44)
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↑ 55% (↑ 43 to ↑ 68)
Cmin: ↑ 39% (↑ 31 to ↑ 48)


Medicinal product by                Effects on drug levels       Recommendation concerning therapeutic areas             Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available           disoproxil 245 mg)
(mechanism)
Sofosbuvir/Velpatasvir               Sofosbuvir:                    Increased plasma concentrations (400 mg/100 mg q.d.) +               AUC: ↓ 28% (↓ 34 to ↓ 20)      of tenofovir resulting from Darunavir/Ritonavir                  Cmax: ↓ 38% (↓ 46 to ↓ 29)     co-administration of tenofovir (800 mg q.d./100 mg q.d.) +                                         disoproxil, sofosbuvir/velpatasvir Emtricitabine/Tenofovir disoproxil   GS-3310072:                    and darunavir/ritonavir may (200 mg/245 mg q.d.)                 AUC: ↔                         increase adverse reactions related Cmax: ↔                        to tenofovir disoproxil, including
Cmin: ↔                        renal disorders. The safety of tenofovir disoproxil when used
Velpatasvir:                   with sofosbuvir/velpatasvir and a
AUC: ↔                         pharmacokinetic enhancer (e.g.
Cmax: ↓ 24% (↓ 35 to ↓ 11)     ritonavir or cobicistat) has not Cmin: ↔                        been established.

Darunavir:                       The combination should be used
AUC: ↔                           with caution with frequent renal
Cmax: ↔                          monitoring (see section 4.4).
Cmin: ↔

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 39% (↑ 33 to ↑ 44)
Cmax: ↑ 55% (↑ 45 to ↑ 66)
Cmin: ↑ 52% (↑ 45 to ↑ 59)


Medicinal product by                Effects on drug levels       Recommendation concerning therapeutic areas             Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available           disoproxil 245 mg)
(mechanism)
Sofosbuvir/Velpatasvir               Sofosbuvir:                    Increased plasma concentrations (400 mg/100 mg q.d.) +               AUC: ↓ 29% (↓ 36 to ↓ 22)      of tenofovir resulting from Lopinavir/Ritonavir                  Cmax: ↓ 41% (↓ 51 to ↓ 29)     co-administration of tenofovir (800 mg/200 mg q.d.) +                                              disoproxil, sofosbuvir/velpatasvir Emtricitabine/Tenofovir disoproxil   GS-3310072:                    and lopinavir/ritonavir may (200 mg/245 mg q.d.)                 AUC: ↔                         increase adverse reactions related Cmax: ↔                        to tenofovir disoproxil, including
Cmin: ↔                        renal disorders. The safety of tenofovir disoproxil when used
Velpatasvir:                   with sofosbuvir/velpatasvir and a
AUC: ↔                         pharmacokinetic enhancer (e.g.
Cmax: ↓ 30% (↓ 41 to ↓ 17)     ritonavir or cobicistat) has not Cmin: ↑ 63% (↑ 43 to ↑ 85)     been established.

Lopinavir:                       The combination should be used
AUC: ↔                           with caution with frequent renal
Cmax: ↔                          monitoring (see section 4.4).
Cmin: ↔

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↑ 42% (↑ 27 to ↑ 57)
Cmin: ↔


Medicinal product by                Effects on drug levels      Recommendation concerning therapeutic areas             Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available           disoproxil 245 mg)
(mechanism)
Sofosbuvir/Velpatasvir               Sofosbuvir:                    No dose adjustment is (400 mg/100 mg q.d.) +               AUC: ↔                         recommended. The increased Raltegravir                          Cmax: ↔                        exposure of tenofovir could (400 mg b.i.d) +                                                    potentiate adverse reactions Emtricitabine/Tenofovir disoproxil   GS-3310072:                    associated with tenofovir (200 mg/245 mg q.d.)                 AUC: ↔                         disoproxil, including renal Cmax: ↔                        disorders. Renal function should
Cmin: ↔                        be closely monitored (see section 4.4).
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔

Raltegravir:
AUC: ↔
Cmax: ↔
Cmin: ↓ 21% (↓ 58 to ↑ 48)

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40% (↑ 34 to ↑ 45)
Cmax: ↑ 46% (↑ 39 to ↑ 54)
Cmin: ↑ 70% (↑ 61 to ↑ 79)
Sofosbuvir/Velpatasvir               Sofosbuvir:                     Concomitant administration of (400 mg/100 mg q.d.) +               AUC: ↔                          sofosbuvir/velpatasvir and Efavirenz/Emtricitabine/Tenofovir    Cmax: ↑ 38% (↑ 14 to ↑ 67)      efavirenz is expected to decrease disoproxil                                                           plasma concentrations of (600 mg/200 mg/245 mg q.d.)          GS-3310072:                     velpatasvir. Co-administration of AUC: ↔                          sofosbuvir/velpatasvir with
Cmax: ↔                         efavirenz-containing regimens is
Cmin: ↔                         not recommended.

Velpatasvir:
AUC: ↓ 53% (↓ 61 to ↓ 43)
Cmax: ↓ 47% (↓ 57 to ↓ 36)
Cmin: ↓ 57% (↓ 64 to ↓ 48)

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 81% (↑ 68 to ↑ 94)
Cmax: ↑ 77% (↑ 53 to ↑ 104)
Cmin: ↑ 121% (↑ 100 to ↑ 143)

Medicinal product by                Effects on drug levels      Recommendation concerning therapeutic areas             Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available           disoproxil 245 mg)
(mechanism)
Sofosbuvir/Velpatasvir              Sofosbuvir:                    No dose adjustment is (400 mg/100 mg q.d.) +              AUC: ↔                         recommended. The increased Emtricitabine/Rilpivirine/Tenofovir Cmax: ↔                        exposure of tenofovir could disoproxil                                                         potentiate adverse reactions (200 mg/25 mg/245 mg q.d.)          GS-3310072:                    associated with tenofovir AUC: ↔                         disoproxil, including renal
Cmax: ↔                        disorders. Renal function should
Cmin: ↔                        be closely monitored (see section 4.4).
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Rilpivirine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40% (↑ 34 to ↑ 46)
Cmax: ↑ 44% (↑ 33 to ↑ 55)
Cmin: ↑ 84% (↑ 76 to ↑ 92)


Medicinal product by                Effects on drug levels        Recommendation concerning therapeutic areas             Mean percent change in AUC,      co-administration with Truvada Cmax, Cmin with 90% confidence   (emtricitabine 200 mg, tenofovir intervals if available            disoproxil 245 mg)
(mechanism)
Sofosbuvir/Velpatasvir/             Sofosbuvir:                      Increased plasma concentrations Voxilaprevir (400 mg/100 mg/        AUC: ↔                           of tenofovir resulting from 100 mg+100 mg q.d.)3 + Darunavir    Cmax: ↓ 30%                      co-administration of tenofovir (800 mg q.d.) + Ritonavir (100 mg   Cmin: N/A                        disoproxil, q.d.) + Emtricitabine/Tenofovir                                      sofosbuvir/velpatasvir/voxilaprevir disoproxil (200 mg/245 mg q.d.)     GS-3310072:                      and darunavir/ritonavir may AUC: ↔                           increase adverse reactions related Cmax:↔                           to tenofovir disoproxil, including Cmin: N/A                        renal disorders. The safety of tenofovir disoproxil when used
Velpatasvir:                     with
AUC: ↔                           sofosbuvir/velpatasvir/voxilaprevir Cmax: ↔                          and a pharmacokinetic enhancer
Cmin: ↔                          (e.g. ritonavir or cobicistat) has not been established.
Voxilaprevir:
AUC: ↑ 143%                      The combination should be used
Cmax:↑ 72%                       with caution with frequent renal
Cmin: ↑ 300%                     monitoring (see section 4.4).

Darunavir:
AUC: ↔
Cmax: ↔
Cmin: ↓ 34%

Ritonavir:
AUC: ↑ 45%
Cmax: ↑ 60%
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 39%
Cmax: ↑ 48%
Cmin: ↑ 47%


Medicinal product by               Effects on drug levels      Recommendation concerning therapeutic areas            Mean percent change in AUC, co-administration with Truvada Cmax, Cmin with 90% confidence (emtricitabine 200 mg, tenofovir intervals if available          disoproxil 245 mg)
(mechanism)
Sofosbuvir                          Sofosbuvir:                    No dose adjustment is required.
(400 mg q.d.) +                     AUC: ↔
Efavirenz/Emtricitabine/Tenofovir   Cmax: ↓ 19% (↓ 40 to ↑ 10) disoproxil
(600 mg/200 mg/245 mg q.d.)         GS-3310072:
AUC: ↔
Cmax: ↓ 23% (↓ 30 to ↑ 16)

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↔
Cmax: ↑ 25% (↑ 8 to ↑ 45)
Cmin: ↔
Ribavirin/Tenofovir disoproxil      Ribavirin:                      No dose adjustment of ribavirin is AUC: ↑ 26% (↑ 20 to ↑ 32)       required.
Cmax: ↓ 5% (↓ 11 to ↑ 1)
Cmin: NC
Herpes virus antiviral agents
Famciclovir/Emtricitabine           Famciclovir:                    No dose adjustment of famciclovir AUC: ↓ 9% (↓ 16 to ↓ 1)         is required.
Cmax: ↓ 7% (↓ 22 to ↑ 11)
Cmin: NC

Emtricitabine:
AUC: ↓ 7% (↓ 13 to ↓ 1)
Cmax: ↓ 11% (↓ 20 to ↑ 1)
Cmin: NC
Antimycobacterials
Rifampicin/Tenofovir disoproxil     Tenofovir:                      No dose adjustment is required.
AUC: ↓ 12% (↓ 16 to ↓ 8)
Cmax: ↓ 16% (↓ 22 to ↓ 10)
Cmin: ↓ 15% (↓ 12 to ↓ 9)


Medicinal product by                   Effects on drug levels               Recommendation concerning therapeutic areas                Mean percent change in AUC,             co-administration with Truvada Cmax, Cmin with 90% confidence          (emtricitabine 200 mg, tenofovir intervals if available                   disoproxil 245 mg)
(mechanism)
ORAL CONTRACEPTIVES
Norgestimate/Ethinyl                      Norgestimate:                         No dose adjustment of oestradiol/Tenofovir disoproxil           AUC: ↓ 4% (↓ 32 to ↑ 34)              norgestimate/ethinyl oestradiol is Cmax: ↓ 5% (↓ 27 to ↑ 24)             required.
Cmin: NC

Ethinyl oestradiol:
AUC: ↓ 4% (↓ 9 to ↑ 0)
Cmax: ↓ 6% (↓ 13 to ↑ 0)
Cmin: ↓ 2% (↓ 9 to ↑ 6)
IMMUNOSUPPRESSANTS
Tacrolimus/Tenofovir                      Tacrolimus:                           No dose adjustment of tacrolimus disoproxil/Emtricitabine                  AUC: ↑ 4% (↓ 3 to ↑ 11)               is required.
Cmax: ↑ 3% (↓ 3 to ↑ 9)
Cmin: NC
Emtricitabine:
AUC: ↓ 5% (↓ 9 to ↓ 1)
Cmax: ↓ 11% (↓ 17 to ↓ 5)
Cmin: NC

Tenofovir:
AUC: ↑ 6% (↓ 1 to ↑ 13)
Cmax: ↑13% (↑ 1 to ↑ 27)
Cmin: NC
NARCOTIC ANALGESICS
Methadone/Tenofovir disoproxil            Methadone:                            No dose adjustment of methadone AUC: ↑ 5% (↓ 2 to ↑ 13)               is required.
Cmax: ↑ 5% (↓ 3 to ↑ 14)
Cmin: NC
NC = not calculated.
N/A = not applicable.
1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provided  similar results.
2 The predominant circulating metabolite of sofosbuvir.
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.