Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low.

Concomitant use not recommended
Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide.

Viread should not be administered concomitantly with adefovir dipivoxil.



Didanosine
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.

Use of tenofovir disoproxil 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).

Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil.

Other interactions
Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily as “q.d.”).

Table 1: Interactions between tenofovir disoproxil and other medicinal products 
Medicinal product by                 Effects on drug levels                     Recommendation therapeutic areas           Mean percent change in AUC, Cmax, Cmin                 concerning (dose in mg)                                                               co-administration with 245 mg tenofovir disoproxil
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors
Atazanavir/Ritonavir              Atazanavir:                                    No dose adjustment is (300 q.d./100 q.d.)               AUC: ↓ 25%                                     recommended. The increased Cmax: ↓ 28%                                    exposure of tenofovir could Cmin: ↓ 26%                                    potentiate
Tenofovir:                                     tenofovir-associated adverse AUC: ↑ 37%                                     events, including renal Cmax: ↑ 34%                                    disorders. Renal function Cmin: ↑ 29%                                    should be closely monitored (see section 4.4).
Lopinavir/Ritonavir               Lopinavir/ritonavir:                           No dose adjustment is (400 b.i.d./100 b.i.d.)           No significant effect on lopinavir/ritonavir   recommended. The increased PK parameters.                                 exposure of tenofovir could Tenofovir:                                     potentiate
AUC: ↑ 32%                                     tenofovir-associated adverse Cmax: ↔                                        events, including renal Cmin: ↑ 51%                                    disorders. Renal function should be closely monitored
(see section 4.4).
Darunavir/Ritonavir               Darunavir:                                     No dose adjustment is (300/100 b.i.d.)                  No significant effect on darunavir/ritonavir   recommended. The increased PK parameters.                                 exposure of tenofovir could Tenofovir:                                     potentiate
AUC: ↑ 22%                                     tenofovir-associated adverse Cmin: ↑ 37%                                    events, including renal disorders. Renal function should be closely monitored
(see section 4.4).


Medicinal product by           Effects on drug levels                    Recommendation therapeutic areas     Mean percent change in AUC, Cmax, Cmin                concerning (dose in mg)                                                        co-administration with 245 mg tenofovir disoproxil
NRTIs
Didanosine                  Co-administration of tenofovir disoproxil     Co-administration of and didanosine results in a 40-60% increase   tenofovir disoproxil and in systemic exposure to didanosine.           didanosine is not recommended
(see section 4.4). 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.
Adefovir dipivoxil          AUC: ↔                                        Tenofovir disoproxil should Cmax: ↔                                       not be administered concurrently with adefovir dipivoxil (see section 4.4).



Medicinal product by                    Effects on drug levels                Recommendation therapeutic areas              Mean percent change in AUC, Cmax, Cmin            concerning (dose in mg)                                                             co-administration with 245 mg tenofovir disoproxil
Entecavir                            AUC: ↔                                   No clinically significant Cmax: ↔                                  pharmacokinetic interactions when tenofovir disoproxil was co-administered with entecavir.
Hepatitis C virus antiviral agents
Ledipasvir/Sofosbuvir                Ledipasvir:                              Increased plasma (90 mg/400 mg q.d.) +                AUC: ↑ 96%                               concentrations of tenofovir Atazanavir/Ritonavir                 Cmax: ↑ 68%                              resulting from (300 mg q.d./100 mg q.d.) +          Cmin: ↑ 118%                             co-administration of Emtricitabine/Tenofovir                                                       tenofovir disoproxil, disoproxil                           Sofosbuvir:                              ledipasvir/sofosbuvir and (200 mg/245 mg q.d.)1                AUC: ↔                                   atazanavir/ritonavir may Cmax: ↔                                  increase adverse reactions related to tenofovir
GS-3310072:                              disoproxil, including renal
AUC: ↔                                   disorders. The safety of
Cmax: ↔                                  tenofovir disoproxil when
Cmin: ↑ 42%                              used with ledipasvir/sofosbuvir and a
Atazanavir:                              pharmacokinetic enhancer
AUC: ↔                                   (e.g. ritonavir or cobicistat) Cmax: ↔                                  has not been established.
Cmin: ↑ 63%
The combination should be
Ritonavir:                               used with caution with
AUC: ↔                                   frequent renal monitoring, if Cmax: ↔                                  other alternatives are not Cmin: ↑ 45%                              available (see section 4.4).

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↑ 47%
Cmin: ↑ 47%


Medicinal product by             Effects on drug levels                  Recommendation therapeutic areas       Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                      co-administration with 245 mg tenofovir disoproxil
Ledipasvir/Sofosbuvir         Ledipasvir:                              Increased plasma (90 mg/400 mg q.d.) +         AUC: ↔                                   concentrations of tenofovir Darunavir/Ritonavir           Cmax: ↔                                  resulting from (800 mg q.d./100 mg q.d.) +   Cmin: ↔                                  co-administration of Emtricitabine/Tenofovir                                                tenofovir disoproxil, disoproxil                    Sofosbuvir:                              ledipasvir/sofosbuvir and (200 mg/245 mg q.d.)1         AUC: ↓ 27%                               darunavir/ritonavir may Cmax: ↓ 37%                              increase adverse reactions related to tenofovir
GS-3310072:                              disoproxil, including renal
AUC: ↔                                   disorders. The safety of
Cmax: ↔                                  tenofovir disoproxil when
Cmin: ↔                                  used with ledipasvir/sofosbuvir and a
Darunavir:                               pharmacokinetic enhancer
AUC: ↔                                   (e.g. ritonavir or cobicistat) Cmax: ↔                                  has not been established.
Cmin: ↔
The combination should be
Ritonavir:                               used with caution with
AUC: ↔                                   frequent renal monitoring, if Cmax: ↔                                  other alternatives are not Cmin: ↑ 48%                              available (see section 4.4).

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 50%
Cmax: ↑ 64%
Cmin: ↑ 59%


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

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

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

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Rilpivirine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40%
Cmax: ↔
Cmin: ↑ 91%



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

Dolutegravir
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 65%
Cmax: ↑ 61%
Cmin: ↑ 115%



Medicinal product by             Effects on drug levels                  Recommendation therapeutic areas       Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                      co-administration with 245 mg tenofovir disoproxil
Sofosbuvir/Velpatasvir        Sofosbuvir:                              Increased plasma (400 mg/100 mg q.d.) +        AUC: ↔                                   concentrations of tenofovir Atazanavir/Ritonavir          Cmax: ↔                                  resulting from (300 mg q.d./100 mg q.d.) +                                            co-administration of Emtricitabine/Tenofovir       GS-3310072:                              tenofovir disoproxil, disoproxil                    AUC: ↔                                   sofosbuvir/velpatasvir and (200 mg/245 mg q.d.)          Cmax: ↔                                  atazanavir/ritonavir may Cmin: ↑ 42%                              increase adverse reactions related to tenofovir
Velpatasvir:                             disoproxil, including renal
AUC: ↑ 142%                              disorders. The safety of
Cmax: ↑ 55%                              tenofovir disoproxil when
Cmin: ↑ 301%                             used with sofosbuvir/velpatasvir and a
Atazanavir:                              pharmacokinetic enhancer
AUC: ↔                                   (e.g. ritonavir or cobicistat) Cmax: ↔                                  has not been established.
Cmin: ↑ 39%
The combination should be
Ritonavir:                               used with caution with
AUC: ↔                                   frequent renal monitoring
Cmax: ↔                                  (see section 4.4).
Cmin: ↑ 29%

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↑ 55%
Cmin: ↑ 39%


Medicinal product by             Effects on drug levels                  Recommendation therapeutic areas       Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                      co-administration with 245 mg tenofovir disoproxil
Sofosbuvir/Velpatasvir        Sofosbuvir:                              Increased plasma (400 mg/100 mg q.d.) +        AUC: ↓28%                                concentrations of tenofovir Darunavir/Ritonavir           Cmax: ↓ 38%                              resulting from (800 mg q.d./100 mg q.d.) +                                            co-administration of Emtricitabine/Tenofovir       GS-3310072:                              tenofovir disoproxil, disoproxil                    AUC: ↔                                   sofosbuvir/velpatasvir and (200 mg/245 mg q.d.)          Cmax: ↔                                  darunavir/ritonavir may Cmin: ↔                                  increase adverse reactions related to tenofovir
Velpatasvir:                             disoproxil, including renal
AUC: ↔                                   disorders. The safety of
Cmax: ↓ 24%                              tenofovir disoproxil when
Cmin: ↔                                  used with sofosbuvir/velpatasvir and a
Darunavir:                               pharmacokinetic enhancer
AUC: ↔                                   (e.g. ritonavir or cobicistat) Cmax: ↔                                  has not been established.
Cmin: ↔
The combination should be
Ritonavir:                               used with caution with
AUC: ↔                                   frequent renal monitoring
Cmax: ↔                                  (see section 4.4).
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 39%
Cmax: ↑ 55%
Cmin: ↑ 52%


Medicinal product by           Effects on drug levels                  Recommendation therapeutic areas     Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                    co-administration with 245 mg tenofovir disoproxil
Sofosbuvir/Velpatasvir      Sofosbuvir:                              Increased plasma (400 mg/100 mg q.d.) +      AUC: ↓ 29%                               concentrations of tenofovir Lopinavir/Ritonavir         Cmax: ↓ 41%                              resulting from (800 mg/200 mg q.d.) +                                               co-administration of Emtricitabine/Tenofovir     GS-3310072:                              tenofovir disoproxil, disoproxil                  AUC: ↔                                   sofosbuvir/velpatasvir and (200 mg/245 mg q.d.)        Cmax: ↔                                  lopinavir/ritonavir may Cmin: ↔                                  increase adverse reactions related to tenofovir
Velpatasvir:                             disoproxil, including renal
AUC: ↔                                   disorders. The safety of
Cmax: ↓ 30%                              tenofovir disoproxil when
Cmin: ↑ 63%                              used with sofosbuvir/velpatasvir and a
Lopinavir:                               pharmacokinetic enhancer
AUC: ↔                                   (e.g. ritonavir or cobicistat) Cmax: ↔                                  has not been established.
Cmin: ↔
The combination should be
Ritonavir:                               used with caution with
AUC: ↔                                   frequent renal monitoring
Cmax: ↔                                  (see section 4.4).
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↑ 42%
Cmin: ↔


Medicinal product by             Effects on drug levels                 Recommendation therapeutic areas       Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                      co-administration with 245 mg tenofovir disoproxil
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       GS-3310072:                              associated with tenofovir disoproxil                    AUC: ↔                                   disoproxil, including renal (200 mg/245 mg q.d.)          Cmax: ↔                                  disorders. Renal function Cmin: ↔                                  should be closely monitored (see section 4.4).
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔

Raltegravir:
AUC: ↔
Cmax: ↔
Cmin: ↓ 21%

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40%
Cmax: ↑ 46%
Cmin: ↑ 70%
Sofosbuvir/Velpatasvir        Sofosbuvir:                              Concomitant administration (400 mg/100 mg q.d.) +        AUC: ↔                                   of sofosbuvir/velpatasvir and Efavirenz/Emtricitabine/      Cmax: ↑ 38%                              efavirenz is expected to Tenofovir disoproxil                                                   decrease plasma (600 mg/200 mg/245 mg q.d.)   GS-3310072:                              concentrations of velpatasvir.
AUC: ↔                                   Co-administration of
Cmax: ↔                                  sofosbuvir/velpatasvir with Cmin: ↔                                  efavirenz-containing regimens is not
Velpatasvir:                             recommended.
AUC: ↓ 53%
Cmax: ↓ 47%
Cmin: ↓ 57%

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 81%
Cmax: ↑ 77%
Cmin: ↑ 121%



Medicinal product by             Effects on drug levels                 Recommendation therapeutic areas       Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                      co-administration with 245 mg tenofovir disoproxil
Sofosbuvir/Velpatasvir       Sofosbuvir:                              No dose adjustment is (400 mg/100 mg q.d.) +       AUC: ↔                                   recommended. The increased Emtricitabine/Rilpivirine/   Cmax: ↔                                  exposure of tenofovir could Tenofovir 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
Cmin: ↔                                  should be closely monitored (see section 4.4).
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Rilpivirine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40%
Cmax: ↑ 44%
Cmin: ↑ 84%



Medicinal product by                 Effects on drug levels                 Recommendation therapeutic areas           Mean percent change in AUC, Cmax, Cmin             concerning (dose in mg)                                                          co-administration with 245 mg tenofovir disoproxil
Sofosbuvir/Velpatasvir/           Sofosbuvir:                              Increased plasma Voxilaprevir (400 mg/100 mg/      AUC: ↔                                   concentrations of tenofovir 100 mg+100 mg q.d.)3 +            Cmax: ↓ 30%                              resulting from co- Darunavir (800 mg q.d.) +         Cmin: N/A                                administration of tenofovir Ritonavir (100 mg q.d.) +                                                  disoproxil, Emtricitabine/Tenofovir           GS-3310072:                              sofosbuvir/velpatasvir/voxila disoproxil (200 mg/245 mg q.d.)   AUC: ↔                                   previr and darunavir/ritonavir Cmax:↔                                   may increase adverse
Cmin: N/A                                reactions related to tenofovir disoproxil, including renal
Velpatasvir:                             disorders.
AUC: ↔                                   The safety of tenofovir
Cmax: ↔                                  disoproxil when used with
Cmin: ↔                                  sofosbuvir/velpatasvir/voxila previr and a pharmacokinetic
Voxilaprevir:                            enhancer (e.g. ritonavir or
AUC: ↑ 143%                              cobicistat) has not been
Cmax:↑ 72%                               established.
Cmin: ↑ 300%
The combination should be
Darunavir:                               used with caution with
AUC: ↔                                   frequent renal monitoring
Cmax: ↔                                  (see section 4.4).
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 therapeutic areas                Mean percent change in AUC, Cmax, Cmin                       concerning (dose in mg)                                                                         co-administration with 245 mg tenofovir disoproxil
Sofosbuvir                              Sofosbuvir:                                        No dose adjustment is (400 mg q.d.) +                         AUC: ↔                                             required.
Efavirenz/Emtricitabine/Tenofovi        Cmax: ↓ 19% r disoproxil
(600 mg/200 mg/245 mg q.d.)             GS-3310072:
AUC: ↔
Cmax: ↓ 23%

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↔
Cmax: ↑ 25%
Cmin: ↔
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.


Studies conducted with other medicinal products
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.

Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir (see section 5.2).