Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Odefsey is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be co-administered with other antiretroviral medicinal products. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. Interaction studies have only been performed in adults.

Emtricitabine

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low.
Co-administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.
Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Rilpivirine

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Rilpivirine inhibits P-glycoprotein (P-gp) in vitro (50% inhibitory concentration [IC50] is 9.2 µM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. Additionally, in a clinical drug-drug interaction study with tenofovir alafenamide, which is more sensitive to intestinal P-gp inhibition, rilpivirine did not affect tenofovir alafenamide exposures when administered concurrently, indicating that rilpivirine is not a P-gp inhibitor in vivo.

Rilpivirine is an in-vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinal products that affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption (see Table 1). Medicinal products that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Odefsey and development of resistance. Co-administration of Odefsey with other medicinal products that inhibit P-gp and BCRP activity (e.g., ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, ciclosporin) is expected to increase the absorption and plasma concentration of tenofovir alafenamide.
Based on data from an in-vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 in vitro. Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is a substrate of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 

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in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.

Concomitant use contraindicated

Co-administration of Odefsey and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine which could potentially lead to loss of virologic response to Odefsey (see section 4.3) and possible resistance to rilpivirine and to the NNRTI class.

Co-administration of Odefsey with proton pump inhibitors has been observed to decrease the plasma concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of virologic response to Odefsey (see section 4.3) and possible resistance to rilpivirine and to the NNRTI class.

Concomitant use where caution is recommended

CYP enzyme inhibitors
Co-administration of Odefsey with medicinal products that inhibit CYP3A enzyme activity has been observed to increase rilpivirine plasma concentrations.

QT prolonging medicinal products
Odefsey should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes (see section 4.4).

Other interactions

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1 in vitro. It is not known whether emtricitabine, or tenofovir alafenamide are inhibitors of other UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro.

Interactions between Odefsey or its individual component(s) and co-administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”).



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Table 1: Interactions between Odefsey or its individual component(s) and other medicinal products

Medicinal product by therapeutic      Effects on medicinal product         Recommendation concerning areas                               levels.                  co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
ANTI-INFECTIVES
Antifungals
Ketoconazole (400 mg once daily)/   Ketoconazole:                         Co-administration is not Rilpivirine1                        AUC: ↓ 24%                            recommended.
Cmin: ↓ 66%
Cmax: ↔

Rilpivirine:
AUC: ↑ 49%
Cmin: ↑ 76%
Cmax: ↑ 30%
Inhibition of CYP3A

Expected:
Tenofovir alafenamide:
AUC: ↑
Cmax: ↑
Inhibition of P-gp
Interaction not studied with tenofovir alafenamide.
Co-administration of ketoconazole is expected to increase plasma concentrations of tenofovir alafenamide (inhibition of P-gp).
Fluconazole                         Interaction not studied with any of   Co-administration is not Itraconazole                        the components of Odefsey.            recommended.
Posaconazole                        Co-administration of these
Voriconazole                        antifungal agents is expected to increase plasma concentrations of rilpivirine (inhibition of CYP3A) and tenofovir alafenamide
(inhibition of P-gp).
Antimycobacterials
Rifampicin/ Rilpivirine             Rifampicin:                           Co-administration is AUC: ↔                                contraindicated.
Cmin: N/A
Cmax: ↔

25-desacetyl-rifampicin:
AUC: ↓ 9%
Cmin: N/A
Cmax: ↔

Rilpivirine:
AUC: ↓ 80%
Cmin: ↓ 89%
Cmax: ↓ 69%
Induction of CYP3A
Expected:

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Medicinal product by therapeutic         Effects on medicinal product         Recommendation concerning areas                                   levels.                 co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
Tenofovir alafenamide:
AUC: ↓
Cmax: ↓
Induction of P-gp

Interaction not studied with tenofovir alafenamide.
Co-administration is likely to cause significant decreases in the plasma concentrations of tenofovir alafenamide (induction of P-gp).
Rifapentine                           Interaction not studied with any of    Co-administration is the components of Odefsey.             contraindicated.
Co-administration is likely to cause significant decreases in the plasma concentrations of rilpivirine
(induction of CYP3A) and tenofovir alafenamide (induction of P-gp).
Rifabutin (300 mg once daily)/        Rifabutin:                             Co-administration is Rilpivirine1                          AUC: ↔                                 contraindicated.
Cmin: ↔
Cmax: ↔

25-O-desacetyl-rifabutin:
AUC: ↔
Cmin: ↔
Cmax: ↔

Rifabutin (300 mg once daily)/        Rilpivirine:
Rilpivirine                           AUC: ↓ 42%
Cmin: ↓ 48%
Cmax: ↓ 31%
Induction of CYP3A

Expected:
Tenofovir alafenamide:
AUC: ↓
Cmax: ↓
Induction of P-gp

Interaction not studied with tenofovir alafenamide.
Co-administration is likely to cause significant decreases in the plasma concentrations of tenofovir alafenamide (induction of P-gp).
Macrolide antibiotics
Clarithromycin                        Interaction not studied with any of    Co-administration is not Erythromycin                          the components of Odefsey. The         recommended.
combination of Odefsey with these macrolide antibiotics may cause an increase in the plasma concentrations of rilpivirine


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Medicinal product by therapeutic      Effects on medicinal product         Recommendation concerning areas                                 levels.                co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
(inhibition of CYP3A) and tenofovir alafenamide (inhibition of
P-gp).
Antiviral agents

Ledipasvir/Sofosbuvir              Ledipasvir:                            No dose adjustment is required.
(90 mg/400 mg once daily)/         AUC: ↑ 2%
Rilpivirine                        Cmin: ↑ 2%
Cmax: ↑ 1%

Sofosbuvir:
AUC: ↑ 5%
Cmax: ↓ 4%
Sofosbuvir metabolite GS-331007:
AUC: ↑ 8%
Cmin: ↑ 10%
Cmax: ↑ 8%

Rilpivirine:
AUC: ↓ 5%
Cmin: ↓ 7%
Cmax: ↓ 3%
Ledipasvir/Sofosbuvir              Tenofovir alafenamide:
(90 mg/400 mg once daily)/         AUC: ↑ 32%
Tenofovir alafenamide              Cmax: ↑ 3%
Sofosbuvir/Velpatasvir             Sofosbuvir:                            No dose adjustment is required.
(400 mg/100 mg once daily)/        AUC: ↔
Rilpivirine2                       Cmax: ↔

Sofosbuvir metabolite GS-331007:
AUC: ↔
Cmin: ↔
Cmax: ↔
Velpatasvir:
AUC: ↔
Cmin: ↔
Cmax: ↔

Rilpivirine:
AUC: ↔
Cmin: ↔
Cmax: ↔



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Medicinal product by therapeutic        Effects on medicinal product      Recommendation concerning areas                                 levels.               co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
Sofosbuvir/Velpatasvir/Voxilaprevir   Sofosbuvir:                        No dose adjustment is required.
(400 mg/100 mg/100 mg + 100 mg        AUC: ↔ once daily)3/                         Cmin: N/A
Emtricitabine/Rilpivirine/Tenofovir   Cmax: ↔ alafenamide (200 mg/25 mg/25 mg once daily)                           Sofosbuvir metabolite GS-331007: AUC: ↔
Cmin: N/A
Cmax: ↔

Velpatasvir:
AUC: ↔
Cmin: ↔
Cmax: ↔

Voxilaprevir:
AUC: ↔
Cmin: ↔
Cmax: ↔
Emtricitabine:
AUC: ↔
Cmin: ↔
Cmax: ↔

Rilpivirine:
AUC: ↔
Cmin: ↔
Cmax: ↔

Tenofovir alafenamide:
AUC: ↑ 52%
Cmin: N/A
Cmax: ↑ 32%
Sofosbuvir (400 mg once daily)/       Sofosbuvir:                        No dose adjustment is required.
Rilpivirine (25 mg once daily)        AUC: ↔
Cmax: ↑ 21%
Sofosbuvir metabolite GS-331007:
AUC: ↔
Cmax: ↔

Rilpivirine:
AUC: ↔
Cmin: ↔
Cmax: ↔



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Medicinal product by therapeutic     Effects on medicinal product          Recommendation concerning areas                              levels.                   co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
ANTICONVULSANTS
Carbamazepine                      Interaction not studied with any of    Co-administration is Oxcarbazepine                      the components of Odefsey.             contraindicated.
Phenobarbital                      Co-administration may cause
Phenytoin                          significant decreases in the plasma concentrations of rilpivirine
(induction of CYP3A) and tenofovir alafenamide (induction of P-gp).
GLUCOCORTICOIDS
Dexamethasone (systemic, except    Interaction not studied with any of    Co-administration is for single dose use)               the components of Odefsey.             contraindicated.
Significant dose dependent decreases in rilpivirine plasma concentrations are expected
(induction of CYP3A).
PROTON PUMP INHIBITORS
Omeprazole (20 mg once daily)/     Omeprazole:                            Co-administration is Rilpivirine1                       AUC: ↓ 14%                             contraindicated.
Cmin: N/A
Cmax: ↓ 14%

Rilpivirine:
AUC: ↓ 40%
Cmin: ↓ 33%
Cmax: ↓ 40%
Reduced absorption, increase in gastric pH
Lansoprazole                       Interaction not studied with any of    Co-administration is Rabeprazole                        the components of Odefsey.             contraindicated.
Pantoprazole                       Significant decreases in rilpivirine Esomeprazole                       plasma concentrations are expected Dexlansoprazole                    (reduced absorption, increase in gastric pH).
HERBAL PRODUCTS
St. John’s wort (Hypericum         Interaction not studied with any of    Co-administration is perforatum)                        the components of Odefsey.             contraindicated.
Co-administration may cause significant decreases in the plasma concentrations of rilpivirine
(induction of CYP3A) and tenofovir alafenamide (induction of P-gp).



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Medicinal product by therapeutic           Effects on medicinal product          Recommendation concerning areas                                    levels.                   co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
H2-RECEPTOR ANTAGONISTS
Famotidine (40 mg single dose            Rilpivirine:                           Only H2-receptor antagonists that taken 12 hours before rilpivirine)/      AUC: ↓ 9%                              can be dosed once daily should be Rilpivirine1                             Cmin: N/A                              used. A strict dosing schedule Cmax: ↔                                with intake of the H2-receptor antagonists at least 12 hours
Famotidine (40 mg single dose            Rilpivirine:                           before or at least 4 hours after taken 2 hours before rilpivirine)/       AUC: ↓ 76%                             Odefsey should be used.
Rilpivirine1                             Cmin: N/A
Cmax: ↓ 85%
Reduced absorption, increase in gastric pH

Famotidine (40 mg single dose            Rilpivirine: taken 4 hours after rilpivirine)/        AUC: ↑ 13%
Rilpivirine1                             Cmin: N/A
Cmax: ↑ 21%
Cimetidine                               Interaction not studied with any of Nizatidine                               the components of Odefsey.
Ranitidine                               Co-administration may cause significant decreases in rilpivirine plasma concentrations (reduced absorption, increase in gastric pH).
ANTACIDS
Antacids (e.g., aluminium or             Interaction not studied with any of    Antacids should only be magnesium hydroxide, calcium             the components of Odefsey.             administered either at least carbonate)                               Co-administration may cause            2 hours before or at least 4 hours significant decreases in rilpivirine   after Odefsey.
plasma concentrations (reduced absorption, increase in gastric pH).
ORAL CONTRACEPTIVES
Ethinylestradiol (0.035 mg once          Ethinylestradiol:                      No dose adjustment is required.
daily)/ Rilpivirine                      AUC: ↔
Cmin: ↔
Cmax: ↑ 17%

Norethindrone (1 mg once daily)/         Norethindrone:
Rilpivirine                              AUC: ↔
Cmin: ↔
Cmax: ↔

Rilpivirine:
AUC: ↔*
Cmin: ↔*
Cmax: ↔*
*based on historic controls



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Medicinal product by therapeutic       Effects on medicinal product         Recommendation concerning areas                                levels.                  co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
Norgestimate                         Norelgestromin:                       No dose adjustment is required.
(0.180/0.215/0.250 mg once daily)/   AUC: ↔
Ethinylestradiol (0.025 mg once      Cmin: ↔ daily)/ Emtricitabine/Tenofovir      Cmax: ↔ alafenamide (200/25 mg once daily)
Norgestrel:
AUC: ↔
Cmin: ↔
Cmax: ↔

Ethinylestradiol:
AUC: ↔
Cmin: ↔
Cmax: ↔
NARCOTIC ANALGESICS
Methadone (60-100 mg once daily,     R(-) methadone:                       No dose adjustments are required.
individualised dose)/ Rilpivirine    AUC: ↓ 16%
Cmin: ↓ 22%                           Clinical monitoring is
Cmax: ↓ 14%                           recommended as methadone maintenance therapy may need to
S(+) methadone:                       be adjusted in some patients.
AUC: ↓ 16%
Cmin: ↓ 21%
Cmax: ↓ 13%

Rilpivirine:
AUC: ↔*
Cmin: ↔*
Cmax: ↔*
*based on historic controls
ANALGESICS
Paracetamol (500 mg single dose)/    Paracetamol:                          No dose adjustment is required.
Rilpivirine1                         AUC: ↔
Cmin: N/A
Cmax: ↔
Rilpivirine:
AUC: ↔
Cmin: ↑ 26%
Cmax: ↔
ANTIARRHYTHMICS
Digoxin/ Rilpivirine                 Digoxin:                              No dose adjustment is required.
AUC: ↔
Cmin: N/A
Cmax: ↔
ANTICOAGULANTS
Dabigatran etexilate                 Interaction not studied with any of   Co-administration should be used the components of Odefsey.            with caution.
A risk for increases in dabigatran plasma concentrations cannot be excluded (inhibition of intestinal
P-gp).



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Medicinal product by therapeutic             Effects on medicinal product             Recommendation concerning areas                                      levels.                      co-administration with Odefsey Mean percent change in AUC,
Cmax, Cmin
IMMUNOSUPPRESSANTS
Ciclosporin                               Interaction not studied with any of       Co-administration is not the components of Odefsey.                recommended.
Co-administration of ciclosporin is expected to increase plasma concentrations of rilpivirine
(inhibition of CYP3A) and tenofovir alafenamide (inhibition of
P-gp).
ANTIDIABETICS
Metformin (850 mg single dose)/  Metformin:                                         No dose adjustment is required.
Rilpivirine                      AUC: ↔
Cmin: N/A
Cmax: ↔
HMG CO-A REDUCTASE INHIBITORS
Atorvastatin (40 mg once daily)/ Atorvastatin:                                      No dose adjustment is required.
Rilpivirine1                     AUC: ↔
Cmin: ↓ 15%
Cmax: ↑ 35%

Rilpivirine:
AUC: ↔
Cmin: ↔
Cmax: ↓ 9%
PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS
Sildenafil (50 mg single dose)/ Sildenafil:                                         No dose adjustment is required.
Rilpivirine1                    AUC: ↔
Cmin: N/A
Cmax: ↔

Rilpivirine:
AUC: ↔
Cmin: ↔
Cmax: ↔
Vardenafil                                Interaction not studied with any of       No dose adjustment is required.
Tadalafil                                 the components of Odefsey. These are medicinal products within class where similar interactions could be predicted.
HYPNOTICS/SEDATIVES
Midazolam (2.5 mg, orally, single         Midazolam:                                No dose adjustment is required.
dose)/ Tenofovir alafenamide              AUC: ↑ 12%
Cmin: N/A
Cmax: ↑ 2%

Midazolam (1 mg, intravenously,           Midazolam: single dose)/ Tenofovir alafenamide       AUC: ↑ 8%
Cmin: N/A
Cmax: ↓ 1%
N/A = not applicable
1  This interaction study has been performed with a dose higher than the recommended dose for rilpivirine hydrochloride assessing the maximal effect on the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of rilpivirine of 25 mg once daily.


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2     Study conducted with emtricitabine/rilpivirine/tenofovir disoproxil fumarate fixed-dose combination tablet.
3     Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

Studies conducted with other medicinal products
Based on drug-drug interaction studies conducted with the components of Odefsey, no clinically significant interactions are expected when Odefsey is combined with the following medicinal products: buprenorphine, naloxone and norbuprenorphine.