Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Medicinal products that affect rilpivirine exposure
Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of rilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine.
Co-administration of rilpivirine and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine.
Co-administration of rilpivirine with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of EDURANT.

Medicinal products that are affected by the use of rilpivirine
Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicines transported by P-glycoprotein that are more sensitive to intestinal P-gp inhibition, e.g. dabigatran etexilate.

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.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in table 1.

Interaction table
Interaction studies have only been performed in adults.

Interactions between rilpivirine and co-administered medicinal products are listed in table 1 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as “CI”).

Table 1:      INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by                   Interaction Geometric     Recommendations therapeutic areas           mean change (%)                           concerning co- ANTI-INFECTIVES                                                            administration Antiretrovirals
HIV NRTIs/N[t]RTIs
Didanosine*#              didanosine AUC ↑12%                No dose adjustment is required.
400 mg once daily         didanosine Cmin NA                 Didanosine should be didanosine Cmax↔                   administered at least two hours rilpivirine AUC↔                   before or at least four hours after rilpivirine Cmin ↔                 rilpivirine.
rilpivirine Cmax ↔
Tenofovir disoproxil *#     tenofovir AUC ↑ 23%                    No dose adjustment is required.
245 mg once daily           tenofovir Cmin ↑ 24% tenofovir Cmax ↑ 19% rilpivirine AUC ↔ rilpivirine Cmin ↔ rilpivirine Cmax ↔
Other NRTIs                 Not studied. No clinically relevant    No dose adjustment is required.
(abacavir, emtricitabine,   drug-drug interactions are expected.
lamivudine, stavudine and zidovudine)
HIV NNRTIs
NNRTIs                      Not studied.                           It is not recommended to (delavirdine, efavirenz,                                           co-administer rilpivirine with other etravirine, nevirapine)                                            NNRTIs.
HIV PIs – with co-administration of low dose ritonavir
Darunavir/ritonavir*#       darunavir AUC ↔                        Concomitant use of rilpivirine with 800/100 mg once daily       darunavir Cmin ↓ 11%                   ritonavir-boosted PIs causes an darunavir Cmax ↔                       increase in the plasma concentrations rilpivirine AUC ↑ 130%                 of rilpivirine, but no dose adjustment rilpivirine Cmin ↑ 178%                is required.
rilpivirine Cmax ↑ 79%

(inhibition of CYP3A enzymes)
Lopinavir/ritonavir         lopinavir AUC ↔
(soft gel capsule)*#        lopinavir Cmin ↓ 11%
400/100 mg twice daily      lopinavir Cmax ↔ rilpivirine AUC ↑ 52% rilpivirine Cmin ↑ 74% rilpivirine Cmax ↑ 29%

(inhibition of CYP3A enzymes)
Other boosted PIs           Not studied.
(atazanavir/ritonavir,
fosamprenavir/ritonavir,
saquinavir/ritonavir,
tipranavir/ritonavir)
HIV PIs – without co-administration of low dose ritonavir
Unboosted PIs               Not studied. Increased exposure of     No dose adjustment is required.
(atazanavir,                rilpivirine is expected.
fosamprenavir,
indinavir, nelfinavir)      (inhibition of CYP3A enzymes)
CCR5 Antagonists
Maraviroc                   Not studied. No clinically relevant    No dose adjustment is required.
drug-drug interaction is expected.
HIV Integrase Strand Transfer Inhibitors
Raltegravir*            raltegravir AUC ↑ 9%                   No dose adjustment is required.
raltegravir Cmin ↑ 27% raltegravir Cmax ↑ 10% rilpivirine AUC ↔ rilpivirine Cmin ↔ rilpivirine Cmax ↔
Other Antiviral Agents
Ribavirin               Not studied. No clinically relevant      No dose adjustment is required.
drug-drug interaction is expected.
Simeprevir*             simeprevir AUC ↔                         No dose adjustment is required.
simeprevir Cmin ↔ simeprevir Cmax ↑ 10% rilpivirine AUC ↔ rilpivirine Cmin ↑ 25% rilpivirine Cmax ↔
OTHER AGENTS
ANTICONVULSANTS
Carbamazepine          Not studied. Significant decreases           Rilpivirine must not be used in Oxcarbazepine          in rilpivirine plasma concentrations         combination with these Phenobarbital          are expected.                                anticonvulsants as co-administration Phenytoin                                                           may result in loss of therapeutic effect (induction of CYP3A enzymes)                      of rilpivirine (see section 4.3).
AZOLE ANTIFUNGAL AGENTS
Ketoconazole*#    ketoconazole AUC ↓ 24%                            At the recommended dose of 25 mg 400 mg once daily ketoconazole Cmin ↓ 66%                           once daily, no dose adjustment is ketoconazole Cmax ↔                               required when rilpivirine is co-administered with ketoconazole.
(induction of CYP3A due to high rilpivirine dose in the study)
 rilpivirine AUC ↑ 49% rilpivirine Cmin ↑ 76% rilpivirine Cmax ↑ 30%

(inhibition of CYP3A enzymes)
Fluconazole            Not studied. Concomitant use of              No dose adjustment is required.
Itraconazole           EDURANT with azole antifungal
Posaconazole           agents may cause an increase in the
Voriconazole           plasma concentrations of rilpivirine.
(inhibition of CYP3A enzymes)
ANTIMYCOBACTERIALS
Rifabutin*         rifabutin AUC ↔                                  Throughout co-administration of 300 mg once daily† rifabutin Cmin ↔                                 rilpivirine with rifabutin, the rilpivirine rifabutin Cmax ↔                                 dose should be increased from 25 mg 25-O-desacetyl-rifabutin AUC ↔                   once daily to 50 mg once daily. When 25-O-desacetyl-rifabutin Cmin ↔                  rifabutin co-administration is stopped, 25-O-desacetyl-rifabutin Cmax ↔                  the rilpivirine dose should be decreased to 25 mg once daily.
300 mg once daily      rilpivirine AUC ↓ 42%
(+ 25 mg once daily    rilpivirine Cmin ↓ 48% rilpivirine)           rilpivirine Cmax ↓ 31%

300 mg once daily      rilpivirine AUC ↑ 16%*
(+ 50 mg once daily    rilpivirine Cmin ↔* rilpivirine)           rilpivirine Cmax ↑ 43%*

* compared to 25 mg once daily rilpivirine alone
(induction of CYP3A enzymes)
Rifampicin*#           rifampicin AUC ↔                             Rilpivirine must not be used in 600 mg once daily      rifampicin Cmin NA                           combination with rifampicin as rifampicin Cmax ↔                            co-administration is likely to result in 25-desacetyl-rifampicin AUC ↓ 9%             loss of therapeutic effect of rilpivirine 25-desacetyl-rifampicin Cmin NA              (see section 4.3).
25-desacetyl-rifampicin Cmax ↔ rilpivirine AUC ↓ 80% rilpivirine Cmin ↓ 89% rilpivirine Cmax ↓ 69%

(induction of CYP3A enzymes)
Rifapentine            Not studied. Significant decreases           Rilpivirine must not be used in in rilpivirine plasma concentrations         combination with rifapentine as are expected.                                co-administration is likely to result in loss of therapeutic effect of rilpivirine
(induction of CYP3A enzymes)                 (see section 4.3).
MACROLIDE ANTIBIOTICS
Clarithromycin     Not studied. Increased exposure of               Where possible, alternatives such as Erythromycin       rilpivirine is expected.                         azithromycin should be considered.

(inhibition of CYP3A enzymes)
GLUCOCORTICOIDS
Dexamethasone                Not studied. Dose dependent            Rilpivirine should not be used in (systemic, except for        decreases in rilpivirine plasma        combination with systemic single dose use)             concentrations are expected.           dexamethasone (except as a single dose) as co-administration may result
(induction of CYP3A enzymes)           in loss of therapeutic effect of rilpivirine (see section 4.3).
Alternatives should be considered,
particularly for long-term use.
PROTON PUMP INHIBITORS
Omeprazole*#       omeprazole AUC ↓ 14%                             Rilpivirine must not be used in 20 mg once daily   omeprazole Cmin NA                               combination with proton pump omeprazole Cmax ↓ 14%                            inhibitors as co-administration is likely rilpivirine AUC ↓ 40%                            to result in loss of therapeutic effect of rilpivirine Cmin ↓ 33%                           rilpivirine (see section 4.3).
rilpivirine Cmax ↓ 40%

(reduced absorption due to gastric pH increase)
Lansoprazole                Not studied. Significant decreases
Rabeprazole                 in rilpivirine plasma concentrations
Pantoprazole                are expected.
Esomeprazole
(reduced absorption due to gastric pH increase)
H2-RECEPTOR ANTAGONISTS
Famotidine*#               rilpivirine AUC ↓ 9%                    The combination of rilpivirine and 40 mg single dose taken    rilpivirine Cmin NA                     H2-receptor antagonists should be used
12 hours before            rilpivirine Cmax ↔                      with particular caution. Only rilpivirine                                                        H2-receptor antagonists that can be Famotidine*#               rilpivirine AUC ↓ 76%                   dosed once daily should be used.
40 mg single dose taken    rilpivirine Cmin NA                     A strict dosing schedule, with intake of
2 hours before rilpivirine rilpivirine Cmax ↓ 85%                  H2-receptor antagonists at least
12 hours before or at least 4 hours
(reduced absorption due to gastric     after rilpivirine should be used.
pH increase)
Famotidine*#                rilpivirine AUC ↑ 13%
40 mg single dose taken     rilpivirine Cmin NA
4 hours after rilpivirine   rilpivirine Cmax ↑ 21%
Cimetidine                  Not studied.
Nizatidine
Ranitidine                  (reduced absorption due to gastric pH increase)
ANTACIDS
Antacids (e.g.,              Not studied. Significant decreases     The combination of rilpivirine and aluminium or magnesium       in rilpivirine plasma concentrations   antacids should be used with particular hydroxide, calcium           are expected.                          caution. Antacids should only be carbonate)                                                          administered either at least 2 hours (reduced absorption due to gastric     before or at least 4 hours after pH increase)                           rilpivirine.
NARCOTIC ANALGESICS
Methadone*            R(-) methadone AUC ↓ 16%                   No dose adjustments are required 60-100 mg once daily, R(-) methadone Cmin ↓ 22%                  when initiating co-administration of individualised dose   R(-) methadone Cmax ↓ 14%                  methadone with rilpivirine. However, rilpivirine AUC ↔*                         clinical monitoring is recommended as rilpivirine Cmin ↔*                        methadone maintenance therapy may rilpivirine Cmax ↔*                        need to be adjusted in some patients.
* based on historic controls
ANTIARRHYTHMICS
Digoxin*              digoxin AUC ↔                              No dose adjustment is required.
digoxin Cmin NA digoxin Cmax ↔
ANTICOAGULANTS
Dabigatran etexilate  Not studied. A risk for increases in       The combination of rilpivirine and dabigatran plasma concentrations           dabigatran etexilate should be used cannot be excluded.                        with caution.

(inhibition of intestinal P-gp)
ANTIDIABETICS
Metformin*                metformin AUC ↔                        No dose adjustment is required.
850 mg single dose        metformin Cmin NA metformin Cmax ↔
HERBAL PRODUCTS
St John's wort            Not studied. Significant decreases     Rilpivirine must not be used in (Hypericum perforatum)    in rilpivirine plasma concentrations   combination with products containing are expected.                          St John’s wort as co-administration may result in loss of therapeutic effect
(induction of CYP3A enzymes)           of rilpivirine (see section 4.3).
ANALGESICS
Paracetamol*#             paracetamol AUC ↔                      No dose adjustment is required.
500 mg single dose        paracetamol Cmin NA paracetamol Cmax ↔ rilpivirine AUC ↔ rilpivirine Cmin ↑ 26% rilpivirine Cmax ↔
ORAL CONTRACEPTIVES
Ethinylestradiol*  ethinylestradiol AUC ↔                        No dose adjustment is required.
0.035 mg once dailyethinylestradiol Cmin ↔
Norethindrone*     ethinylestradiol Cmax ↑ 17%
1 mg once daily    norethindrone AUC ↔ norethindrone Cmin ↔ norethindrone Cmax ↔ rilpivirine AUC ↔* rilpivirine Cmin ↔* rilpivirine Cmax ↔*
* based on historic controls
HMG CO-A REDUCTASE INHIBITORS
Atorvastatin*#     atorvastatin AUC ↔                            No dose adjustment is required.
40 mg once daily   atorvastatin Cmin ↓ 15% atorvastatin Cmax ↑ 35% rilpivirine AUC ↔ rilpivirine Cmin ↔ rilpivirine Cmax ↓ 9%
PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS
Sildenafil*#       sildenafil AUC ↔                              No dose adjustment is required.
50 mg single dose  sildenafil Cmin NA sildenafil Cmax ↔ rilpivirine AUC ↔ rilpivirine Cmin ↔ rilpivirine Cmax ↔
Vardenafil         Not studied.                                  No dose adjustment is required.
Tadalafil
* The interaction between rilpivirine and the medicinal product was evaluated in a clinical study. All other drug-drug interactions shown are predicted.
#
This interaction study has been performed with a dose higher than the recommended dose for rilpivirine 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.
†
This interaction study has been performed with a dose higher than the recommended dose for rilpivirine.


QT prolonging medicinal products
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1). EDURANT should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes.