Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

REKAMBYS, in combination with cabotegravir injection, is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV-1. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. From a drug interaction perspective, there are no limitations on the use of other antiretroviral medicinal products after discontinuing REKAMBYS.
For the oral lead-in rilpivirine treatment and in case missed doses are replaced by oral rilpivirine treatment, refer to the oral rilpivirine tablet SmPC for information about drug interactions.

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.

When using oral rilpivirine, proton pump inhibitors are contraindicated (see rilpivirine tablet SmPC, section 4.3).

Medicinal products that are affected by the use of rilpivirine

Rilpivirine 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, oral rilpivirine (25 mg once daily) did not significantly affect the pharmacokinetics of digoxin.

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.

Interaction table

Selected established and theoretical interactions between rilpivirine and co-administered medicinal products are listed in Table 6 and are based on the studies conducted with oral rilpivirine or are potential drug interactions that may occur (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as “CI”).
Table 6         Interactions and dose recommendations with other medicinal products Medicinal products by           Interaction                                       Recommendations concerning therapeutic areas               Geometric mean change (%)Ω                        co-administration ANTIVIRAL AGENTS
Cabotegravir                    cabotegravir AUC ↔                                No dose adjustment is required.
cabotegravir Cmin↔ cabotegravir Cmax ↔ rilpivirine AUC ↔ rilpivirine Cmin ↓ 8% rilpivirine Cmax ↔

Ribavirin                   Not studied. No clinically relevant drug-drug     No dose adjustment is required.
interaction is expected.
ANTICONVULSANTS
Carbamazepine Oxcarbazepine    Not studied. Significant decreases in rilpivirine Rilpivirine must not be used in Phenobarbital Phenytoin        plasma concentrations are expected.               combination with these anticonvulsants as co-administration
(induction of CYP3A enzymes)                      may result in loss of therapeutic effect of rilpivirine (see section 4.3).

AZOLE ANTIFUNGAL AGENTS



Ketoconazole*#      ketoconazole AUC ↓ 24%                        No dose adjustment is required.
400 mg once daily   ketoconazole Cmin ↓ 66% ketoconazole Cmax ↔
(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                      REKAMBYS with azole antifungal agents Posaconazole                      may cause an increase in the plasma Voriconazole                      concentrations of rilpivirine.

(inhibition of CYP3A enzymes)
ANTIMYCOBACTERIALS
Rifabutin*#                       rifabutin AUC ↔                              REKAMBYS must not be used in 300 mg once daily                 rifabutin Cmin ↔                             combination with rifabutin as specific rifabutin Cmax ↔                             dosing recommendations have not been 25-O-desacetyl-rifabutin AUC ↔               established.
25-O-desacetyl-rifabutin Cmin ↔              Co-administration is likely to result in 25-O-desacetyl-rifabutin Cmax ↔              loss of therapeutic effect of rilpivirine (see section 4.3).
300 mg once daily (+ 25 mg once   rilpivirine AUC ↓ 42% daily rilpivirine)                rilpivirine Cmin ↓ 48% rilpivirine Cmax ↓ 31%

300 mg once daily (+ 50 mg once   rilpivirine AUC ↑ 16%* daily rilpivirine)                rilpivirine Cmin ↔* 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 co- rifampicin Cmax ↔                            administration is likely to result in loss 25-desacetyl-rifampicin AUC ↓ 9% 25-         of therapeutic effect of rilpivirine (see desacetyl-rifampicin Cmin NA 25-             section 4.3).
desacetyl-rifampicin Cmax ↔ rilpivirine AUC ↓ 80% rilpivirine Cmin ↓ 89% rilpivirine Cmax ↓ 69%

(induction of CYP3A enzymes)
Rifapentine                       Not studied. Significant decreases in        Rilpivirine must not be used in rilpivirine plasma concentrations are        combination with rifapentine as co- expected.                                    administration is likely to result in loss of therapeutic effect of rilpivirine (see
(induction of CYP3A enzymes)                 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 OR CORTICOSTEROIDS
Dexamethasone (systemic, except Not studied. Dose dependent decreases in       Rilpivirine should not be used in for single dose use)            rilpivirine plasma concentrations are          combination with systemic expected.                                      dexamethasone (except as a single dose) as co-administration may result in loss of
(induction of CYP3A enzymes)                 therapeutic effect of rilpivirine (see section 4.3).
Alternatives should be considered,
particularly for long-term use.



NARCOTIC ANALGESICS
Methadone*                          R(-) methadone AUC ↓ 16%                       No dose adjustments are required when 60- 100 mg once daily,              R(-) methadone Cmin ↓ 22%                      initiating co-administration of methadone individualised dose                 R(-) methadone Cmax ↓ 14%                      with rilpivirine.
rilpivirine AUC ↔* rilpivirine                 However, clinical monitoring is Cmin ↔* rilpivirine Cmax ↔*                    recommended as methadone maintenance * based on historic controls                   therapy may need to be adjusted in some patients.

ANTIARRHYTHMICS
Digoxin*                            digoxin AUC ↔                                  No dose adjustment is required.
digoxin Cmin NA digoxin Cmax ↔
ANTIDIABETICS
Metformin*                          metformin AUC ↔                                No dose adjustment is required.
metformin Cmin NA metformin Cmax ↔
HERBAL PRODUCTS
St John's wort (Hypericum           Not studied. Significant decreases in          Rilpivirine must not be used in perforatum)                         rilpivirine plasma concentrations are          combination with products containing St expected.                                      John’s wort as co-administration may result in loss of therapeutic effect of
(induction of CYP3A enzymes)                   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 daily                 ethinylestradiol 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*# 40 mg once daily atorvastatin AUC ↔                        No dose adjustment is required.
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
Ω    % increase/decrease based on Drug-Drug Interaction studies with oral rilpivirine *   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.
QT prolonging medicinal products
Oral rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Rilpivirine plasma concentrations after REKAMBYS injections at the recommended dose of 600 mg monthly or 900 mg every 2 months, are comparable to those achieved with oral rilpivirine at a dose of 25 mg qd. In a study of healthy subjects, supratherapeutic doses of oral 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). REKAMBYS should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes (see section 4.4).