Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Vocabria injection, in combination with rilpivirine injection, is indicated for the treatment of HIV-1, therefore, the prescribing information for rilpivirine injection should be consulted for associated interactions.

Effect of other medicinal products on the pharmacokinetics of cabotegravir 
Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy (see section 4.3 and table 6 below). In poor metabolizers of UGT1A1, representing a maximum clinical UGT1A1 inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. The impact of an UGT1A1 inhibitor may be slightly more pronounced, however, considering the safety margins of cabotegravir, this increase is not expected to be clinically relevant. No dosing adjustments for Vocabria are, therefore, recommended in the presence of UGT1A1 inhibitors (e.g. atazanavir, erlotinib, sorafenib).

Cabotegravir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), however, because of its high permeability, no alteration in absorption is expected when co- administered with either P-gp or BCRP inhibitors.

Effect of cabotegravir on the pharmacokinetics of other medicinal products 
In vivo, cabotegravir did not have an effect on midazolam, a cytochrome P450 (CYP) 3A4 probe. In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

In vitro cabotegravir inhibited organic anion transporters (OAT) 1 (IC50=0.81 µM) and OAT3 (IC50=0.41 µM). Therefore, caution is advised when co-dosing with narrow therapeutic index OAT1/3 substrate drugs (e.g. methotrexate).

Vocabria and rilpivirine injections are 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. The following information regarding drug-drug interactions with other antiretroviral medicinal products is provided in the event that Vocabria and rilpivirine injections are stopped and initiation of an alternative antiviral therapy is necessary (see section 4.4). Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti- retroviral medications including protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors or ibalizumab.

No drug interaction studies have been performed with cabotegravir injection. The drug interaction data provided in Table 6 is obtained from studies with oral cabotegravir (increase is indicated as “↑”, decrease as “ ”, no change as “ ”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”).



Table 6         Drug Interactions

Medicinal products      Interaction              Recommendations concerning by therapeutic areas Geometric mean change (%)   co-administration
HIV-1 Antiviral medicinal products
Non-nucleoside          Cabotegravir            Etravirine did not significantly change Reverse Transcriptase AUC  1%                   cabotegravir plasma concentration. No dose Inhibitor:              Cmax  4%                adjustment of Vocabria is necessary when Etravirine              Cτ  0%                  initiating injections following etravirine use.

Non-nucleoside           Cabotegravir           Rilpivirine did not significantly change Reverse Transcriptase    AUC  12%               cabotegravir plasma concentration. No dose Inhibitor:               Cmax  5%               adjustment of Vocabria injection is necessary when Rilpivirine              Cτ  14%                co-administered with rilpivirine.

Rilpivirine 
AUC  1%
Cmax  4%
Cτ  8%

Anticonvulsants
Carbamazepine            Cabotegravir           Metabolic inducers may significantly decrease Oxcarbazepine                                    cabotegravir plasma concentration. Concomitant Phenytoin                                        use is contraindicated (see section 4.3).
Phenobarbital
Antimycobacterials
Rifampicin               Cabotegravir           Rifampicin significantly decreased cabotegravir AUC  59%               plasma concentration which is likely to result in Cmax  6%               loss of therapeutic effect. Dosing recommendations for co-administration of Vocabria with rifampicin have not been established and co-administration of
Vocabria with rifampicin is contraindicated (see section 4.3).

Rifapentine              Cabotegravir           Rifapentine may significantly decrease cabotegravir plasma concentrations. Concomitant use is contraindicated (see section 4.3).
Rifabutin                Cabotegravir           Rifabutin may decrease cabotegravir plasma AUC  21%               concentration. Concomitant use should be avoided.
Cmax  17%
Cτ  8%
Oral contraceptives
Ethinyl estradiol (EE)   EE                     Cabotegravir did not significantly change ethinyl and Levonorgestrel       AUC  2%                estradiol and levonorgestrel plasma concentrations (LNG)                    Cmax  8%               to a clinically relevant extent. No dose adjustment Cτ  0%                 of oral contraceptives is necessary when co- administered with Vocabria.
LNG 
AUC  12%
Cmax  5%
Cτ  7%