Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

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

Effect of other agents 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 2 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 the 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).

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 and ibalizumab.

The drug interaction data provided in Table 2 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 2 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 tablets is necessary.
Etravirine              Cτ  0%
Non-nucleoside          Cabotegravir                        Rilpivirine did not significantly change Reverse Transcriptase AUC  12%                              cabotegravir plasma concentration. No dose Inhibitor:              Cmax  5%                            adjustment of Vocabria tablets 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 concentrations, concomitant Phenytoin                                                    use is contraindicated (see section 4.3).
Phenobarbital
Antacids
Antacids (e.g.            Cabotegravir                      Co-administration of antacid supplements has the magnesium,                                                   potential to decrease oral cabotegravir absorption aluminium, or                                                and has not been studied.
calcium)                                                     Antacid products containing polyvalent cations are recommended to be administered at least 2 hours before or 4 hours after oral Vocabria (see section
4.4).
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 did not significantly change cabotegravir AUC  21%                          plasma concentration. No dose adjustment is Cmax  17%                         required.
Cτ  8%                            Prior to initiation of oral cabotegravir therapy, the prescribing information for cabotegravir injection should be consulted regarding concomitant use with rifabutin.
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 tablets.
LNG 
AUC  12%
Cmax  5%
Cτ  7%