Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction
In vitro studies indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not inhibit UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, raltegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1- mediated glucuronidation pathway.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir.

Effect of raltegravir on the pharmacokinetics of other medicinal products 
In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir disoproxil fumarate, hormonal contraceptives, methadone, midazolam or boceprevir.

In some studies, co-administration of raltegravir with darunavir resulted in a modest decrease in darunavir plasma concentrations; the mechanism for this effect is unknown. However, the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically meaningful.

Effect of other medicinal products on the pharmacokinetics of raltegravir 
Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering raltegravir with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of raltegravir can be considered in adults. There are no data to guide co-administration of raltegravir with rifampicin in patients below 18 years of age (see section 4.4). The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of raltegravir.

Co-administration of raltegravir with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir disoproxil fumarate may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir disoproxil fumarate, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir disoproxil fumarate was generally similar to the safety profile of patients who did not use these agents. Therefore, no dose adjustment is required.

Co-administration of raltegravir with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminium and magnesium antacid within 6 hours of raltegravir administration significantly decreased raltegravir plasma levels. Therefore, co-administration of raltegravir with aluminium and/or magnesium containing antacids is not recommended. Co-administration of raltegravir with a calcium carbonate 
antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when raltegravir is co-administered with calcium carbonate containing antacids no dose adjustment is required.

Co-administration of raltegravir with other agents that increase gastric pH (e.g., omeprazole and famotidine) may increase the rate of raltegravir absorption and result in increased plasma levels of raltegravir (see Table 1). Safety profiles in the subgroup of patients in Phase III trials taking proton pump inhibitors or H2 antagonists were comparable with those who were not taking these antacids.
Therefore, no dose adjustment is required with use of proton pump inhibitors or H2 antagonists.

All interaction studies were performed in adults.

Table 1
Pharmacokinetic Interaction Data
Medicinal products by therapeutic         Interaction                      Recommendations area                                      (mechanism, if known)            concerning co-administration
ANTI-RETROVIRAL
Protease inhibitors (PI) atazanavir /ritonavir                   raltegravir AUC    41 %         No dose adjustment required (raltegravir 400 mg Twice Daily)        raltegravir C12hr  77 %         for raltegravir.
raltegravir C max  24 %

(UGT1A1 inhibition) tipranavir /ritonavir                   raltegravir AUC    24 %         No dose adjustment required (raltegravir 400 mg Twice Daily)        raltegravir C12hr  55 %         for raltegravir.
raltegravir Cmax  18 %

(UGT1A1 induction)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz                               raltegravir AUC    36 %         No dose adjustment required (raltegravir 400 mg Single Dose)        raltegravir C12hr  21 %         for raltegravir.
raltegravir Cmax  36 %

(UGT1A1 induction) etravirine                              raltegravir AUC     10 %        No dose adjustment required (raltegravir 400 mg Twice Daily)        raltegravir C12hr  34 %         for raltegravir or etravirine.
raltegravir C max  11 %

(UGT1A1 induction)
 etravirine AUC     10 % etravirine C12hr  17 % etravirine C max  4 %
Nucleoside/tide reverse transcriptase inhibitors tenofovir disoproxil fumarate           raltegravir AUC    49 %         No dose adjustment required (raltegravir 400 mg Twice Daily)        raltegravir C12hr  3 %          for raltegravir or tenofovir raltegravir Cmax ↑ 64 %          disoproxil fumarate.


(mechanism of interaction unknown)
 tenofovir AUC     10 % tenofovir C24hr  13 % tenofovir C max ↓ 23 %
CCR5 inhibitors

Medicinal products by therapeutic    Interaction                 Recommendations area                                 (mechanism, if known)       concerning co-administration maraviroc                          raltegravir AUC    37 %    No dose adjustment required (raltegravir 400 mg Twice Daily)   raltegravir C12hr  28 %    for raltegravir or maraviroc.
raltegravir C max  33 %

(mechanism of interaction unknown)
 maraviroc AUC      14 % maraviroc C12hr  10 % maraviroc C max ↓ 21 %
HCV ANTIVIRALS
NS3/4A protease inhibitors (PI) boceprevir                           raltegravir AUC   4%       No dose adjustment required (raltegravir 400 mg Single Dose)     raltegravir C12hr  25 %    for raltegravir or boceprevir.
raltegravir C max  11 %

(mechanism of interaction unknown)
ANTIMICROBIALS
Antimycobacterial rifampicin                         raltegravir AUC    40 %    Rifampicin reduces plasma (raltegravir 400 mg Single Dose)   raltegravir C12hr  61 %    levels of raltegravir. If raltegravir C max  38 %    co-administration with rifampicin is unavoidable, a
(UGT1A1 induction)          doubling of the dose of raltegravir can be considered
(see section 4.4).
SEDATIVE midazolam                          midazolam AUC  8 %         No dosage adjustment required (raltegravir 400 mg Twice Daily)   midazolam C max ↑ 3 %       for raltegravir or midazolam.

These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.


Medicinal products by therapeutic    Interaction                    Recommendations area                                 (mechanism, if known)          concerning co-administration
METAL CATION ANTACIDS aluminium and magnesium             raltegravir AUC     49 %      Aluminium and magnesium hydroxide antacid                   raltegravir C12 hr  63 %      containing antacids reduce (raltegravir 400 mg Twice Daily)    raltegravir C max  44 %       raltegravir plasma levels. Co- administration of raltegravir
2 hours before raltegravir     with aluminium and/or raltegravir AUC    51 %       magnesium containing antacids raltegravir C12 hr  56 %      is not recommended.
raltegravir C max  51 %

2 hours after raltegravir raltegravir AUC    30 % raltegravir C 12 hr  57 % raltegravir Cmax  24 %

6 hours before raltegravir raltegravir AUC     13 % raltegravir C12 hr  50 % raltegravir Cmax  10 %
6 hours after raltegravir raltegravir AUC    11 % raltegravir C12 hr  49 % raltegravir C max  10 %

(chelation of metal cations) calcium carbonate antacid          raltegravir AUC    55 %       No dose adjustment required (raltegravir 400 mg Twice Daily)   raltegravir C 12 hr  32 %     for raltegravir.
raltegravir C max  52 %

(chelation of metal cations)

Other METAL CATION
Iron salts                         Expected:                      Given simultaneously iron salts Raltegravir AUC               are expected to reduce raltegravir plasma levels;
taking iron salts at least two
(chelation of metal cations)   hours from the administration of raltegravir may allow to limit this effect.
H2 BLOCKERS AND PROTON PUMP INHIBITORS omeprazole                       raltegravir AUC ↑ 37 %            No dose adjustment required (raltegravir 400 mg Twice Daily) raltegravir C12 hr ↑ 24 %         for raltegravir.
raltegravir C max ↑ 51 %

(increased solubility)
 famotidine                         raltegravir AUC ↑ 44 %         No dose adjustment required (raltegravir 400 mg Twice Daily)   raltegravir C12 hr ↑ 6 %       for raltegravir.
raltegravir C max ↑ 60 %

(increased solubility)


Medicinal products by therapeutic      Interaction                      Recommendations area                                   (mechanism, if known)            concerning co-administration
HORMONAL CONTRACEPTIVES
Ethinyl Estradiol                     Ethinyl Estradiol AUC  2 %      No dosage adjustment required Norelgestromin                        Ethinyl Estradiol C max ↑ 6 %    for raltegravir or hormonal (raltegravir 400 mg Twice Daily)      Norelgestromin AUC ↑ 14 %        contraceptives (estrogen- Norelgestromin C max ↑ 29 %      and/or progesterone-based).
OPIOID ANALGESICS methadone                             methadone AUC ↔                  No dose adjustment required (raltegravir 400 mg Twice Daily)      methadone C max ↔                for raltegravir or methadone.