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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.
600-mg: In vitro, raltegravir is a weak inhibitor of organic anion transporter (OAT) 1 (IC50 of 109 μM) and OAT3 (IC50 of 18.8 μM). Caution is recommended when co-administering raltegravir 1,200 mg once daily with sensitive OAT1 and/or OAT3 substrates.
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 is not an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, organic cation transporters (OCT)1 and OCT2, or multidrug and toxin extrusion proteins (MATE)1 and MATE2-K. Based on these data, raltegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or transporters.
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: 400-mg: 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.
600-mg: In drug interaction studies performed using raltegravir 400 mg twice daily, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir disoproxil fumarate, hormonal contraceptives, methadone, midazolam or boceprevir. These findings can be extended to raltegravir 1,200 mg once daily and no dosage adjustment is required for these agents.
In some studies, co-administration of raltegravir 400 mg tablets twice daily with darunavir resulted in a modest but clinically insignificant decrease in darunavir plasma concentrations. Based on the magnitude of effect seen with raltegravir 400 mg tablets twice daily, it is expected that the effect of raltegravir 1,200 mg once daily on darunavir plasma concentrations is likely to be not clinically meaningful.
Effect of other medicinal products on the pharmacokinetics of raltegravir: 400-mg: 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 Precautions). 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 7). 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 7). 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.
600-mg: Inducers of drug metabolizing enzymes: The impact of medicinal products that are strong inducers of UGT1A1 such as rifampicin on raltegravir 1,200 mg once daily is unknown, but co-administration is likely to decrease raltegravir trough levels based on the reduction in trough concentrations observed with raltegravir 400 mg twice daily; therefore, co-administration with raltegravir 1,200 mg once daily is not recommended. The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown; therefore, co-administration with raltegravir 1,200 mg once daily is not recommended. In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of raltegravir 1,200 mg once daily; therefore, other less potent inducers (e.g., efavirenz, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of raltegravir.
Inhibitors of UGT1A1: Co-administration of atazanavir with raltegravir 1,200 mg once daily significantly increased plasma levels of raltegravir; therefore, co-administration of raltegravir 1,200 mg once daily and atazanavir is not recommended.
Antacids: Co-administration of raltegravir 1,200 mg once daily with aluminium/magnesium and calcium carbonate containing antacids are likely to result in clinically meaningful reductions in the plasma trough levels of raltegravir. Based on these findings, co-administration of aluminium/magnesium and calcium carbonate containing antacids with raltegravir 1,200 mg once daily is not recommended.
Agents that increase gastric pH: Population pharmacokinetic analysis from ONCEMRK (Protocol 292) showed that co-administration of raltegravir 1,200 mg once daily with PPIs or H2 blockers did not result in statistically significant changes in the pharmacokinetics of raltegravir. Comparable efficacy and safety results were obtained in the absence or presence of these gastric pH-altering agents. Based on these data, proton pump inhibitors and H2 blockers may be co-administered with raltegravir 1,200 mg once daily.
Additional considerations: No studies have been conducted to evaluate the drug interactions of ritonavir, tipranavir/ritonavir, boceprevir or etravirine with raltegravir 1,200 mg (2 x 600 mg) once daily. While the magnitudes of change on raltegravir exposure from raltegravir 400 mg twice daily by ritonavir, boceprevir or etravirine were small, the impact from tipranavir/ritonavir was greater (GMR Ctrough=0.45, GMR AUC=0.76). Co-administration of raltegravir 1,200 mg once daily and tipranavir/ritonavir is not recommended.
Previous studies of raltegravir 400 mg twice daily showed that co-administration of tenofovir disoproxil fumarate (a component of emtricitabine/tenofovir disoproxil fumarate) increased raltegravir exposure. Emtricitabine/tenofovir disoproxil fumarate was identified to increase raltegravir 1,200 mg once daily bioavailability by 12%, however its impact is not clinically meaningful. Therefore, co-administration of emtricitabine/tenofovir disoproxil fumarate and raltegravir 1,200 mg once daily is permitted.
All interaction studies were performed in adults.
Comprehensive drug interaction studies were performed with raltegravir 400 mg twice daily and a limited number of drug interaction studies were performed for raltegravir 1,200 mg once daily.
Table 7 displays all available interaction study data along with recommendations for co-administration. (See Table 7.)
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