Isentress HD

Isentress HD Drug Interactions

raltegravir

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Drug Interactions
Effect of Raltegravir on the Pharmacokinetics of Other Agents: Raltegravir does not inhibit (IC50>100 μM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of meaningful effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate.
Similarly, raltegravir is not an inhibitor (IC50>50 μM) of the UDP-glucuronosyltransferases (UGTs) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).
In drug interaction studies performed using the 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, maraviroc, tenofovir, midazolam, lamivudine, etravirine, darunavir/ritonavir and boceprevir. In a multiple-dose drug interaction study, ethinyl estradiol and norelgestromin AUC values were 98% and 114%, respectively, when coadministered with raltegravir as compared to when administered without raltegravir. In a multiple-dose drug interaction study, tenofovir AUC and trough concentrations when coadministered with raltegravir were 90% and 87% of values obtained with tenofovir disoproxil fumarate monotherapy. In another drug interaction study, midazolam AUC from coadministration was 92% of the value obtained with midazolam alone. In a Phase II study, lamivudine pharmacokinetics were similar in patients receiving combinations with raltegravir versus with efavirenz. Findings from clinical studies conducted for ISENTRESS 400 mg twice daily to evaluate the effect of raltegravir on coadministered drugs and presented in Table 2 can be extended to raltegravir 1200 mg once daily, unless otherwise noted.
Effect of Other Agents on the Pharmacokinetics of Raltegravir: Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes.
Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Inducers of Drug Metabolizing Enzymes: Coadministration of ISENTRESS 400 mg twice daily with drugs that are potent inducers of UGT1A1, such as rifampin (an inducer of numerous drug metabolizing enzymes), reduces plasma concentrations of raltegravir. Caution should be used when coadministering ISENTRESS 400 mg twice daily with rifampin or other strong inducers of UGT1A1. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age (see Precautions). The impact of other potent inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Other less potent inducers (e.g., efavirenz, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS 400 mg twice daily.
The impact of drugs that are strong inducers of UGT1A1 such as rifampin on ISENTRESS 1200 mg (2 x 600 mg) once daily is unknown, but co-administration is likely to decrease raltegravir trough levels based on the reduction in trough concentrations observed with ISENTRESS 400 mg twice daily; therefore coadministration with ISENTRESS 1200 mg (2 x 600 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 coadministration with ISENTRESS 1200 mg (2 x 600 mg) once daily is not recommended. In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of ISENTRESS 1200 mg (2 x 600 mg) once daily, therefore other less potent inducers (e.g., efavirenz, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with ISENTRESS 1200 mg (2 x 600 mg) once daily.
Inhibitors of UGT1A1: Coadministration of ISENTRESS 400 mg twice daily with drugs that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) increases plasma levels of raltegravir. However, the degree of increase is modest and combination therapy with these inhibitors was well tolerated in the clinical studies such that no dose adjustment is required for ISENTRESS 400 mg twice daily.
Coadministration of atazanavir with ISENTRESS 1200 mg (2 x 600 mg) once daily significantly increased plasma levels of raltegravir therefore coadministration of ISENTRESS 1200 mg (2 x 600 mg) once daily and atazanavir is not recommended.
Antacids: Coadministration of ISENTRESS 400 mg twice daily with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminum and magnesium antacid within 6 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, coadministration of ISENTRESS 400 mg twice daily with aluminum and/or magnesium containing antacids is not recommended. Coadministration of ISENTRESS 400 mg twice daily with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS 400 mg twice daily is coadministered with calcium carbonate containing antacids, no dose adjustment is recommended.
Coadministration of ISENTRESS 1200 mg (2 x 600 mg) once daily with aluminum/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, coadministration of aluminum/magnesium and calcium carbonate containing antacids with ISENTRESS 1200 mg (2 x 600 mg) once daily, is not recommended.
Agents that Increased Gastric pH: Coadministration of ISENTRESS 400 mg twice daily with drugs that are known to increase gastric pH (e.g., omeprazole) may increase raltegravir plasma levels based on increased solubility of ISENTRESS at higher pH. In subjects who received ISENTRESS 400 mg twice daily in combination with proton pump inhibitors (PPIs) or H2 blockers in Protocols 018 and 019, comparable safety profiles were observed in this subgroup relative to subjects not receiving proton pump inhibitors or H2 blockers. Based on these data, proton pump inhibitors and H2 blockers may be coadministered with ISENTRESS 400 mg twice daily without dose adjustment.
Population pharmacokinetic analysis from ONCEMRK (Protocol 292) showed that co-administration of ISENTRESS 1200 mg (2 x 600 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 coadministered with ISENTRESS 1200 mg (2 x 600 mg) once daily.
Additional Considerations: In drug interaction studies of ISENTRESS 400 mg twice daily, atazanavir, efavirenz, ritonavir, tenofovir, and tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of raltegravir. Rifampin, which is a strong inducer of drug metabolizing enzymes, caused a decrease in trough levels of raltegravir (see Inducers of Drug Metabolizing Enzymes and Inhibitors of UGT1A1 as previously mentioned).
No studies have been conducted to evaluate the drug interactions of ritonavir, tipranavir/ritonavir, boceprevir or etravirine with ISENTRESS 1200 mg (2 x 600 mg) once daily. While the magnitudes of change on raltegravir exposure from ISENTRESS 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). Coadministration of ISENTRESS 1200 mg (2 x 600 mg) once daily and tipranavir/ritonavir is not recommended.
Previous studies of ISENTRESS 400 mg twice daily showed that coadministration of tenofovir disoproxil fumarate (a component of TRUVADA) increased raltegravir exposure. TRUVADA was identified to increase raltegravir 1200 mg (2 x 600 mg) once daily bioavailability by 12%, however its impact is not clinically meaningful. Therefore, coadministration of TRUVADA and ISENTRESS 1200 mg (2 x 600 mg) once daily is permitted.
All interaction studies were performed in adults. Drug interactions are further described as follows in Table 17. (See Table 17.)

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Laboratory Test Findings: Laboratory Abnormalities: Treatment-Experienced: The percentages of treatment-experienced adult patients receiving either ISENTRESS 400 mg twice daily or placebo (both with OBT), in P018 and P019 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 18. (See Table 18.)

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Treatment-Naïve: STARTMRK (Protocol 021; ISENTRESS 400 mg twice daily): The percentages of treatment-naïve adult patients receiving either ISENTRESS 400 mg twice daily or efavirenz (both with emtricitabine (+) tenofovir disoproxil fumarate), in P021 with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 19. (See Table 19.)

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Lipids, Change from Baseline: For P021, changes from baseline in fasting lipids are shown in Table 20. (See Table 20.)

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ONCEMRK (Protocol 292; ISENTRESS 1200 mg [2 x 600 mg] once daily): The percentages of patients receiving either ISENTRESS 1200 mg (2 x 600 mg) once daily or ISENTRESS 400 mg twice daily in ONCEMRK (P292) with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 21. (See Table 21.)

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