Januvia Drug Interactions

In Vitro Assessment of Drug Interactions: Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
In Vivo Assessment of Drug Interactions: Effects of Sitagliptin on Other Drugs: In clinical studies, as described as follows, sitagliptin did not meaningfully alter the pharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin, and oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, 2C8, or 2C9, and organic cationic transporter (OCT).
Digoxin: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (C_max, 18%) of digoxin with the co-administration of 0.25 mg digoxin and 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.
Metformin: Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.
Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that JANUVIA is not an inhibitor of CYP2C8-mediated metabolism. Clinically meaningful interactions with pioglitazone are not expected because pioglitazone predominantly undergoes CYP2C8- or CYP3A4-mediated metabolism.
Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Effects of Other Drugs on Sitagliptin: Clinical data described as follows suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications: Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Cyclosporine: The AUC and C_max of sitagliptin were increased approximately 29% and 68%, respectively, in subjects with co-administration of a single 100-mg oral dose of JANUVIA and a single 600-mg oral dose of cyclosporine, a potent probe inhibitor of p-glycoprotein. The observed changes in sitagliptin pharmacokinetics are not considered likely to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Population Pharmacokinetics: Population pharmacokinetic analyses have been conducted in patients with type 2 diabetes. Concomitant medications did not have a clinically meaningful effect on the pharmacokinetics of sitagliptin. Medications assessed were those that are commonly administered to patients with type 2 diabetes including cholesterol-lowering agents (e.g., statins, fibrates, ezetimibe), anti-platelet agents (e.g., clopidogrel), antihypertensives (e.g., ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, celecoxib), anti-depressants (e.g., bupropion, fluoxetine, sertraline), antihistamines (e.g., cetirizine), proton-pump inhibitors (e.g., omeprazole, lansoprazole), and medications for erectile dysfunction (e.g., sildenafil).