Sitagliptin and Metformin: Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1000 mg twice daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.
Pharmacokinetic drug interaction studies with Janumet have not been performed; however, such studies have been conducted with the individual components of Janumet, sitagliptin and metformin.
Sitagliptin Phosphate: In drug interaction studies, sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following: Metformin, rosiglitazone, glyburide, simvastatin, warfarin and oral contraceptives. Based on these data, sitagliptin does not inhibit CYP isozymes CYP3A4, 2C8 or 2C9. Based on in vitro data, sitagliptin is also not expected to inhibit CYP2D6, 1A2, 2C19 or 2B6 or to induce CYP3A4.
Population pharmacokinetic analyses have been conducted in patients with type 2 diabetes. Concomitant medications did not have a clinically meaningful effect on sitagliptin pharmacokinetics. Medications assessed were those that are commonly administered to patients with type 2 diabetes including cholesterol-lowering agents (eg, statins, fibrates, ezetimibe), antiplatelet agents (eg, clopidogrel), antihypertensives (eg, ACE inhibitors, angiotensin receptor blockers, β-blockers, calcium-channel blockers, hydrochlorothiazide); analgesics and nonsteroidal anti-inflammatory agents (eg, naproxen, diclofenac, celecoxib); antidepressants (eg, bupropion, fluoxetine, sertraline), antihistamines (eg, cetirizine), proton-pump inhibitors (eg, omeprazole, lansoprazole) and medications for erectile dysfunction (eg, sildenafil).
There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of sitagliptin. These increases are not considered to be clinically meaningful. Patients receiving digoxin should be monitored appropriately. The AUC and Cmax of sitagliptin were increased approximately 29% and 68%, respectively, in subjects with co-administration of a single oral dose of Januvia 100 mg and a single oral dose of cyclosporine 600 mg, a potent probe inhibitor of p-glycoprotein. The observed changes in sitagliptin pharmacokinetics are not considered to be clinically meaningful.
Metformin Hydrochloride: Glyburide: In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain.
Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22%, and blood AUC by 15% without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32% without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Cationic Drugs: Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations, and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Janumet and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Others: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium-channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving Janumet, the patient should be closely observed to maintain adequate glycemic control.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs eg, salicylates, sulfonamides, chloramphenicol and probenecid, as compared to the sulfonylureas which are extensively bound to serum proteins.