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Sitagliptin: Sitagliptin is a DPP-4 inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
Metformin hydrochloride: Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects except in certain circumstances (see Bullous Pemphigoid under Precautions) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacodynamics: Sitagliptin: In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Sitagliptin and Metformin hydrochloride Co-administration: In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology: In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.
In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
Clinical Studies: The co-administration of sitagliptin and metformin immediate-release has been studied in patients with type 2 diabetes inadequately controlled on diet and exercise and in combination with other antidiabetic medications.
There have been no clinical efficacy or safety studies conducted with JANUMET XR to characterize its effect on hemoglobin A1c (A1C) reduction. Bioequivalence of JANUMET XR tablets with co-administered sitagliptin and extended-release metformin tablets has been demonstrated for all tablet strengths (see Pharmacokinetics as follows).
Metformin Extended-Release Compared to Metformin Immediate-Release in Patients with Type 2 Diabetes: In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial extended-release metformin 1500 mg once daily, extended-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening), and extended-release metformin 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to extended-release metformin began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA1c and fasting plasma glucose, each of the extended-release metformin regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of extended-release metformin was as effective as twice daily dosing of the immediate-release metformin formulation.
Pharmacokinetics: JANUMET XR: The results of a study in healthy subjects demonstrated that the JANUMET XR (sitagliptin and metformin HCl extended-release) 50 mg/500 mg and 100 mg/1000 mg tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin hydrochloride extended-release.
Bioequivalence between two JANUMET XR 50 mg/500 mg tablets and one JANUMET XR 100 mg/1000 mg tablet was also demonstrated.
After administration of two JANUMET XR 50 mg/1000 mg tablets once daily with the evening meal for 7 days in healthy adult subjects, steady-state for sitagliptin and metformin is reached by Day 4 and 5, respectively. The median Tmax value for sitagliptin and metformin at steady state is approximately 3 and 8 hours postdose, respectively. The median Tmax value for sitagliptin and metformin after administration of a single tablet of JANUMET is 3 and 3.5 hours postdose, respectively.
Absorption: JANUMET XR: After administration of JANUMET XR tablets with a high-fat breakfast, the AUC for sitagliptin was not altered. The mean Cmax was decreased by 17%, although the median Tmax was unchanged relative to the fasted state. After administration of JANUMET XR with a high-fat breakfast, the AUC for metformin increased 62%, the Cmax for metformin decreased by 9%, and the median Tmax for metformin occurred 2 hours later relative to the fasted state.
Sitagliptin: The absolute bioavailability of sitagliptin is approximately 87%. Co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.
Distribution: Sitagliptin: The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metformin hydrochloride: Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism: Sitagliptin: Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Metformin hydrochloride: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted.
Excretion: Sitagliptin: Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t½ following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Metformin hydrochloride: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations: Renal Impairment: JANUMET XR: JANUMET XR should not be used in patients with renal impairment (see Contraindications and Vitamin B12 Levels under Precautions).
Sitagliptin: An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment, and an approximately 4-fold increase was observed in patients with severe renal impairment including patients with end-stage renal disease (ESRD) on hemodialysis, as compared to normal healthy control subjects.
Metformin hydrochloride: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment: Sitagliptin: In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of sitagliptin. These differences are not considered to be clinically meaningful.
There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9).
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Gender: Sitagliptin: Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Geriatric: Sitagliptin: When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
As is true for all patients, JANUMET XR treatment should not be initiated in geriatric patients unless measurement of creatinine clearance demonstrates that renal function is normal (see Lactic Acidosis and Vitamin B12 Levels under Precautions).
Pediatric: No studies with JANUMET XR have been performed in pediatric patients.
Race: Sitagliptin: Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.
Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Body Mass Index (BMI): Sitagliptin: Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Drug Interactions: Sitagliptin and Metformin hydrochloride: Co-administration of multiple doses of sitagliptin (50 mg) and metformin (1000 mg) given 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 XR have not been performed; however, such studies have been conducted with the individual components of JANUMET XR (sitagliptin and metformin hydrochloride extended-release).
Sitagliptin: 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: See Tables 1, 2, 3 and 4.
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