Janumet

Sitagliptin phosphate, metformin HCl.

Each film-coated tablet contains sitagliptin phosphate monohydrate 64.25 mg and metformin hydrochloride equivalent to: Sitagliptin 50 mg as free base and metformin hydrochloride 500 mg (50/500 mg), 850 mg (50/850 mg) or 1000 mg (50/1000 mg).

Pharmacology: Mechanism of Action: Janumet combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: Sitagliptin phosphate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin Phosphate: Sitagliptin phosphate is a member of a class of oral antihyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors which improve glycemic control in patients with type 2 diabetes by enhancing the levels of active incretin 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. 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 β-cells by intracellular signaling pathways involving cyclic adenosine monophosphate (AMP). Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve β-cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic α-cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent. When blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin secretion is enhanced as glucose rises above normal concentrations. GLP-1 does not impair the normal glucagon response to hypoglycemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4; thereby, increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. This glucose-dependent mechanism is unlike the mechanism seen with sulfonylureas where insulin is released even when glucose levels are low which can lead to hypoglycemia in patients with type 2 diabetes and in normal subjects. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to lower hemoglobin A_1c (HbA_1c) and lower fasting and postprandial glucose concentrations. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, α-glucosidase inhibitors, and amylin analogues.
Metformin hydrochloride: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Precautions: Metformin hydrochloride) 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 Phosphate: General: In patients with type 2 diabetes, administration of single oral doses of sitagliptin leads to inhibition of DPP-4 enzyme activity for a 24-hr period resulting in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, increased plasma levels of insulin and C-peptide, decreased glucagon concentrations, reduced fasting glucose and reduced glucose excursion following an oral glucose load or a meal.
In Phase III clinical studies of 18- and 24-week duration, treatment with sitagliptin 100 mg daily in patients with type 2 diabetes significantly improved β-cell function as assessed by several markers including Homeostasis Model Assessment-β (HOMA-β), proinsulin to insulin ratio and measures of β-cell responsiveness from the frequently-sampled meal tolerance test. In Phase II studies, sitagliptin 50 mg twice daily provided similar glycemic efficacy compared to sitagliptin 100 mg once daily.
In a randomized, placebo-controlled, double-blind, double-dummy, 4-period crossover 2-day study in healthy adult subjects, the effects on post-meal plasma concentrations of active and total GLP-1 and glucose after co-administration of sitagliptin and metformin were compared with those after administration of sitagliptin alone, metformin alone or placebo, each administered for 2 days. The incremental 4-hr post-meal weighted mean active GLP-1 concentrations were increased approximately 2-fold after either administration of sitagliptin alone or metformin alone compared with placebo. The effect on active GLP-1 concentrations after co-administration of sitagliptin and metformin were additive, with active GLP-1 concentrations increased by approximately 4-fold compared with placebo. Sitagliptin alone increased only active GLP-1 concentrations, reflecting inhibition of DPP-4, whereas metformin alone increased active and total GLP-1 concentrations to a similar extent. These data are consistent with different mechanisms for the increase in active GLP-1 concentrations. Results from the study also demonstrated that sitagliptin, but not metformin, enhances active GIP concentrations.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose-dependent.
Effects on Blood Pressure: In a randomized, placebo-controlled crossover study in hypertensive patients on one or more antihypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, β-blockers and diuretics), co-administration with sitagliptin was generally well tolerated. In these patients, sitagliptin had a modest blood pressure-lowering effect; sitagliptin 100 mg/day reduced 24-hr mean ambulatory systolic blood pressure by approximately 2 mmHg, as compared to placebo. Reductions have not been observed in subjects with normal blood pressure.
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 hrs post-dose was 8 millisec. This small increase was 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 with 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: Clinical studies of the co-administration of sitagliptin and metformin demonstrated significant improvements in glycemic control in patients with type 2 diabetes. There have been no clinical efficacy studies conducted with Janumet tablets; however, bioequivalence of Janumet tablets with co-administered sitagliptin and metformin hydrochloride tablets was demonstrated.
Sitagliptin and Metformin as Initial Therapy in Patients with Type 2 Diabetes: A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the safety and efficacy of initial therapy with the combination of sitagliptin and metformin. Approximately equal numbers of patients were randomized to receive initial therapy with placebo; sitagliptin 100 mg once daily; metformin 500 or 1000 mg twice daily; or sitagliptin 50 mg in combination with metformin 500 or 1000 mg twice daily.
Initial therapy with the combination of sitagliptin and metformin provided significant improvements in HbA_1c, FPG and 2-hr PPG compared to placebo, to metformin alone, and to sitagliptin alone (p<0.001) (see Figure 1 and Table 1). An improvement in FPG, with near maximal FPG reduction, was achieved by the 3-week time point (the first time point assessed after initiation of therapy) and sustained throughout the 24-week study. Measures of β-cell function, HOMA-β and the proinsulin to insulin ratio also showed greater improvement with the co-administration of sitagliptin and metformin compared with either monotherapy alone. Lipid effects were generally neutral. The decrease in bodyweight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo. Mean reductions from baseline in HbA_1c compared with placebo were generally greater for patients with higher baseline HbA_1c values. The improvement in HbA_1c was generally consistent across subgroups defined by gender, age, race or baseline BMI. Mean reductions from baseline in HbA_1c for patients not on an antihyperglycemic agent at study entry were: Sitagliptin 100 mg once daily, -1.06%; metformin 500 mg twice daily, -1.09%; metformin 1000 mg twice daily, -1.24%; sitagliptin 50 mg twice daily with metformin 500 mg twice daily, -1.59%; and sitagliptin 50 mg twice daily with metformin 1000 mg twice daily, -1.94%; and for patients receiving placebo, -0.17%.

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In addition, this study included patients (N=117) with more severe hyperglycemia (HbA_1c >11% or blood glucose >280 mg/dL) who were treated with open-label sitagliptin 50 mg and metformin 1000 mg twice daily. In this group of patients, the baseline HbA_1c value was 11.15%, FPG was 314.4 mg/dL and 2-hr PPG was 441 mg/dL. After 24 weeks, decreases from baseline of -2.94% for HbA_1c, -126.7 mg/dL for FPG and -207.9 mg/dL for 2-hr PPG were observed. In this open-label cohort, a modest increase in body weight of 1.3 kg was observed at 24 weeks.
Sitagliptin Add-On Therapy in Patients Inadequately Controlled on Metformin Alone: The combination of sitagliptin and metformin has been evaluated for safety and efficacy in 2 double-blind, placebo-controlled clinical studies in patients with type 2 diabetes mellitus. In both studies, patients with inadequate glycemic control on stable doses of metformin ≥1500 mg were randomized to receive either sitagliptin 100 mg/day or placebo in addition to ongoing treatment with metformin.
In 1 study, 701 patients received sitagliptin 100 mg or placebo once daily for 24 weeks. The addition of sitagliptin to ongoing metformin treatment provided significant improvements compared with the addition of placebo to ongoing metformin treatment in HbA_1c (-0.65%), FPG (-25.4 mg/dL) and 2-hr PPG (-50.6 mg/dL) (see Figure 2 and Table 2). This improvement in HbA_1c compared to placebo was not affected by baseline HbA_1c value, prior antihyperglycemic therapy, gender, age, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). Compared to patients taking placebo, patients taking sitagliptin demonstrated slight decreases in total cholesterol, non-high-density lipoprotein (HDL) cholesterol and triglycerides. A similar decrease in body weight was observed for both treatment groups.

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In a separate study, 24-hr plasma glucose values were assessed. 28 patients received either sitagliptin 50 mg or placebo twice daily for 4 weeks in addition to their twice-daily metformin regimen. Following 4 weeks of treatment, the difference in glucose-lowering efficacy was assessed as a 24-hr weighted mean glucose (WMG) based upon collection of multiple blood samples including those obtained before and after meals as well as overnight. Sitagliptin 50 mg co-administered twice daily with metformin significantly lowered the 24-hr WMG (-32.8 mg/dL) compared to placebo co-administered with metformin. In addition, sitagliptin administered with metformin, compared with placebo administered with metformin, substantially lowered fasting glucose concentrations and demonstrated smaller glucose excursions after all 3 meals (see Figure 3). In patient-collected glucose measurements, treatment with sitagliptin administered with metformin also provided significant reductions compared to placebo administered with metformin in mean fasting plasma glucose (-20.3 mg/dL), 7-point glucose average (-28 mg/dL), and 2-hr post-glucose concentrations (-36.6 mg/dL).

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Sitagliptin Add-On Therapy in Patients Inadequately Controlled on the Combination of Metformin and Glimepiride: A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin 100 mg once daily compared to placebo in combination with glimepiride (alone or in combination with metformin). In this study, 220 patients were on the combination of glimepiride (≥4 mg/day) and metformin (≥1500 mg/day); the results of the glycemic endpoints, including HbA_1c and FPG, are described in the following text.
The combination of sitagliptin, glimepiride and metformin provided significant reduction from baseline in HbA_1c (-0.89%) and FPG (-20.7 mg/dL) compared to placebo (see Table 3). Mean reductions from baseline in HbA_1c compared with placebo were generally greater for patients with higher baseline HbA_1c values. Patients treated with sitagliptin had a modest increase in body weight compared to those given placebo.

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Sitagliptin Add-On Therapy in Patients Inadequately Controlled on the Combination of Metformin and Rosiglitazone: A total of 262 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin and rosiglitazone. Patients with inadequate glycemic control on a stable regimen of metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day) were randomized to the addition of either sitagliptin 100 mg or placebo, administered once daily. Glycemic parameters were evaluated at the primary time point of week 18 and 54.
In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in HbA_1c, FPG and 2-hr PPG compared to placebo with metformin and rosiglitazone (see Table 4 and Figure 4) at week 18, with improvements sustained through the end of the study. Lipid effects were generally neutral. There was no significant difference between sitagliptin and placebo in body weight change.

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Sitagliptin Add-On Therapy in Patients Inadequately Controlled on the Combination of Metformin and Insulin: A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin 100 mg once daily in combination insulin. Approximately 75% of patients were also taking metformin. Patients on pre-mixed, long-acting or intermediate-acting insulin (with or without metformin) were randomized to the addition of either sitagliptin 100 mg or placebo. Glycemic endpoints measured included HbA_1c, FPG and 2-hr PPG.
The combination of sitagliptin, metformin and insulin provided significant improvements in HbA_1c, FPG and 2-hr PPG compared to placebo (see Table 5). The improvement in HbA_1c compared to placebo was generally consistent across subgroups defined by gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). There was no meaningful change from baseline in body weight in either group.

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Active (Glipizide)-Controlled Study in Combination with Metformin: Long-term maintenance of effect was evaluated in a 52-week, double-blind, glipizide-controlled trial in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy at ≥1500 mg/day. In this study, patients were randomized to the addition of either sitagliptin 100 mg daily (N=588) or glipizide (N=584) for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated by the investigator to a target FPG of <110 mg/dL, without significant hypoglycemia, over the next 18 weeks. A maximum dosage of 20 mg/day was allowed to optimize glycemic control. Thereafter, the glipizide dose was to have been kept constant. The mean dose of glipizide after the titration period was 10.3 mg.
Both treatments resulted in a statistically significant improvement in glycemic control from baseline. After 52 weeks, the reduction from baseline in HbA_1c was 0.67% for sitagliptin 100 mg daily and 0.67% for glipizide, confirming comparable efficacy of the 2 agents. The reduction in FPG was sitagliptin 10 mg/dL and glipizide 7.5 mg/dL. In a post-hoc analysis, patients with higher baseline HbA_1c (≥9%) in both groups had greater reductions from baseline in HbA_1c (sitagliptin, -1.68%; glipizide, -1.76%). In this study, the proinsulin to insulin ratio, a marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with glipizide treatment. The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly lower than that in the glipizide group (32%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered with glipizide (-1.5 kg vs +1.1 kg).
Metformin hydrochloride: The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: A significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034.
A significant reduction of the absolute risk of diabetes-related mortality: Metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017.
A significant reduction of the absolute risk of overall mortality: Metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021).
A significant reduction in the absolute risk of myocardial infarction: Metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Pharmacokinetics: The results of a definitive bioequivalence study in healthy subjects demonstrated that the Janumet (sitagliptin/metformin hydrochloride) 50 mg/500 mg and 50 mg/1000 mg combination tablets are bioequivalent to co-administration of corresponding doses of sitagliptin phosphate (Januvia) and metformin hydrochloride as individual tablets.
Because bioequivalence is demonstrated at the lowest and highest combination tablet-dose strengths available, bioequivalence is conferred to the (sitagliptin/metformin) 50 mg/850 mg fixed-dose combination (FDC) tablet.
Absorption: Sitagliptin Phosphate: The absolute bioavailability of sitagliptin is approximately 87%. Co-administration of a high-fat meal with sitagliptin phosphate had no effect on the pharmacokinetics of sitagliptin.
Metformin hydrochloride: The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50-60%. Studies using single-oral doses of metformin hydrochloride tablets 500-1500 mg and 850-2550 mg indicate that there is a lack of dose proportionality with increasing doses which is due to decreased absorption rather than an alternation in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C_max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-min prolongation of time to peak plasma concentration (T_max) following administration of a single tablet of metformin 850 mg with food, compared to the same tablet strength administered during fasting. The clinical relevance of these decreases is unknown.
Distribution: Sitagliptin Phosphate: The mean volume of distribution at steady state following a single IV dose of sitagliptin 100-mg dose to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metformin hydrochloride: The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are >90% protein bound. 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 hrs, 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 Phosphate: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
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: IV 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) nor biliary excretion.
Elimination: Sitagliptin Phosphate: 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 1 week of dosing. The apparent terminal t_½ following an oral dose of sitagliptin 100-mg was approximately 12.4 hrs 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 hrs with a plasma elimination half-life of approximately 6.2 hrs. In blood, the elimination half-life is approximately 17.6 hrs, suggesting that the erythrocyte mass may be a compartment of distribution.
Characteristics in Patients: Type 2 Diabetes: Sitagliptin Phosphate: The pharmacokinetics of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.
Metformin hydrochloride: In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects, nor is there any accumulation of metformin in either group at usual clinical doses.
Renal Insufficiency: Janumet should not be used in patients with renal insufficiency (see Contraindications).
Sitagliptin Phosphate: An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency and in 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 Insufficiency: Sitagliptin Phosphate: In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), mean AUC and C_max of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single dose of sitagliptin phosphate 100 mg. These differences are not considered to be clinically meaningful.
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic insufficiency is not expected to affect the pharmacokinetics of sitagliptin.
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
Gender: Sitagliptin Phosphate: 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.
Elderly: Sitagliptin Phosphate: Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65-80 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 C_max 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.
Janumet treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Precautions).
Pediatric: No studies with Janumet have been performed in pediatric patients.
Race: Sitagliptin Phosphate: Race 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 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 Phosphate: Body mass index (BMI) 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.

As initial therapy in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise do not provide adequate glycemic control.
As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus inadequately controlled on metformin or sitagliptin alone, or in patients already being treated with the combination of sitagliptin and metformin.
As part of triple combination therapy with a sulfonylurea as an adjunct to diet and exercise in patients with type 2 diabetes mellitus inadequately controlled with any 2 of the 3 agents: Metformin, sitagliptin or a sulfonylurea.
As triple combination therapy with a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (ie, thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.
As add-on to insulin (ie, triple combination therapy) as an adjunct to diet and exercise to improve glycemic control in patients, when stable dosage of insulin and metformin alone do not provide adequate glycemic control.

General: The dosage of antihyperglycemic therapy with Janumet should be individualized on the basis of the patient's current regimen, effectiveness and tolerability while not exceeding the maximum recommended daily dose of sitagliptin 100 mg and metformin 2000 mg. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the healthcare provider.
Janumet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects associated with metformin.
The starting dose of Janumet should be based on the patient's current regimen. Janumet should be given twice daily with meals.
Patients Inadequately Controlled with Diet and Exercise Alone: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with diet and exercise alone, the recommended starting dose is sitagliptin 50 mg/metformin hydrochloride 500 mg twice daily. Patients with inadequate glycemic control on this dose can be titrated up to sitagliptin 50 mg/metformin hydrochloride 1000 mg twice daily.
Patients Inadequately Controlled on Metformin Monotherapy: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient inadequately controlled on metformin alone, the recommended starting dose of Janumet should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose), and the dose of metformin already being taken.
Patients Inadequately Controlled on Sitagliptin Monotherapy: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient inadequately controlled on sitagliptin alone, the recommended starting dose of Janumet is sitagliptin 50 mg/metformin hydrochloride 500 mg twice daily. Patients with inadequate control on this dose can be titrated up to sitagliptin 50 mg/metformin hydrochloride 1000 mg twice daily. Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to Janumet.
Patients Switching from Co-Administration of Sitagliptin and Metformin: For patients switching from sitagliptin co-administered with metformin, Janumet may be initiated at the dose of sitagliptin and metformin already being taken.
Patients Inadequately Controlled on Dual Combination Therapy with Any 2 of the Following 3 Antihyperglycemic Agents: Sitagliptin, Metformin or a Sulfonylurea: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate in this setting, the usual starting dose of Janumet should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose). In determining the starting dose of the metformin component, the patient's level of glycemic control and current dose (if any) of metformin should be considered. Gradual dose escalation to reduce the GI side effect associated with metformin should be considered. Patients currently on or initiating a sulfonylurea may require lower sulfonylurea doses to reduce the risk of hypoglycemia.
Patients Inadequately Controlled on Dual Combination Therapy with the Maximal Tolerated Dose of Metformin and a PPARγ Agonist: The dose of Janumet should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.
Patients Inadequately Controlled on Dual Combination Therapy with Insulin and the Maximal Tolerated Dose of Metformin: The dose of Janumet should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Janumet is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycemia (see Precautions).
No studies have been performed specifically examining the safety and efficacy of Janumet in patients previously treated with other oral antihyperglycemic agents and switched to Janumet. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Symptoms: Sitagliptin Phosphate: During controlled clinical trials in healthy subjects, single doses of up to sitagliptin 800 mg were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in 1 study at a dose of sitagliptin 800 mg (see Pharmacology under Actions). There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg/day for 10 days and 400 mg/day for periods of up to 28 days.
Metformin hydrochloride: Overdosage of metformin hydrochloride has occurred, including ingestion of amounts >50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see Precautions).
Treatment: Sitagliptin Phosphate: In the event of an overdosage, it is reasonable to employ the usual supportive measures eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram) and institute supportive therapy if required.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hr hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
Metformin hydrochloride: Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride or to any of the excipients of Janumet (see Precautions).
Renal disease or renal dysfunction eg, as suggested by serum creatinine levels ≥1.5 mg/dL (males), ≥1.4 mg/dL (females) or abnormal creatinine clearance which may also result from conditions eg, cardiovascular collapse (shock), acute myocardial infarction and septicemia.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.
Janumet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials because the use of such products may result in acute alteration of renal function (see Precautions).

Janumet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: In post-marketing experience there have been reports of acute pancreatitis including fatal and nonfatal hemorrhagic or necrotizing pancreatitis (see Side Effects) in patients taking sitagliptin. Because these reports are made voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patients should be informed of the characteristic symptom of acute pancreatitis: Persistent, severe abdominal pain.
Resolution of pancreatitis has been observed after discontinuation of sitagliptin. If pancreatitis is suspected, Janumet and other potentially suspected medicinal products should be discontinued.
Monitoring of Renal Function: Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Janumet. In patients with advanced age, Janumet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. In elderly patients, particularly those ≥80 years, renal function should be monitored regularly.
Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Janumet be discontinued if evidence of renal impairment is present.
Sitagliptin Phosphate: Hypoglycemia in Combination with a Sulfonylurea or with Insulin: In clinical trials of sitagliptin as monotherapy and as part of combination therapy with agents not known to cause hypoglycemia [ie, metformin or a PPARγ agonist (eg, thiazolidinedione)], rates of hypoglycemia reported with sitagliptin were similar to rates in patients taking placebo. As typical with other antihyperglycemic agents, when sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of sulfonylurea- or insulin-induced hypoglycemia was increased over that of placebo (see Side Effects). Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered (see Dosage & Administration).
Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Janumet. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin with some reports occurring after the 1st dose. If a hypersensitivity reaction is suspected, discontinue Janumet; assess for other potential causes for the event and institute alternative treatment for diabetes (see Contraindications and Side Effects).
Metformin hydrochloride: Lactic Acidosis: Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during treatment with Janumet (sitagliptin phosphate/metformin hydrochloride); when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In >20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis is often subtle and accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms, and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal, but <5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis, and may be explainable by other mechanisms eg, poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see Contraindications).
Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (eg, sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs.
Use of Concomitant Medications that may Affect Renal Function or Metformin Disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change, or may interfere with the disposition of metformin eg, cationic drugs that are eliminated by renal tubular secretion (see Interactions), should be used with caution.
Radiologic Studies Involving the Use of Intravascular Iodinated Contrast Materials [eg, IV Urogram, IV Cholangiography, Angiography and Computed Tomography (CT) Scans with Intravascular Contrast Materials]: Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see Contraindications). Therefore, in patients in whom any such study is planned, Janumet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hrs subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Janumet therapy, the drug should be promptly discontinued.
Surgical Procedures: Use of Janumet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Therefore, patients should be warned against excessive acute or chronic alcohol intake while receiving Janumet.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Janumet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Levels: In a 29-week duration of controlled clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels without clinical manifestations was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Janumet, and any apparent abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes: A patient with type 2 diabetes previously well controlled on Janumet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Janumet must be stopped immediately and other appropriate corrective measures initiated.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Janumet and temporarily administer insulin. Janumet may be reinstituted after the acute episode is resolved.
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women with Janumet or its individual components; therefore, the safety of Janumet in pregnant women is not known. Janumet, like other oral antihyperglycemic agents, is not recommended for use in pregnancy.
No animal studies have been conducted with the combined products in Janumet to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.
Sitagliptin Phosphate: Sitagliptin was not teratogenic in rats at oral doses up to 250 mg/kg or in rabbits given up to 125 mg/kg during organogenesis (up to 32 and 22 times, respectively, the human exposure based on the recommended daily adult human dose of 100 mg/day). In rats, a slight increase in the incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) was observed at oral doses of 1000 mg/kg/day (approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Slight decreases in mean preweaning body weights of both sexes and postweaning body weight gains of males were observed in the offspring of rats given oral dose of 1000 mg/kg/day. However, animal reproduction studies are not always predictive of the human response.
Metformin hydrochloride: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 times and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Use in lactation: No studies in lactating animals have been conducted with the combined components of Janumet. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin is excreted in human milk. Therefore, Janumet should not be used by a woman who is nursing.
Use in children: Safety and effectiveness of Janumet in pediatric patients under 18 years have not been established.
Use in the elderly: Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, Janumet should be used with caution as age increases. Care should be taken in dose selection, and should be based on careful and regular monitoring of renal function (see previously mentioned Monitoring of Renal Function).
Sitagliptin Phosphate: In clinical studies, the safety and effectiveness of sitagliptin in the elderly (≥65 years) were comparable to those seen in younger patients (<65 years).
Metformin hydrochloride: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin should only be used in patients with normal renal function (see Contraindications).

Use in pregnancy: There are no adequate and well-controlled studies in pregnant women with Janumet or its individual components; therefore, the safety of Janumet in pregnant women is not known. Janumet, like other oral antihyperglycemic agents, is not recommended for use in pregnancy.
No animal studies have been conducted with the combined products in Janumet to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.
Sitagliptin Phosphate: Sitagliptin was not teratogenic in rats at oral doses up to 250 mg/kg or in rabbits given up to 125 mg/kg during organogenesis (up to 32 and 22 times, respectively, the human exposure based on the recommended daily adult human dose of 100 mg/day). In rats, a slight increase in the incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) was observed at oral doses of 1000 mg/kg/day (approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Slight decreases in mean preweaning body weights of both sexes and postweaning body weight gains of males were observed in the offspring of rats given oral dose of 1000 mg/kg/day. However, animal reproduction studies are not always predictive of the human response.
Metformin hydrochloride: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 times and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Use in lactation: No studies in lactating animals have been conducted with the combined components of Janumet. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin is excreted in human milk. Therefore, Janumet should not be used by a woman who is nursing.

In patients with type 2 diabetese mellitus, in placebo-controlled clinical trials the combination of sitagliptin and metformin was generally well tolerated. The overall incidence of side effects reported in patients receiving the combination of sitagliptin and metformin was similar to that reported in patients receiving the combination of placebo and metformin.
Combination Therapy with Sitagliptin and Metformin: Initial Therapy: In a 24-week placebo-controlled factorial study of initial therapy with sitagliptin 50 mg twice daily in combination with metformin at 500 or 1000 mg twice daily, the drug-related adverse reactions reported in ≥1% of patients receiving combination therapy (and greater than in patients receiving placebo) are shown in Table 6.

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Add-On Combination Therapy to Metformin: In a 24-week placebo-controlled study of sitagliptin added to ongoing metformin therapy, 464 patients on metformin were treated with sitagliptin 100 mg once daily and 237 patients were given placebo with metformin. The only drug-related adverse reaction reported that occurred with an incidence of ≥1% and higher than placebo in patients receiving sitagliptin and metformin was nausea (sitagliptin 100 mg and metformin, 1.1%; placebo and metformin, 0.4%).
Hypoglycemia and Gastrointestinal Adverse Experiences: In the placebo-controlled studies of combination therapy with sitagliptin and metformin, the incidence of hypoglycemia (regardless of investigator assessment of causality) reported in patients treated with the combination of sitagliptin and metformin was similar to that reported for patients treated with metformin and placebo. The incidences of prespecified gastrointestinal adverse experiences in patients treated with the combination of sitagliptin and metformin were similar to those reported for patients treated with metformin alone (see Table 7).

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In all studies, adverse experiences of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required.
Sitagliptin in Combination with Metformin and a Sulfonylurea: In a 24-week placebo-controlled study of sitagliptin 100 mg daily added to ongoing combination treatment with glimepiride ≥4 mg daily and metformin ≥1500 mg daily, the drug-related adverse reactions reported in ≥1% of patients treated with sitagliptin (N=116), and more commonly than in patients treated with placebo (N=113) were hypoglycemia (sitagliptin, 13.8%; placebo, 0.9%) and constipation (1.7%, 0%).
Sitagliptin in Combination with Metformin and a PPARγ Agonist: In a placebo-controlled study of sitagliptin 100 mg daily added to ongoing combination treatment with metformin and rosiglitazone, the drug-related adverse reactions reported through the primary time point at week 18 in ≥1% of patients treated with sitagliptin (N=170) and more commonly than in patients treated with placebo (N=92) were: Headache (sitagliptin, 2.4%; placebo, 0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0%) and vomiting (1.2%, 0%). Through week 54, the drug-related adverse reactions reported in ≥1% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: Headache (2.4%, 0%), hypoglycemia (2.4%, 0%), upper respiratory tract infection (1.8%, 0%), nausea (1.2%, 1.1%), cough (1.2%, 0%), fungal skin infection (1.2%, 0%), peripheral edema (1.2%, 0%), and vomiting (1.2%, 0%).
Sitagliptin in Combination with Metformin and Insulin: In a 24-week, placebo-controlled study of sitagliptin 100 mg added to ongoing combination treatment with metformin ≥1500 mg daily and insulin, the only drug-related adverse reaction reported in ≥1% of patients treated with sitagliptin (N=229) and more commonly than in patients treated with placebo (N=233) was hypoglycemia (sitagliptin, 10.9%; placebo, 5.2%).
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1/100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). (See Precautions.)
With the combination of sitagliptin and metformin, no clinically significant changes in vital signs or in ECG (including in QTc interval) were observed.
Established Adverse Reactions with Sitagliptin: There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving sitagliptin.
Established Adverse Reactions with Metformin: Gastrointestinal symptoms eg, nausea, vomiting, diarrhea, abdominal pain and loss of appetite (>10%) are very common. These occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Metallic taste (3%) is common.
Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (<0.01%).
A decrease of vitamin B12 absorption with decrease of serum levels have been observed in patients treated with long-term metformin and appears generally to be without clinical significance (<0.01%).
Lactic acidosis (0.03 cases/1000 patient-years) is very rare.
Post-Marketing Experience: The following additional adverse reactions have been identified during post-marketing use of Janumet or sitagliptin, one of the components of Janumet. These reactions have been reported when Janumet or sitagliptin have been used alone and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis and exfoliative skin conditions including Stevens-Johnson syndrome (see Contraindications and Precautions); acute pancreatitis including fatal and nonfatal hemorrhagic and necrotizing pancreatitis (see Precautions); worsening renal function including acute renal failure (sometimes requiring dialysis); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache.
Laboratory Test Findings: Sitagliptin Phosphate: The incidence of laboratory adverse experiences was similar in patients treated with sitagliptin and metformin compared to patients treated with placebo and metformin. Across clinical studies, a small increase in white blood cell (WBC) count (approximately 200 cells/microL difference in WBC versus placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.
Metformin hydrochloride: In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels without clinical manifestations was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation (see Precautions).

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 (C_max, 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 C_max 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 C_max 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 C_max by 22%, and blood AUC by 15% without any significant change in metformin renal clearance. When administered with metformin, the C_max 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 C_max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T_max 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.

Store below 30°C (86°F).

Antidiabetic Agents

A10BD07 - metformin and sitagliptin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

B