Co-Zincretin 50/500/Co-Zincretin 50/1000/Co-Zincretin XR 100/1000

Co-Zincretin 50/500/Co-Zincretin XR 100/1000: Sitagliptin Phosphate + Metformin HCl combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl peptidase 4 (OPP-4) inhibitor; and metformin hydrochloride, a member of the biguanide class.
Sitagliptin Phosphate: Sitagliptin Phosphate is an orally-active, potent and highly selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 enzyme is a class of agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). 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. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduce hepatic glucose production. The mechanism is unlike the mechanism seen with sulfonylureas; sulfonylureas cause insulin release even when glucose levels are low, which can lead to sulfonylurea-induced hypoglycemia in patients with type 2 diabetes and in normal subjects. 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 pharmacologic action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-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 Metformin hydrochloride 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.
Sitagliptin Phosphate + Metformin HCl contains sitagliptin phosphate and metformin hydrochloride. Sitagliptin Phosphate is a white or almost white powder. Soluble in water and N, N-Dimethylfonnamide, slightly soluble in methanol and insoluble in 2-propanol. Sitagliptin Phosphate is chemically designated as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoromethyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine phosphate (1:1) monohydrate. Its empirical formula is C₁₆H₁₅F₆N₅₀H₃PO₄H₂O and its molecular weight is 523.32.
Metformin Hydrochloride is a white or almost white crystalline powder. Freely soluble in water, slightly soluble in Alcohol, practically insoluble in Acetone and Methylene dichloride. Metformin Hydrochloride is chemically designated as N, N- dimethylbiguanide Hydrochloride. N'-dimethlyguanylguanidine Hydrochloride LA-6023 (Metformin or Metformin Hydrochloride); Metformina, hidrocloruro de; Metforrnini Hydrochloridum. 1, 1-Dimethylbiguanide hydrochloride. Its empirical formula is C₄H₁₁N_5,HCl, and its molecular weight is 165.65.
Co-Zincretin 50/500: Each Film-Coated tablet contains: Sitagliptin Phosphate Monohydrate, USP Eq. to Sitagliptin 50 mg, Metformin Hydrochloride, BP 500 mg.
Sitagliptin Phosphate + Metformin Hydrochloride is a extended release film coated tablets, White colored, elongated shaped, biconvex film coated tablets having one side central breakline & other side plain. It contains the following inactive ingredients: Microcrystalline Cellulose, Maize starch, PVP K-30, Methyl Paraben Sodium, Propyl Paraben Sodium, Purified Water, Sodium Starch Glycolate, Purified Talc, Magnesium Stearate, Colloidal anhydrous silica, Film Coat, Titanium Dioxide, Isopropyl Alcohol & Dichloromethane.
Co-Zincretin 50/1000: Each Film-Coated Tablet contains: Sitagliptin (as phosphate monohydrate) 50 mg, Metformin Hydrochloride 1 g.
White coloured, capsule shaped, biconvex, film-coated tablet, plain on both sides.
Co-Zincretin XR 100/1000: Each Extended Release Film-Coated tablet contains Sitagliptin Phosphate Monohydrate, USP Eq. to Sitagliptin 100 mg, Metformin Hydrochloride, BP 1 g.
Sitagliptin Phosphate + Metformin HCl is a extended release film coated tablets, Red colored, elongated shaped, biconvex extended release, film coated tablets having one side central break line & other side plain. It contains the following inactive ingredients: Microcrystalline Cellulose, Maize starch, PVP K-30, Methyl Paraben Sodium, Propyl Paraben Sodium, Purified Water, Sodium Starch Glycolate, Purified Talc, Magnesium Stearate, Colloidal anhydrous silica, Film Coat, Red oxide Iron, Isopropyl Alcohol & Dichloromethane.

Co-Zincretin 50/1000: Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs.
Pharmacology: Mechanism of Action: Combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin: Sitagliptin is a DPP-4 inhibitor, which is believed to exert 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.
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.
Pharmacodynamics: Co-Zincretin 50/500/Co-Zincretin XR 100/1000: 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-hour 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 beta cell function, as assessed by several markers, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and measures of beta 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, four-period crossover two-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 two days. The incremental 4-hour 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 anti-hypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, beta-blockers and diuretics), co-administration with sitagliptin was generally well tolerated. In these patients, sitagliptin had a modest blood pressure lowering effect; 100 mg per day of sitagliptin reduced 24-hour 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 hours post dose was 8.0 msec. 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 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.
Co-Zincretin 50/1000: Sitagliptin: General: 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. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Pharmacokinetics: Co-Zincretin 50/500/Co-Zincreetin XR 100/1000: Sitagliptin + Metformin: The results of a definite bioequivalence study in healthy subjects demonstrated that the Sitagliptin Phosphate + Metformin HCl 50 mg/500 mg and 100 mg/1 g combination tablets are bioequivalent to co-administration of corresponding doses of Sitagliptin Phosphate 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 mg to 1500 mg, and 850 mg to 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-minute prolongation of time to peak plasma concentration (T_max) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution: Sitagliptin phosphate: 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: 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 more than 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 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 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: 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) nor biliary excretion.
Elimination: Sitagliptin phosphate: Following administrationof 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 t_½ 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.
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 Impairment: Sitagliptin Phosphate + Metformin HCl: Sitagliptin Phosphate + Metformin HCl 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 ESRD on hemodialysis, as compared to normal heal thy 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 phosphate: In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and C_max of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of sitagliptin phosphate. 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 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 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.
Pediatric: No studies with Sitagliptin Phosphate + Metformin HCl 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 is of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Co-Zincretin 50/1000: A bioequivalence study in healthy subjects demonstrated that the Sitagliptin/Metformin hydrochloride combination tablets are bioequivalent to co-administration of sitagliptin phosphate and metformin hydrochloride as individual tablets.
Sitagliptin: Absorption: Following oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 μMhr, C_max was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C_max and C_24h (C_max increased in a greater than dose-proportional manner and C_24hr increased in a less than dose-proportional manner).
Distribution: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Biotransformation: 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 sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin.
Elimination: Following administration of an oral sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing. The apparent terminal t_½ ;following a 100 mg oral dose of sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 mL/min.
Metformin: Absorption: After an oral dose of metformin, t_max is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 4 μg/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean V_d ranged between 63-276 L.
Biotransformation: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Sitagliptin Phosphate + Metformin HCl is indicated as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin.
Co-Zincretin 50/1000: For adult patients with type 2 diabetes mellitus: Indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea.
Indicated as triple combination therapy with a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.
Also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycaemic control.

The dose of antihyperglycaemic therapy with Sitagliptin Phosphate + Metformin Hydrochloride should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.
Co-Zincretin 50/1000: Adults with normal renal function (GFR ≥90 mL/min): For patients not adequately controlled on metformin alone: The usual starting dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken.
For patients switching from co-administration of sitagliptin and metformin: Should be initiated at the dose of sitagliptin and metformin already being taken.
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea: The dose 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 sitagliptin and metformin is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia.
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a PPARγ agonist: The dose 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.
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin: The dose 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 sitagliptin and metformin is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia.
All patients should continue their recommended diet with an adequate distribution of carbohydrate intake during the day.
Or as directed by physician.
Method of administration: For Oral Administration.

Co-Zincretin 50/500/Co-Zincreetin XR 100/1000: Sitagliptin phosphate: During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin (see Pharmacology: Pharmacodynamics: Cardiac Electrophysiology 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 per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., 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-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. 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 Metformin hydrochloride under Precautions). 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.
Co-Zincretin 50/1000: A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis which is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.

Co-Zincretin 50/500/Co-Zincretin XR 100/1000: Sitagliptin Phosphate + Metformin HCl is contraindicated in patients with: Severe renal impairment, (eGFR <30 mL/min/1.73 m²) (see Metformin hydrochloride: Renal Impairment under Precautions).
Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride known hypersensitivity to sitagliptin phosphate, metformin hydrochloride or any other component of Sitagliptin Phosphate + Metformin HCl (see Sitagliptin phosphate: Hypersensitivity Reactions under Precautions and Post-Marketing Experience under Adverse Reactions).
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Sitagliptin Phosphate + Metformin HCl 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 Metformin hydrochloride under Precautions).
Co-Zincretin 50/1000: Contraindicated in patients with: Hypersensitivity to the active substances or to any of the excipients; diabetic ketoacidosis, diabetic pre-coma; moderate and severe renal impairment (creatinine clearance <6 mL/min); acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents; acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, hepatic impairment; acute alcohol intoxication, alcoholism; breast-feeding.

Co-Zincretin 50/500/Co-Zincretin XR 100/1000: Sitagliptin Phosphate + Metformin HCl: Sitagliptin Phosphate + Metformin HCl 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 Adverse Reactions), in patients taking sitagliptin. 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, Sitagliptin Phosphate + Metformin HCl and other potentially suspect 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. Sitagliptin Phosphate + Metformin HCl is contraindicated in severe renal impairment, patients with an eGFR <30 mL/min/1.73 m² (see Dosage & Administration, Contraindications and Metformin hydrochloride: Lactic acidosis as follows).
Before initiation of therapy with Sitagliptin Phosphate + Metformin HCl 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 Sitagliptin Phosphate + Metformin HCl discontinued if evidence of renal impairment is present.
Hypoglycemia in Combination with a Sulfonylurea or with Insulin: As is typical with other antihyperglycemic agents, when sitagliptin was used in combination with metformin and a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of sulfonylurea- or insulin-induced hypoglycemia was increased over that of placebo in combination with metformin and a sulfonylurea or insulin (see Adverse Reactions). Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered (see Dosage & Administration).
Sitagliptin phosphate: Hypoglycemia in Combination with a Sulfonylurea or Insulin: In clinical trials of sitagliptin as monotherapy and as part of combination therapy with agents not known to cause hypoglycemia (i.e., metformin or a PPARγ-agonist (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 Adverse Reactions). 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 postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Sitagliptin Phosphate + Metformin HCl. 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 first dose. If a hypersensitivity reaction is suspected, discontinue Sitagliptin Phosphate + Metformin HCl, assess for other potential causes for the event, and institute alternative treatment for diabetes (see Contraindications and Post-Marketing Experience under Adverse Reactions).
Bullous Pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immuno suppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving Sitagliptin Phosphate + Metformin HCl. If bullous pemphigoid is suspected, Sitagliptin Phosphate + Metformin HCl should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Metformin hydrochloride: Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Sitagliptin Phosphate + Metformin HCl; 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 μg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1,000 patient-years, with approximately 0.015 fatal cases/1,000 patient-years). In more than 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. 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 often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmia 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 less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as 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 (such as 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 in 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, such as cationic drugs that are eliminated by renal tubular secretion (see Metformin hydrochloride under Interactions) should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example intravenous urogram, intravenous 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 with an eGFR ≥30 to <60 mL/min/1.73 m². in patients with a history of hepatic impairment, alcoholism, or heart failure, or in patients who will be administered intra-arterial iodinated contrast, Sitagliptin Phosphate + Metformin HCl should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be acceptable (see Dosage & Administration).
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 Sitagliptin Phosphate + Metformin HCl therapy, the drug should be promptly discontinued.
Surgical procedures: Use of Sitagliptin Phosphate + Metformin HCl 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 acceptable (see Dosage & Administration).
Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Sitagliptin Phosphate + Metformin HCl.
Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Sitagliptin Phosphate + Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B₁₂ levels: In controlled clinical trials of metformin of 29 weeks 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. Measurement of hematologic parameters on an annual basis is advised in patients on Sitagliptin Phosphate + Metformin HCl 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 two- to three-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 Sitagliptin Phosphate + Metformin HCl 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, Sitagliptin Phosphate + Metformin HCl 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 such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Sitagliptin Phosphate + Metformin HCl and temporarily administer insulin. Sitagliptin Phosphate + Metformin HCl may be reinstituted after the acute episode is resolved.
Use in Children: Safety and effectiveness of Sitagliptin Phosphate + Metformin HCl 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, Sitagliptin Phosphate + Metformin HCl 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.
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.
Co-Zincretin 50/1000: General: Sitagliptin and Metformin should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis.
Pancreatitis: 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 (with or without supportive treatment).
Lactic acidosis: Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation.
Renal function: Metformin and sitagliptin are known to be substantially excreted by the kidney. Metformin-related lactic acidosis increases with the degree of impairment of renal function, therefore, serum creatinine concentrations should be determined regularly: at least once a year in patients with normal renal function; at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients.
Hypoglycaemia: Patients receiving Sitagliptin and Metformin in combination with a sulphonylurea or with insulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.

Co-Zincretin 50/500/Co-Zincretin XR 100/1000: Sitagliptin Phosphate + Metformin HCl: There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate + Metformin HCl or its individual components; therefore, the safety of Sitagliptin Phosphate + Metformin HCl in pregnant women is not known. Sitagliptin Phosphate + Metformin HCl, like other oral antihyperglycemic agents, is not recommended for use in pregnancy.
No animal studies have been conducted with the combined products in Sitagliptin Phosphate + Metformin HCl to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.
Sitagliptin phosphate: 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 pre weaning 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 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Nursing Mothers: No studies in lactating animals have been conducted with the combined components of Sitagliptin Phosphate + Metformin HCl. 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, Sitagliptin Phosphate + Metformin HCl should not be used by a woman who is nursing.
Co-Zincretin 50/1000: Pregnancy: There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses of sitagliptin.
If a patient wishes to become pregnant or if a pregnancy occurs, treatment with Sitagliptin and Metformin should be discontinued and switched to insulin treatment as soon as possible.
Breast-feeding: Metformin is excreted in human milk in small amounts. It is not known whether sitagliptin is excreted in human milk. Sitagliptin and Metformin must therefore not be used in women who are breast-feeding.

Co-Zincretin 50/500/Co-Zincretin XR 100/1000: In placebo-controlled clinical trials, in patients with type 2 diabetes mellitus, 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 1 (see Table 1).

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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 (100 mg sitagliptin 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 pre-specified 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 2.)

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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%, 0.0%).
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, 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0%), and vomiting (1.2%, 0.0%). 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%, 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory tract infection (1.8%, 0.0%), nausea (1.2%, 1.1%), cough (1.2%, 0.0%), fungal skin infection (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), and vomiting (1.2%, 0.0%).
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 stable-dose 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 another 24-week study of patients receiving sitagliptin as add-on therapy while undergoing insulin intensification (with or without metformin), the only drug-related adverse reaction reported in ≥1% in patients treated with sitagliptin and metformin and more commonly than in patients treated with placebo and metformin was vomiting (sitagliptin and metformin, 1.1 %; placebo and metformin, 0.4%).
Pancreatitis: 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 per 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 also TECOS Cardiovascular Safety Study, as follows. (See Pancreatitis under Precautions).
With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.
Adverse Reactions with Sitagliptin: There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving sitagliptin.
Adverse Reaction Reported with Metformin: Adverse reactions reported (regardless of causality) in greater than 5% of patients treated with metformin and more commonly than in patients treated with placebo are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.
Adverse reactions reported (regardless of causality) in greater than 5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo are diarrhea and nausea/vomiting.
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m²), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors. The study population included a total of 2,004 patients ≥75 years of age (970 treated with sitagliptin and 1,034 treated with placebo). The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo. Assessment of pre-specified diabetes-related complications revealed similar incidences between groups including infections (18.4% of the sitagliptin-treated patients and 17.7% of the placebo-treated patients) and renal failure (1.4% of sitagliptin-treated patients and 1.5% of placebo-treated patients). The adverse event profile in patients ≥75 years of age was generally similar to the overall population.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 1.0% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients. The incidence of adjudication-confirmed malignancy events was 3.7% in sitagliptin-treated patients and 4.0% in placebo-treated patients.
Post-Marketing Experience: Additional adverse reactions have been identified during postmarketing use of Sitagliptin Phosphate + Metformin HCl or sitagliptin, one of the components of Sitagliptin Phosphate + Metformin HCl. These reactions have been reported when Sitagliptin Phosphate + Metformin HCl 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 Hypersensitivity Reactions under Precautions); acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see Pancreatitis under Precautions); worsening renal function, including acute renal failure (sometimes requiring dialysis); bullous pemphigoid (see Bullous Pemphigoid under Precautions); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain; pruritus.
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 count (approximately 200 cells/microL difference in WBC vs 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 weeks 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 Metformin hydrochloride under Precautions).
Co-Zincretin 50/1000: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000). (See Table 3.)

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Co-Zincretin 50/500/Co-Zincretin XR 100/1000: Sitagliptin and metformin: Co-administration of multiple doses of sitagliptin (50 mg b.i.d.) and metformin (1,000 mg b.i.d.) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes. Pharmacokinetic drug interaction studies with Sitagliptin Phosphate + Metformin HCl have not been performed; however, such studies have been conducted with the individual components of Sitagliptin Phosphate + Metformin HCl, 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 (e.g., statins, fibrates, ezetimibe), anti-platelet agents (e.g., clopidogrel), antihypertensives (e.g., ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and nonsteroidal anti -inflammatory agents (e.g., naproxen, diclofenac, celecoxib), anti-depressants (e.g., bupropion, fluoxetine, sertraline), antihistamines (e.g., cetirizine), proton-pump inhibitors (e.g., omeprazole, lansoprazole), and medications for erectile dysfunction (e.g., sildenafil).
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 coadministration 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 coadministration of a single 100-mg oral dose of Sitagliptin Phosphate (Co-Zincretin 50/500/Co-Zincretin XR 100/1000) and a single 600 mg oral dose of cyclosporine, a potent probe inhibitor of p-glycoprotein. The observed changes in sitagliptin pharmacokinetics are not considered likely to be clinically meaningful.
Metformin hydrochloride: Glyburide: In a single-dose interaction study in type 2 diabetes patients, coadministration 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 coadministration. 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 coadministered chronically.
Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration 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.
Drugs that reduce metformin clearance: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.
Other: 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 Sitagliptin Phosphate + Metformin HCl 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 coadministered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
Co-Zincretin 50/1000: Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 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 sitagliptin and metformin have not been performed; however, such studies have been conducted with the individual active substances, sitagliptin and metformin.
Concomitant use not recommended: Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Iodinated contrast agents: The product must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable.
Combinations requiring precautions for use: Some medicinal products can adversely affect renal function, which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when such products are co-administered.
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

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

Rx