Lupigliptin Plus

Each film-coated tablet contains: Sitagliptin (as Phosphate Monohydrate) 50 mg, Metformin HCl 500 mg.
Lupigliptin Plus 50 mg/500 mg is available as white to off-white, capsule shaped film-coated tablet, biconvex plain on both sides.
Each film-coated tablet contains: Sitagliptin (as Phosphate Monohydrate) 50 mg, Metformin HCl 1 g.
Lupigliptin Plus 50 mg/1 g is available as white to off-white capsule shaped film-coated tablet, biconvex plain on both sides.

Pharmacology: Pharmacodynamics: Sitagliptin Phosphate: General: In patients with type 2 diabetes, administration of single oral doses leads to inhibition of DDP-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.
Pharmacokineticcs: Absorption: Sitagliptin phosphate: The absolute bioavailability of sitagliptin phosphate 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 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lock 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 re more than 90% protein bound. Metformin partitions into erythrocytes, most likely as 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 dis not exceed 5 mcg/mL, even at maximum doses.
Metabolism: Sitagliptin phosphate: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is 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 are 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 the metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in human) 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 one week of dosing. The apparent terminal t_1/2 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.
Metformin hydrochloride: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicated 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 studies.
Renal Impairment: Metformin HCl + Sitagliptin phosphate should not be used in patients with renal impairment.
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 impairment and in patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
Metformin hydrochloride: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment: Sitagliptin phosphate: In patients with moderate hepatic insufficiency (Child-Pugh score to 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 venally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Gender: Sitagliptin phosphate: Gender had no clinically meaningful effect on the 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 fife 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 e primarily accounted for by a change in renal function.
Pediatric: No studies with Sitagliptin phosphate + Metformin HCI 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 1 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 pharmacokinetics 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 pharmacokinetics data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Sitagliptin + Metformin HCl is indicated as initial therapy in patents with type 2 diabetes mellitus to improve glycemic control when diet and exercise do not provide adequate glycemic control.
Sitagliptin + Metformin HCl is indicated 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 patents already being treated with the combination of sitagliptin and metformin.
Sitagliptin + Metformin HCl is indicated 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 two of the three agents: sitagliptin, metformin, or sulfonylurea.
Sitagliptin + Metformin HCl is indicated as part of triple combination therapy with a PPARγ agonist (i.e., thiazolidinediones) as an adjunct to diet and exercise in patients with type 2 diabetes mellitus inadequately controlled with any two of the three agents: sitagliptin, metformin, or a PPARγ agonist.
Sitagliptin + Metformin HCl is indicated in patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve control in combination with insulin.

The dosage of antihyperglycemic therapy with Sitagliptin + Metformin HCl should be individualized on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.
Sitagliptin + Metformin HCl should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects associated with metformin.
Dosing Recommendations: The starting dose of Sitagliptin phosphate + Metformin HCl should be on the patient's current regimen. Sitagliptin phosphate + Metformin HCl should be given twice daily meals. The following doses are available: 50 mg Sitagliptin phosphate/500 mg Metformin HCl; 50 mg Sitagliptin phosphate/850 mg Metformin HCl; 50 mg Sitagliptin phosphate/1 g Metformin HCl.
As initial therapy: For patients with type 2 diabetes mellitus, whose hyperglycemia is inadequately controlled with diet and exercise alone, the recommended starting dose of Sitagliptin phosphate + Metformin HCl is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients may be titrated up to 50 mg Sitagliptin phosphate/1 g Metformin HCl twice daily.
For patients inadequately controlled on sitagliptin monotherapy: For patients inadequately controlled on sitagliptin alone, the usual starting dose of Sitagliptin phosphate + Metformin HCl is 50 mg Sitagliptin phosphate/500 mg Metformin HCl twice daily. Patients may be titrated up to 50 mg Sitagliptin phosphate/1 g Metformin HCl twice daily. Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to Sitagliptin phosphate + Metformin HCl.
For patients inadequately controlled on metformin monotherapy: For patients not adequately controlled on metformin alone, the usual starting dose of Sitagliptin phosphate + Metformin HCl should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken.
For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agent: sitagliptin, metformin or a PPARγ agonist (i.e., thiazolidinediones): The usual starting dose of Sitagliptin phosphate + Metformin HCl should provide sitagliptin dosed at 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 gastrointestinal (GI) side effects associated with metformin should be considered.
For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agents: metformin, sitagliptin or a sulfonylurea: The usual starting dose of Sitagliptin phosphate + Metformin HCl 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 gastrointestinal (GI) side effects associated with metformin should be considered. Patients currently on or initiating a sulfonylurea may require lower sulfonylurea doses to reduce the risk of sulfonylurea-induced hypoglycemia.
For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agents: metformin, sitagliptin or insulin: The usual starting dose of Sitagliptin phosphate + Metformin HCl 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 gastrointestinal (GI) side effects associated with metformin should be considered. Patents currently on or initiating insulin therapy may require lower doses of insulin to reduce the risk of hypoglycemia.
No studies have been performed specifically examining the safety and efficacy of Sitagliptin phosphate + Metformin HCl in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin phosphate + Metformin HCl. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.
Mode of Administration: Sitagliptin phosphate + Metformin HCl is available for oral administration as tablets. It should generally be given twice daily with meals.

Sitagliptin: 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 known if sitagliptin is dialyzable by peritoneal dialysis.
Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amount greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no casual association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. 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.

Sitagliptin phosphate + Metformin HCl is contraindicated in patients with: Severe renal impairment, (eGFR <30 mL/min/1.73 m²).
Known hypersensitivity to Metformin HCl, Sitagliptin phosphate or any other component.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis. with or without coma.
Sitagliptin phosphate + Metformin HCI should be temporarily discontinued in patents undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because the use of such products may result in acute alteration of renal function.

Sitagliptin phosphate + Metformin HCl should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: There have been reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin. Patients should be informed of the characteristic symptoms 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: Sitagliptin phosphate and Metformin HCl 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. Metformin HCl + Sitagliptin phosphate is contraindicated in severe renal impairment, patients with an eGFR <30 mL/min/1.73 m².
Before initiation therapy with Sitagliptin phosphate + Metformin HCl and at least annually thereafter, renal function should be assessed. 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, hypoglycemia has been observed when metformin and sitagliptin were used in combination with insulin or a sulfonylurea. Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered.
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. 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. 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 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 acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patents 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 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.
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 glucose0lowering 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 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, such as cationic drugs that are eliminated by renal tubular secretion should be used with caution.
Radiologic studies involving the use of intravascular iodinated 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. 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.
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.
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: Certain individuals (those with adequate 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 develop 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 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: Sitagliptin Phosphate + Metformin Hydrochloride: Because Sitagliptin Phosphate + Metformin Hydrochloride are substantially excreted by the kidney and because aging can be associated with reduced renal function, Sitagliptin Phosphate + Metformin Hydrochloride 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.

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 was not teratogenic in rats at oral doses up to 250 mg/kg or in rabbits 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 1,000 mg/kg/day (approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Slight decrease 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 1,000 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 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.

Adverse Reactions Reported with Sitagliptin: There were no drug-related adverse reactions reported that occurred with an incidence ≥1% in patients receiving sitagliptin.
Adverse Reactions 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.

Sitagliptin Phosphate + Metformin Hydrochloride: Coadministration 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 Hydrochloride, sitagliptin and metformin.
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 the pharmacokinetics parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C_max by 22% 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 coadministration 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 cation. 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.
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.

Store at temperatures not exceeding 30°C. Protect from moisture.

Antidiabetic Agents

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

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