Reditn M

REDITN M 50 mg/500 mg: White to off-white colored, bi-convex, oval tablet with "5" debossed on one side and plain on the other side.
Sitagliptin 50 mg and Metformin Hydrochloride 500 mg/tablet.
REDITN M 50 mg/1000 mg: Yellow colored, bi-convex, oval tablet with "10" debossed on one side and plain on the other side.
Sitagliptin 50 mg and Metformin Hydrochloride 1000 mg/tablet.
Excipients/Inactive Ingredients: REDITN M 50 mg/500 mg: Microcrystalline Cellulose, Croscarmellose sodium, Copovidone, Isopropyl Alcohol, Colloidal Silicon Dioxide, Low substituted Hydroxypropyl Cellulose, Magnesium Stearate, Opadry II White 85F18422, Purified Water.
REDITN M 50 mg/1000 mg: Microcrystalline Cellulose, Croscarmellose sodium, Copovidone, Isopropyl Alcohol, Colloidal Silicon Dioxide, Low substituted Hydroxypropyl Cellulose, Magnesium Stearate, Opadry II Yellow 85F520260, Purified Water.

Pharmacology: Pharmacodynamics: Combination products containing metformin and sitagliptin are used to improve glycemic control in type 2 diabetes mellitus (DM).
Metformin: Metformin decreases hepatic gluconeogenesis production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin improves glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetics without some residual functioning pancreatic islet cells. Metformin causes a 10% to 20% decrease in fatty-acid oxidation and a slight increase in glucose oxidation. Unlike phenformin, metformin does not inhibit the mitochondrial oxidation of lactate unless its plasma concentrations become excessive (i.e., in patients with renal failure) and/or hypoxia is present. Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25% to 30%. Unlike oral sulfonylureas, it rarely causes hypoglycemia. Thus, metformin demonstrates more of an antihyperglycemic action than a hypoglycemic action. Metformin does not cause weight gain and in fact, may cause a modest weight loss due to drug-induced anorexia. Metformin also decreases plasma VLDL triglycerides resulting in modest decreases in plasma triglycerides and total cholesterol. Patients receiving metformin show a significant improvement in hemoglobin A1C, and a tendency toward improvement in the lipid profile, especially when baseline values are abnormally elevated.
Sitagliptin: Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which exerts its actions in patients with type 2 DM 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, and GLP-1 slows gastric emptying time. Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is less than 90 mg/dL. The contributions of GIP, which increases insulin secretion and regulates fat metabolism, to the overall effects of sitagliptin are unclear at this time. Sitagliptin is of benefit in patients with type 2 DM as their GLP-1 concentrations are decreased in response to a meal. The long-term safety of DPP-4 inhibitors are currently under investigation as DPP-4 is not an enzyme specific for the breakdown of incretin hormones. In fact, DPP-4 is responsible for the metabolism of many peptides including peptide YY, neuropeptide Y, and growth hormone-releasing hormone. DPP-4 is involved with T-cell activation and is expressed on lymphocytes as CD26. Whether there are long-term neurological or immunological consequences of inhibiting DPP-4 is unclear at this time.
Pharmacokinetics: Metformin; sitagliptin is administered orally.
Metformin: Metformin is distributed rapidly into peripheral body tissues and fluids and appears to distribute slowly into erythrocytes and to a deep tissue compartment (most likely GI tissues). The highest concentrations of metformin are found in the GI tract (10 times the concentrations in the plasma) and lower concentrations in the kidney, liver, and salivary gland tissue. Metformin is negligibly bound to plasma proteins. In healthy adult subjects receiving two metformin 1,000 mg; sitagliptin 50 mg XR tablets once daily with the evening meal for 7 days, steady-state for metformin is reached by Day 5 and the median T_max value for metformin is approximately 8 hours post-dose. The median T_max value for metformin after a single tablet of metformin-sitagliptin is 3.5 hours post-dose. It is not metabolized by the liver, which may explain why the risk of lactic acidosis is much lower for metformin than for phenformin (i.e., approximately 10% of patients have an inherited defect in the ability to metabolize phenformin).
About 90% of a dose is excreted by the kidneys, largely unchanged, through an active tubular process. Tubular secretion may be altered by many cationic drugs. Approximately 10% of an oral dose is excreted in the feces, presumably as unabsorbed metformin. Although the average elimination half-life in the plasma is 6.2 hours in patients with normal renal function, metformin is distributed to and accumulates in red blood cells, which leads to a much longer elimination half-life in the blood (17.6 hours).
Sitagliptin: Sitagliptin is not highly bound to plasma proteins (38%). In healthy adult subjects receiving two metformin 1,000 mg; sitagliptin 50 mg XR tablets once daily with the evening meal for 7 days, steady-state for sitagliptin is reached by Day 4 and the median T_max value for sitagliptin is approximately 3 hours post-dose. The median T_max value for sitagliptin after a single tablet of metformin-sitagliptin is 3 hours post-dose.
Metabolism is a minor pathway of elimination for sitagliptin with approximately 16% of a dose excreted as metabolites. The primary enzymes responsible for this limited metabolism are CYP3A4 and CYP2C8. Six metabolites have been detected at trace concentrations and are not expected to contribute significantly to sitagliptin activity. Elimination occurs primarily via renal excretion and involves active tubular secretion; approximately 79% of a dose is excreted unchanged in the urine. 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 this has not been established. Sitagliptin is also a substrate of P-glycoprotein, which may also be involved in mediating renal elimination. The apparent terminal half-life of sitagliptin 100 mg is 12.4 hours. One hundred percent of an administered dose is excreted in the urine (87%) or feces (13%) within 1 week of dosing.

Sitagliptin + metformin is indicated as one of the choices of drugs for initial therapy in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise do not provide adequate glycemic control.
Sitagliptin + metformin 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 patients already being treated with the combination of sitagliptin and metformin.
Sitagliptin + metformin 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: metformin, sitagliptin, or a sulfonylurea.
Sitagliptin + metformin 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: metformin, sitagliptin, or a PPARγ agonist.
Sitagliptin + metformin is indicated in patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control in combination with insulin.

Recommended Dose: General: The dosage of antihyperglycemic therapy with Sitagliptin + metformin 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 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 + metformin should be based on the patient's current regimen.
Sitagliptin + metformin should be given twice daily with meals. The following doses are available: 50 mg sitagliptin/500 mg metformin hydrochloride; 50 mg sitagliptin/1000 mg metformin hydrochloride.
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 + metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients may be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.
For patients inadequately controlled on metformin monotherapy: For patients inadequately controlled on metformin alone, the usual starting dose of Sitagliptin + metformin 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 sitagliptin monotherapy: For patients inadequately controlled on sitagliptin alone, the usual starting dose of Sitagliptin + metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients may be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.
Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to sitagliptin + metformin.
For patients switching from coadministration of sitagliptin and metformin: For patients switching from coadministration of sitagliptin and metformin, sitagliptin + metformin may be initiated at the dose of sitagliptin and metformin already being taken.
For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agents: sitagliptin, metformin or a sulfonylurea: The usual starting dose of Sitagliptin + metformin 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: sitagliptin, metformin or a PPARγ agonist (i.e. thiazolidinediones): The usual starting dose of Sitagliptin + metformin 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.
For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agents: sitagliptin, metformin or insulin: The usual starting dose of Sitagliptin + metformin 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 insulin therapy may require lower doses of insulin to reduce the risk of hypoglycemia (see Precautions). No studies have been performed specifically examining the safety and efficacy of Sitagliptin + metformin in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin + metformin. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.
Recommendations for use in renal impairment: Assess renal function prior to initiation of Sitagliptin + metformin and periodically thereafter.
Sitagliptin + metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m². Sitagliptin + metformin is not recommended in patients with an eGFR ≥30 mL/min/1.73 m² and <45 mL/min/1.73 m² because these patients require a lower dosage of sitagliptin than what is available in the fixed combination Sitagliptin + metformin product.
Discontinuation for iodinated contrast imaging procedures: Discontinue Sitagliptin + metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR ≥30 to <60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Sitagliptin + metformin if renal function is acceptable.
Mode of Administration: Oral use, Sitagliptin + metformin should be given twice daily with meals.

Sitagliptin: 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. 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. 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.

Metformin; sitagliptin combination is contraindicated in patients with a known metformin hypersensitivity or sitagliptin hypersensitivity or any excipients hypersensitivity.
Patients with diabetic ketoacidosis (DKA), with or without coma and metabolic acidosis.
Patients with renal failure or severe renal impairment.

Warning according to the announcement of Ministry of Public Health: Use this drug according to medical prescription. If feeling dizziness, consult the physician.
Do not use in patient with known hypersensitivity to this medicine.
Do not use in type I diabetes treatment, patients with ketoacidosis, severe infection or serious accident.
Avoid to use in pregnancy and lactation.
Should not use concomitantly with alcohol.
This drug may increase risk of severe joint pain.

Exfoliative dermatitis, history of angioedema, serious rash: Metformin; sitagliptin is contraindicated in patients with a known metformin hypersensitivity or sitagliptin hypersensitivity such as anaphylaxis, urticaria, angioedema, exfoliative dermatitis or other serious skin conditions (serious rash), including Stevens-Johnson syndrome. A risk of serious hypersensitivity reactions or anaphylaxis has been reported in patients during the first 3 months of therapy with sitagliptin; some reports occurred after the first dose. Use caution in patients with a history of angioedema or anaphylaxis to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to serious reactions with sitagliptin. Postmarketing cases of serious rash, specifically bullous pemphigoid, requiring hospitalization have been reported with DPP-4 inhibitor use. Treatment with topical or systemic immunosuppressives and discontinuation of the DPP-4 inhibitor has typically resulted in resolution of the rash. Inform patients of the risk of serious rash and tell them to report development of blisters or erosions while receiving metformin; sitagliptin. If a serious reaction is suspected, discontinue metformin; sitagliptin and refer the patient to a dermatologist for diagnosis and appropriate treatment.
Diabetic ketoacidosis, type 1 diabetes mellitus: Metformin; sitagliptin use is contraindicated in patients with diabetic ketoacidosis (DKA), with or without coma. This combination is not intended for the treatment of type 1 diabetes mellitus.
Acidemia, hypoxemia, lactic acidosis, metabolic acidosis: Metformin; sitagliptin is contraindicated in patients with metabolic acidosis. Metformin is associated with a risk for lactic acidosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; 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 or significant renal dysfunction. Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1,000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. 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 bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin; sitagliptin 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.
Pancreatitis: Use metformin; sitagliptin with caution in patients with a history of pancreatitis; use in these patients has not been studied. It is not known whether these patients are at an increased risk for developing pancreatitis. During postmarketing surveillance between October 2006 and February 2009, acute pancreatitis was reported in 88 patients taking sitagliptin or metformin; sitagliptin. In 19 of the 88 reported cases (21%), pancreatitis occurred within 30 days of starting sitagliptin or metformin; sitagliptin. Upon discontinuation of sitagliptin, 47 of the 88 cases (53%) resolved. At least one other risk factor for developing pancreatitis was evident in 45 cases (51%). In March 2013, the FDA announced that it is evaluating unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. In February 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics, including the dipeptidyl peptidase 4 (DPP-4) inhibitors. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although the totality of the reviewed data provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available. Monitor patients carefully after initiation or dose increases; if pancreatitis is suspected, sitagliptin; metformin should be discontinued.
Adrenal insufficiency, diarrhea, fever, gastroparesis, GI obstruction, hypercortisolism, hyperglycemia, hyperthyroidism, hypoglycemia, hypothyroidism, ileus, malnutrition, pituitary insufficiency, vomiting: Conditions that predispose patients to developing hypoglycemia or hyperglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency, or hypothyroidism. The risk of hypoglycemia is also increased when metformin; sitagliptin is used in combination with insulin or sulfonylureas. The risk of hypoglycemia when metformin; sitagliptin is used in combination with other drugs known to cause hypoglycemia (e.g., exenatide, nateglinide, repaglinide) is not known. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Gastrointestinal (GI) side effects may occur during metformin; sitagliptin initiation; however, later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis. Patients stable on metformin; sitagliptin who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms and rule out serious GI conditions.
Furthermore, withholding metformin; sitagliptin therapy until the cause of the GI symptoms is known may be necessary. Finally, diarrhea and nausea/vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood glucose. Patients should be advised to contact their prescriber if an increase in GI symptoms occurs while taking metformin; sitagliptin.
Patients should also be advised to monitor their blood glucose concentrations more frequently. Changes in gastric emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully.
Renal disease, renal failure, renal impairment: Due to the metformin component, sitagliptin; metformin is contraindicated for use in patients with renal failure or severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m². Initiating metformin in patients with an eGFR between 30 to 45 mL/minute/1.73 m² is not recommended. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. Certain medications that are eliminated via the kidney when used concomitantly with metformin may also increase the risk of lactic acidosis. Sitagliptin requires dosage adjustment in renal impairment when patients have a CrCl less than 50 mL/min. Before initiation of metformin; sitagliptin and at least annually thereafter, renal function should be assessed in all patients receiving sitagliptin; metformin, using an eGFR to assess renal function. In those patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently. In patients taking sitagliptin; metformin whose eGFR later falls below 45 mL/minute/1.73 m², assess the benefits and risks of continuing treatment. Discontinue sitagliptin; metformin if the patient's eGFR later falls below 30 mL/minute/1.73 m². Based on the results of a comprehensive FDA safety review, the FDA concluded that metformin can be used safely in patients with mild renal impairment, and in some patients with moderate renal impairment. The measure of kidney function used to determine whether a patient can receive metformin has been changed from serum creatinine to the eGFR; this is because in addition to serum creatinine concentration, the eGFR takes into account additional parameters that are important, such as the patient's age, gender, race and/or weight.
Acute heart failure, acute myocardial infarction, cardiac disease, cardiogenic shock, heart failure: Use metformin; sitagliptin with caution in patients who have a history of or who have increased risk factors for heart failure, including patients with existing cardiac disease or kidney disease. Observe patients receiving metformin; sitagliptin for signs and symptoms of heart failure, and if heart failure develops, consider discontinuing the drug and monitoring for diabetic control. In patients receiving other DPP-4 inhibitors, including linagliptin and saxagliptin, an increased risk of hospitalization for heart failure has been reported. In the EXAMINE trial, 5,380 patients with type 2 diabetes and established cardiovascular disease who had a recent acute coronary syndrome event were randomized to receive either alogliptin therapy or placebo. More patients randomized to the alogliptin group (3.9%) experienced at least 1 hospitalization for heart failure compared to patients randomized to placebo (3.3%). In the SAVOR trial, 16,492 patients with type 2 diabetes who had either a history of cardiovascular events or a risk for cardiovascular events were randomized to receive either saxagliptin therapy or placebo. Although the SAVOR trial was not specifically designed to assess heart failure risk, results showed that 3.5% of patients in the saxagliptin group were hospitalized for heart failure compared to 2.8% of patients in the placebo group (HR 1.27, 95% CI 1.07 to 1.51; p = 0.007). Metformin; sitagliptin should also be used with caution in patients with congestive heart failure requiring pharmacologic treatment. Acute congestive heart failure characterized by acute hypoxia has been associated with the development of lactic acidosis in patients taking metformin. To reduce the risk of lactic acidosis, metformin; sitagliptin should be promptly withheld in the presence of any condition associated with hypoxemia. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia.
Alcoholism, ethanol intoxication, hepatic disease: The use of metformin has been associated with lactic acidosis in rare instances. Since the liver is important for clearing accumulated lactic acid, metformin; sitagliptin should generally be avoided in patients with hepatic disease as the risk of lactic acidosis may be increased. Hepatic disease also causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism and patients should be warned against ethanol intoxication (acute or chronic) while on metformin; sitagliptin. This drug is not recommended for those with alcoholism.
Radiographic contrast administration: Discontinue sitagliptin; metformin at the time of or before radiographic contrast administration in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/minute/1.73 m²; in patients with a history of hepatic disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Reevaluate the eGFR 48 hours after the imaging procedure; restart sitagliptin; metformin if renal function is stable.
Burns, dehydration, infection, sepsis, surgery, trauma: The use of metformin has been associated with lactic acidosis in rare instances. To reduce the risk of lactic acidosis, metformin; sitagliptin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin; sitagliptin therapy should be temporarily suspended for any surgery, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any change in clinical status, including diarrhea or vomiting, may also increase the risk of lactic acidosis and may require laboratory evaluation in patients on metformin; sitagliptin and may require the drug to be withheld.
Anemia, pernicious anemia, vitamin B12 deficiency: As the metformin component of metformin; sitagliptin has been associated with suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex, use this medication with caution, if at all, in patients with vitamin B12 deficiency or vitamin B12-dependent anemia. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Certain individuals may be predisposed to this type of anemia; a nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15 to 3.87) as did taking metformin for 3 or more years (OR 2.39, 95% CI 1.46 to 3.91). Annual measurement of hematologic parameters is recommended in all patients on chronic metformin; sitagliptin treatment.
Arthralgia: Cases of severe, sometimes disabling, arthralgia (joint pain) have been reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin. Advise patients not to discontinue therapy but to contact their health care professional immediately if they experience severe and persistent joint pain while taking metformin; sitagliptin. Consider metformin; sitagliptin as a possible cause of joint pain and discontinue if appropriate. The FDA has identified 33 cases of severe arthralgia with the use of DPP-4 inhibitors, all of which resulted in substantial reduction of the patient's prior level of activity and, in 10 cases, required hospitalization. In the reported cases, the onset of symptoms occurred from 1 day to several years after the start of therapy with a DPP-4 inhibitor. Symptoms resolved with discontinuation of therapy, usually in less than a month; however, some patients experienced a recurrence of joint pain when restarting the same drug or switching to another DPP-4 inhibitor.
Effects on ability to drive and use machines: Sitagliptin + metformin has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin.
In addition, patients should be alerted to the risk of hypoglycaemia when Sitagliptin + metformin is used in combination with a sulphonylurea or with insulin.
Use in Pregnancy: Polycystic ovary syndrome, pregnancy: There are no adequate and well-controlled studies with the combination of metformin; sitagliptin in pregnant women; use during pregnancy only if clearly needed. Placental transfer of sitagliptin has been demonstrated in animal studies. Sitagliptin doses of up to 30 times the human exposure at the maximum recommended human dose (MRHD) were not teratogenic when administered to rats and rabbits on gestation days 6 to 20; a dose of 1,000 mg/kg (100 times the human exposure at the MRHD) caused rib malformations in offspring and the dose resulted in a decrease in offspring weight; neither functional nor behavioral toxicity was observed. Metformin does pass through the placenta and the fetus is exposed to therapeutic concentrations of metformin. Epidemiologic data suggest no increase in the rates of expected birth defects in women taking metformin who become pregnant. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes mellitus and gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta. Per ACOG, in women who decline insulin therapy or are unable to safely administer insulin, metformin monotherapy is the preferred second-line choice. Per the ADA, metformin monotherapy may be used to treat GDM as a treatment option; however, no long term safety data are available for any oral agent. Metformin may cause a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin; however, some data suggest that metformin may slightly increase the risk of prematurity. The ADA notes that in some clinical studies, nearly 50% of GDM patients initially treated with metformin have needed the addition of insulin in order to achieve acceptable glucose control. Many studies and analyses of metformin in use in pregnancy have been published. Data suggest no increase in the rates of expected birth defects or other adverse outcomes in exposed infants and studies comparing metformin to insulin in the treatment of gestational diabetes have generally found no significant differences in glycemic control or pregnancy outcomes. Premenopausal anovulatory females with insulin resistance, such as those with polycystic ovary syndrome (PCOS), may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used.
Use in Lactation: Caution should be used when administering metformin; sitagliptin to women who are breast-feeding. No studies have been conducted with the combined ingredients of metformin; sitagliptin. Sitagliptin is secreted in the milk of lactating rats at a plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies. Furthermore, the use of metformin 2,550 mg/day by mothers breastfeeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known. In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11% to 1.08% of the mother's dose. The results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant. If patients elect to continue metformin; sitagliptin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin; sitagliptin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Metformin monotherapy may be a consideration. Other oral hypoglycemics may also be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected; therefore, this agent may represent a reasonable alternative for some patients.
Use in Children: The safety and effectiveness of metformin; sitagliptin in pediatric patients less than 18 years of age has not been established. Sitagliptin is not indicated for the treatment of children, adolescents, or infants; sitagliptin is not proven to improve blood sugar control in pediatric patients. Three 20-week double-blind, placebo-controlled studies were conducted in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes, with or without insulin therapy (A1C 6.5% to 10% for patients not on insulin, A1C 7% to 10% for patients on insulin); the effect of treatment with sitagliptin was not significantly different from placebo. In study 1, at week 20, the change from baseline in A1C in patients treated with sitagliptin (n = 95) was 0.06% compared to 0.23% in patients treated with placebo (n = 95), a difference of -0.17% (95% CI -0.62, 0.28). In studies 2 and 3, at week 20, the change from baseline in A1C in patients treated with sitagliptin (n = 107) was -0.23% compared to 0.09% in patients treated with placebo (n = 113), a difference of -0.33% (95% CI -0.70, 0.05).
Use in the Elderly: Use the combination of metformin; sitagliptin with caution in geriatric patients. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Sitagliptin dosing is recommended to be decreased in patients with a CrCl less than 50 mL/min. Obtain an estimated glomerular filtration rate (eGFR) at least annually in all patients taking metformin; sitagliptin. In patients at increased risk for the development of renal impairment such as geriatric patients, renal function should be assessed more frequently. Unless estimated renal function via the eGFR is determined to not be reduced, do not use metformin in geriatric patients 80 years of age and older. Generally, geriatric or debilitated patients should not be titrated up to maximum metformin dosages. Older, debilitated, or malnourished patients are also particularly susceptible to hypoglycemic effects of antidiabetic agents; monitor blood glucose frequently. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function. Metformin has been associated with lactic acidosis, which is more likely to occur under the following conditions: serum creatinine of 1.5 mg/dL or higher in males or 1.4 mg/dL or higher in females, abnormal creatinine clearance from any cause, age of 80 years or older unless measurement of creatinine clearance verifies normal renal function, radiologic studies in which intravascular iodinated contrast materials are given, congestive heart failure requiring pharmacologic management, or acute/chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).

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.
A limited amount of data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development.
Sitagliptin + metformin should not be used during pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment should be discontinued and the patient switched to insulin treatment as soon as possible.
Breast-feeding: No studies in lactating animals have been conducted with the combined active substances of this medicinal product. In studies performed with the individual active substances, both sitagliptin and metformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether sitagliptin is excreted in human milk. Sitagliptin + metformin must therefore not be used in women who are breast-feeding.
Fertility: Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

Metabolic: Metformin-sitagliptin: Very common (10% or more): Hypoglycemia (13.8% when combined with sulfonylurea; 10.9% when combined with insulin).
Common (1% to 10%): Hypoglycemia, decrease levels of vitamin B12 without clinical manifestations and rarely associated with anemia.
Rare (less than 0.1%): Lactic acidosis due to metformin.
Sitagliptin: Uncommon (0.1% to 1%): Hypoglycemia.
Metformin: Common (1% to 10%): Hypoglycemia (5% or more when combined with glyburide).
Uncommon (0.1% to 1%): Hypoglycemia.
Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency.
In metformin-treated patients, the incidence of lactic acidosis has been about 1.5 cases per 10,000 patient years. The risk of lactic acidosis has been particularly high in patients with underlying renal insufficiency and rarely in patients with normal renal function. Concomitant cardiovascular or liver disease, sepsis, and hypoxia have also increased the risk of lactic acidosis.
Signs and symptoms of severe acidosis may include vomiting, abdominal pain, nausea, dyspnea, hypothermia, hypotension, and bradycardia.
Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption. Malabsorption of vitamin B12, due to intrinsic factor deficiency and possibly other mechanisms, in as many as 30% of treated patients, were reported. Megaloblastic anemia has occurred. Decreased levels of vitamin B12 appear to be reversible with discontinuation of metformin or vitamin B12 supplementation.
Gastrointestinal: Common (1% to 10%): Diarrhea, nausea, flatulence, vomiting.
Uncommon (0.1% to 1%): Constipation, upper abdominal pain, dry mouth.
Postmarketing reports: Indigestion, abdominal discomfort, dyspepsia, abdominal pain, acute pancreatitis (including fatal and non-fatal hemorrhagic and necrotizing pancreatitis), mouth ulceration, stomatitis.
Metformin: Very common (10% or more): Nausea, vomiting, diarrhea, abdominal pain, loss of appetite.
Sitagliptin: Rare (less than 0.1%): Pancreatitis.
Nervous system: Metformin-sitagliptin: Common (1% to 10%): Headache.
Uncommon (0.1% to 1%): Somnolence.
Frequency not reported: Asthenia.
Metformin: Common (1% to 10%): metallic taste.
Respiratory: Common (1% to 10%): Upper respiratory tract infections, nasopharyngitis, pharyngolaryngeal pain, bronchitis, sinusitis, influenza.
Postmarketing reports: Interstitial lung disease.
Hypersensitivity: Frequency not reported: Hypersensitivity reactions including anaphylaxis.
Hepatic: Metformin-sitagliptin: Postmarketing reports: Hepatic enzyme elevation.
Metformin: Very rare (less than 0.01%): Liver function disorders, hepatitis.
Renal: Frequency not reported: Impaired renal function, acute renal failure (sometimes requiring dialysis).
Musculoskeletal: Between October 2006 and December 2013, thirty-three cases of severe arthralgia have been reported to the FDA Adverse Event Reporting System Database. Each case involved the use of 1 or more dipeptidyl peptidase-4 (DPP-4) inhibitor. In all cases, substantial reduction in prior activity level was reported, 10 patients were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of starting therapy, in 23 cases symptoms resolved less than 1 month after discontinuation. A positive rechallenge was reported in 8 cases, with 6 cases involving use of a different DPP-4 inhibitor. Sitagliptin had the greatest number of cases reported (n=28) followed by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2).
Common (1% to 10%): Arthralgia.
Postmarketing reports: Myalgia, pain in extremities, back pain, rhabdomyolysis.
General: Common (1% to 10%): Peripheral edema.
Dermatologic: Postmarketing reports: Angioedema, rash, urticaria, pruritus, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome.
Metformin: Very rare (less than 0.01%): Urticaria, erythema, pruritus.
Hematologic: Decreased serum vitamin B12 levels, without clinical manifestations (rarely megaloblastic anemia), has been reported in approximately 7% of patients. The reduction in vitamin B12 levels may be due to interference with B12 absorption from the B12-intrinsic factor complex and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.
Rare (less than 0.1%): Megaloblastic anemia.

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: Sitagliptin and metformin 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 anti-hyperglycaemic 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.
Effects of other medicinal products on sitagliptin: In vitro and clinical data described as follows suggest that the risk for clinically meaningful interactions following co-administration of other medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting of renal impairment have not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and C_max of sitagliptin by approximately 29% and 68%, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products: Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11%, and the plasma C_max on average by 18%. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Storage condition: Store below 30°C.
Shelf Life: 24 months from manufacturing date.

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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