This combination is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both Sitagliptin and metformin is appropriate.

Important limitations of use:

• This medicine should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it is not effective in these conditions.
• It has not been adequately studied in patients with a history of Pancreatitis. It is not known whether such patients have an increased risk of developing pancreatitis while using this medicine.

This tablet contains two antihyperglycemic agents with complementary actions to improve blood sugar control in type 2 diabetes patients: Sitagliptin and Metformin HCl. Sitagliptin is a DPP-4 inhibitor that works by slowing the breakdown of incretin hormones. These hormones include GLP-1 and GIP, which are released from the intestine throughout the day and increase after meals. DPP-4 normally inactivates these hormones quickly. When blood glucose is normal or high, GLP-1 and GIP increase insulin production and release from pancreatic beta cells through cyclic AMP–mediated pathways. GLP-1 also reduces glucagon secretion from alpha cells, leading to decreased glucose production in the liver. By increasing active incretin levels, Sitagliptin enhances insulin release and lowers glucagon levels in a glucose-dependent manner. Metformin HCl has a different mechanism from other oral antidiabetic drugs. It reduces glucose production in the liver, decreases glucose absorption from the intestine, and increases glucose uptake and utilization in peripheral tissues.

Dose of film-coated tablet: The dosage of this tablet 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 and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.
The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifically examining the safety and efficacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCl extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Cationic drugs: Cationic drugs that are eliminated through renal tubular secretion should be used with caution when given with this medicine.

Phenprocoumon: Metformin may reduce the anticoagulant effect of phenprocoumon. Therefore, close monitoring of INR is recommended.

Levothyroxine: Levothyroxine may decrease the blood sugar–lowering effect of metformin. Blood glucose should be monitored, especially when thyroid therapy is started or stopped, and metformin dose should be adjusted if needed.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction (serum creatinine ≥1.5 mg/dL in males, ≥1.4 mg/dL in females, or abnormal creatinine clearance), including conditions such as shock, acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma
• History of serious hypersensitivity reaction to this tablet or Sitagliptin, such as anaphylaxis or angioedema

This tablet should be temporarily stopped in patients undergoing radiologic studies with iodinated contrast, as it may affect kidney function.

Common adverse reactions (≥5%) in patients starting Sitagliptin with metformin include diarrhea, upper respiratory tract infection, and headache.

When used with sulfonylurea and metformin, common reactions include hypoglycemia and headache.

When used with insulin and metformin, hypoglycemia is the most common adverse reaction.

With sitagliptin monotherapy, nasopharyngitis is the most common reaction.

Metformin-related side effects (>5%) include diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, weakness (asthenia), and headache.

Pregnancy Category B. There are no adequate controlled studies in pregnant women for this combination or its components. Therefore, safety in pregnancy is not fully established. It should be used during pregnancy only if clearly needed.

It is not known whether Sitagliptin passes into human breast milk. Since many drugs are excreted in milk, caution is required when used in breastfeeding women.

Lactic Acidosis:

• Lactic acidosis may occur due to accumulation of metformin. The risk is increased in conditions such as sepsis, dehydration, excessive alcohol intake, liver impairment, kidney dysfunction, and acute congestive heart failure.
• Symptoms include weakness, muscle pain, breathing difficulty, increasing drowsiness, and non-specific abdominal discomfort. Laboratory findings may show low blood pH, increased anion gap, and elevated blood lactate levels.
• If lactic acidosis is suspected, this tablet should be stopped immediately and the patient should be hospitalized.
• Regular monitoring of thyroid-stimulating hormone (TSH) is recommended in patients with hypothyroidism.
• Long-term use of metformin may reduce vitamin B12 levels, which can lead to peripheral neuropathy. Monitoring vitamin B12 levels is advised.

Others:

• This tablet should not be used in patients with liver disease.
• Post-marketing reports have shown cases of acute kidney failure, sometimes requiring dialysis. Kidney function should be assessed before starting treatment and at least once yearly thereafter.
• Cases of acute Pancreatitis, including severe hemorrhagic or necrotizing forms (sometimes fatal), have been reported. If pancreatitis is suspected, the medicine should be stopped immediately.
• Blood parameters should be checked annually.
• Patients should be warned to avoid excessive alcohol intake.
• Temporary discontinuation of this tablet and use of insulin may be required during stress conditions such as fever, trauma, infection, or surgery when food and fluid intake is reduced.
• Patients who were previously stable on this medicine but develop abnormal lab results or illness should be evaluated promptly for ketoacidosis or lactic acidosis.
• When used with insulin or sulfonylurea, dose reduction of these agents may be required to reduce the risk of hypoglycemia.
• Serious allergic reactions related to Sitagliptin have been reported, including anaphylaxis, angioedema, and severe skin reactions such as Stevens-Johnson syndrome. In such cases, the drug should be stopped immediately and appropriate treatment should be started.
• No conclusive clinical evidence exists that this combination reduces macrovascular risk compared to other anti-diabetic therapies.

Sitagliptin: In case of overdose, standard supportive treatment should be given. This includes removal of unabsorbed drug from the gastrointestinal tract, close clinical monitoring (including ECG), and supportive care based on the patient’s condition. Sitagliptin is only modestly removed by dialysis. Prolonged hemodialysis may be considered if clinically necessary. It is not known whether peritoneal dialysis can remove this drug.

Metformin hydrochloride: Overdose of metformin hydrochloride has been reported, including ingestion of more than 50 grams. Metformin can be effectively removed by hemodialysis, with a clearance rate of up to 170 mL/min under good circulation conditions. Therefore, hemodialysis may be useful in suspected overdose cases to remove accumulated drug. Pancreatitis may also occur in metformin overdose.

Combination oral hypoglycemic preparation

Store below 25°C in a dry place, protected from light. Keep out of reach of children. Do not use after expiry date. Use only on prescription of a registered physician.