Sitaphil Plus

It is a white colored, capsule shaped, biconvex, film-coated tablet plain on both sides.
Each film-coated tablet contains: Metformin Hydrochloride 1,000 mg, Sitagliptin Phosphate Monohydrate Eq. to Sitagliptin 50mg, Excipients q.s.

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs.
Pharmacology: Pharmacodynamics: Metformin Hydrochloride + Sitagliptin combines two antihyperglycemic medicinal products with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: Sitagliptin phosphate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and Metformin hydrochloride, a member of the biguanide class.
Sitagliptin: Mechanism of Action: Sitagliptin phosphate is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of agents that act as in certain enhancers. By inhibiting the DPP-4 enzyme, Sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. When blood glucose levels are low, insulin release is not enhanced and glucagon secretion is not suppressed. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha glucosidase inhibitors, and amylin analogues.
Metformin: Mechanism of Action: Metformin is a biguanide with anti hyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via three mechanisms: By reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilization; by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

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

Posology: The dose of antihyperglycemic therapy with Metformin Hydrochloride + Sitagliptin 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.
Adults with normal renal function (GFR=90 mL/min): For patients inadequately controlled on maximal tolerated dose of metformin monotherapy: For patients not adequately controlled on metformin alone, the usual starting dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken.
For patients switching from co-administration of sitagliptin and metformin: For patients switching from co-administration of sitagliptin and metformin, Metformin Hydrochloride + Sitagliptin should be initiated at the dose of sitagliptin and metformin already being taken.
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulfonylurea: The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Metformin Hydrochloride + Sitagliptin is used in combination with a sulfonylurea, a lower dose of the sulfonylurea may be required to reduce the risk of hypoglycemia.
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a PPARγ agonist: The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin: The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Metformin Hydrochloride + Sitagliptin is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycemia.
For the different doses on metformin, Metformin Hydrochloride + Sitagliptin is available in strengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1,000 mg metformin hydrochloride.
All patients should continue their recommended diet with an adequate distribution of carbohydrate intake during the day.
Special populations: Renal impairment: No dose adjustment is needed for patients with mild renal impairment (glomerular filtration rate [GFR]=60 mL/min). A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR <60 mL/min.
If no adequate strength of Metformin Hydrochloride + Sitagliptin is available, individual mono components should be used instead of the fixed-dose combination. (See Table 1.)

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Hepatic impairment: Metformin Hydrochloride + Sitagliptin must not be used in patients with hepatic impairment.
Elderly: As Metformin and Sitagliptin are excreted by the kidney, Metformin Hydrochloride + Sitagliptin should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly.
Pediatric population: The safety and efficacy of Metformin Hydrochloride + Sitagliptin in children and adolescents from birth to <18 years of age have not been established. No data are available.
Method of administration: Metformin Hydrochloride + Sitagliptin should be given twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. 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.
A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis which is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is hemodialysis.
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 dialysable by peritoneal dialysis.
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.

Metformin Hydrochloride + Sitagliptin is contraindicated in patients with: Hypersensitivity to the active substances or to any of the excipients; any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis); diabetic pre-coma; severe renal failure (GFR <30 mL/min); acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents; acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock; hepatic impairment; acute alcohol intoxication, alcoholism; breastfeeding.

General: Metformin Hydrochloride + Sitagliptin should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis.
Acute pancreatitis: Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or hemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Metformin Hydrochloride + Sitagliptin and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Metformin Hydrochloride + Sitagliptin should not be restarted.
Caution should be exercised in patients with a history of pancreatitis.
Lactic acidosis: Lactic acidosis, a rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe vomiting, diarrhea, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis.
Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.
Renal function: GFR should be assessed before treatment initiation and regularly thereafter. Metformin Hydrochloride + Sitagliptin is contraindicated in patients with GFR <30 mL/min and should be temporarily discontinued during conditions with the potential to alter renal function.
Hypoglycemia: Patients receiving Metformin Hydrochloride + Sitagliptin in combination with a sulfonylurea or with insulin may be at risk for hypoglycemia. Therefore, a reduction in the dose of the sulfonylurea or insulin may be necessary.
Effects on ability to drive and use machines: Metformin Hydrochloride + Sitagliptin 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 hypoglycemia when Metformin Hydrochloride + Sitagliptin is used in combination with a sulfonylurea or with insulin.

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.
Metformin Hydrochloride + Sitagliptin 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.
Lactation: 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. Metformin Hydrochloride + Sitagliptin must therefore not be used in women who are breastfeeding.
Fertility: Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

Summary of the safety profile: There have been no therapeutic clinical trials conducted with Metformin Hydrochloride + Sitagliptin tablets, however bioequivalence of Metformin Hydrochloride + Sitagliptin with co-administered sitagliptin and metformin has been demonstrated. Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycemia has been reported in combination with sulfonylurea (13.8%) and insulin (10.9%).
Sitagliptin and metformin: Tabulated list of adverse reactions: Adverse reactions are listed as follows as MedDRA preferred term by system organ class and absolute frequency (Table 2).
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). (See Table 2.)

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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 Metformin Hydrochloride + Sitagliptin 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.
lodinated contrast agents: Metformin Hydrochloride + Sitagliptin 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 glycemic 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 hyperglycemic 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-hyperglycemic 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-hyperglycemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

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