Metformin

For adult patients with type 2 diabetes mellitus:

Sitagliptin/Metformin hydrochloride is indicated as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin.

, triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea. , a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.

, triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycaemic control.

Posology The dose of antihyperglycaemic therapy with sitagliptin/metformin hydrochloride should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.

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, sitagliptin/metformin hydrochloride should be initiated at the dose of sitagliptin and metformin already being taken.

For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.

4). 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.

4). For the different doses on metformin, sitagliptin/metformin hydrochloride is available in strengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1000 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.

, every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. 4) should be reviewed before considering initiation of metformin in patients with GFR < 60 mL/min. If no adequate strength of sitagliptin/metformin hydrochloride is available, individual monocomponents should be used instead of the fixed-dose combination.

GFR mL/min Metformin Sitagliptin 60-89 Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function. Maximum daily dose is 100 mg. 45-59 Maximum daily dose is 2000 mg. Maximum daily dose is 100 The starting dose is at most half of the maximum dose.

mg. 30-44 Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose. Maximum daily dose is 50 mg. < 30 Metformin is contraindicated. Maximum daily dose is 25 mg. 2). Elderly As metformin and sitagliptin are excreted by the kidney, sitagliptin/metformin hydrochloride should be used with caution as age increases.

4). Paediatric population Sitagliptin/Metformin hydrochloride should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. 2. Sitagliptin/Metformin hydrochloride has not been studied in paediatric patients under 10 years of age.

Method of administration Sitagliptin/Metformin hydrochloride should be given twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.

2). Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. 9 %). Tabulated list of adverse reactions Sitagliptin and metformin Adverse reactions are listed below as MedDRA preferred term by system organ class and absolute frequency (Table 1).

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000) and not known (cannot be estimated from the available data).

Table 1:

The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin and metformin alone, and post-marketing experience Adverse reaction Frequency of adverse reaction Blood and lymphatic system disorders thrombocytopenia Rare Immune system disorders hypersensitivity reactions including anaphylactic responses*,† Frequency not known Metabolism and nutrition disorders hypoglycaemia† Common Vitamin B12 decrease/deficiency† Common Nervous system disorders somnolence Uncommon Respiratory, thoracic and mediastinal disorders interstitial lung disease* Frequency not known Gastrointestinal disorders diarrhoea Uncommon nausea Common flatulence Common constipation Uncommon upper abdominal pain Uncommon vomiting Common acute pancreatitis*,†,‡ Frequency not known fatal and non-fatal haemorrhagic and necrotizing pancreatitis*,† Frequency not known Skin and subcutaneous tissue disorders pruritus* Uncommon angioedema*,† Frequency not known rash*,† Frequency not known urticaria*,† Frequency not known cutaneous vasculitis*,† Frequency not known exfoliative skin conditions including Stevens-Johnson syndrome*,† Frequency not known bullous pemphigoid* Frequency not known Musculoskeletal and connective tissue disorders arthralgia* Frequency not known myalgia* Frequency not known pain in extremity* Frequency not known back pain* Frequency not known arthropathy* Frequency not known Renal and urinary disorders impaired renal function* Frequency not known acute renal failure* Frequency not known *Adverse reactions were identified through post-marketing surveillance.

4. ‡ See TECOS Cardiovascular Safety Study below. Description of selected adverse reactions Some adverse reactions were observed more frequently in studies of combination use of sitagliptin and metformin with other anti-diabetic medicinal products than in studies of sitagliptin and metformin alone.

These included hypoglycaemia (frequency very common with sulphonylurea or insulin), constipation (common with sulphonylurea), peripheral oedema (common with pioglitazone), and headache and dry mouth (uncommon with insulin). Sitagliptin In monotherapy studies of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions reported were headache, hypoglycaemia, constipation, and dizziness.

Among these patients, adverse events reported regardless of causal relationship to medicinal product occurring in at least 5 % included upper respiratory tract infection and nasopharyngitis. 5 % higher among sitagliptin users than that in the control group).

Metformin Gastrointestinal symptoms were reported very commonly in clinical studies and post- marketing use of metformin. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

Additional adverse reactions associated with metformin include metallic taste (common); lactic acidosis, liver function disorders, hepatitis, urticaria, erythema, and pruritus (very rare). Frequency categories are based on information available from metformin Summary of Product Characteristics available in the EU.

Paediatric population In clinical studies with sitagliptin/metformin hydrochloride in paediatric patients with type 2 diabetes mellitus aged 10 to 17 years, the profile of adverse reactions was generally comparable to that observed in adults.

In paediatric patients on or not on background insulin, sitagliptin was associated with an increased risk of hypoglycaemia. 73 m2), and 7339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors.

The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo. 7 % in placebo-treated patients. 2 % in placebo-treated patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card […]

4); • 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; • breast-feeding.

1 INDICATIONS AND USAGE Metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. Metformin hydrochloride tablets is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.

(1)

1 Adult Dosage The recommended starting dose of metformin hydrochloride tablets is 500 mg orally twice a day or 850 mg once a day, given with meals. Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses.

Doses above 2000 mg may be better tolerated given 3 times a day with meals. 2 Pediatric Dosage for Metformin Hydrochloride Tablets The recommended starting dose of metformin hydrochloride tablets for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals.

Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily. 3 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride tablets and periodically thereafter.

73 m 2 . 73 m 2 is not recommended. 73 m 2 , assess the benefit risk of continuing therapy. 1) ]. 73 m 2 ; 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 metformin hydrochloride tablets if renal function is stable.

0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. 1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. gov/medwatch . 1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

S. clinical trial of metformin hydrochloride in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride up to 2550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride treated patients and that were more common than in placebo-treated patients, are listed in Table 1.

Table 1:

Adverse Reactions from a Clinical Trial of Metformin Hydrochloride Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride (n=141) Placebo (n=145) Diarrhea 53% 12% Nausea/Vomiting 26% 8% Flatulence 12% 6% Asthenia 9% 6% Indigestion 7% 4% Abdominal Discomfort 6% 5% Headache 6% 5% Diarrhea led to discontinuation of metformin hydrochloride in 6% of patients.

Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride treated patients and were more commonly reported with metformin hydrochloride than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

In metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Pediatric Patients In clinical trials with metformin hydrochloride in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.

2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

1) ]. Hypersensitivity to metformin. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. 1) Hypersensitivity to metformin (4) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

(4)

METFORMIN ER (metformin hydrochloride) extended-release tablets are indicated for: • the control of hyperglycemia in adult patients with type 2 (non-insulin-dependent, mature onset) diabetes, as an adjunct to dietary management, exercise, and weight reduction, or when insulin therapy is not appropriate.

• may be used as monotherapy, or concomitantly with a sulfonylurea. 1 Pediatrics (< 18 years of age) No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 2 Geriatrics Controlled clinical studies of metformin hydrochloride did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients.

3 Pharmacokinetic). From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Metformin treatment should not be initiated in patients greater than 80 years of age unless their renal function is not significantly reduced.

In patients with advanced age, metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function (see 7 WARNINGS AND PRECAUTIONS, Renal). Metformin is contraindicated in patients with severe renal impairment (see 2 CONTRAINDICATION).

4 Geriatrics).

1 Dosing Considerations Care should be taken in dose selection for the elderly and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin.

4 Geriatrics). METFORMIN ER extended-release tablets must be taken once daily with food to ensure optimum delivery of the metformin dose to the systemic circulation. 3 Pharmacokinetics). In adult type 2 diabetic patients, individual determination of the minimum METFORMIN ER dose that will adequately lower blood glucose should be made, aiming for glycemic targets as close to normal as possible.

A lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to METFORMIN ER, and to identify the minimum effective dose for the patients.

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. ” Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of METFORMIN ER in patients with renal impairment.

Caution should be exercised when using concomitant medication(s) that may decrease renal function (like diuretics, particularly loop diuretics) or may interfere with the disposition of metformin, such as cationic drugs, that are eliminated by renal tubular secretion, due to the increased risk of developing lactic acidosis during co-administration.

4 Drug-Drug Interactions, Cationic Drugs and Other). In patients in whom the maximum recommended dose fails to lower the blood glucose adequately, the drug should be discontinued. 2 Recommended Dose and Dosage Adjustment METFORMIN ER therapy should usually be initiated at 1000 mg once-daily, taken with the METFORMIN ER (Metformin Hydrochloride Extended- Release Tablets) Page 7 of 46 evening meal.

METFORMIN ER extended-release tablets must be taken with food to ensure optimum delivery of the metformin dose to the systemic circulation. Gradual dose escalation in increments of 500 mg weekly are recommended, to reduce gastrointestinal side effects, and to permit identification of the minimum dose required for adequate glycemic control.

The maximum recommended dose is 2000 mg once daily, taken with the evening meal. 73m2) and in elderly patients (see 7 WARNINGS AND PRECAUTIONS, Renal). 73 m2 is 1000 mg. Transfer Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents, other than chlorpropamide, to METFORMIN ER, no transition period generally is necessary.

Patients treated with immediate release metformin have been switched to metformin hydrochloride extended-release tablets once daily without incident (see 14 CLINICAL TRIALS). Following switching, from the IR formulation to metformin hydrochloride extended-release tablets, glycemic control should be closely monitored, and dosage adjustments made accordingly.

When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant METFORMIN ER and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to four weeks of the maximum dose of METFORMIN ER monotherapy, consideration should be given to gradual addition of oral sulfonylurea while continuing METFORMIN ER at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred.

With concomitant metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior treatment with glyburide, 15 mg/day, the efficacy of metformin hydrochloride in combination with glyburide was compared to the efficacy of glyburide alone (placebo), to achieve glycemic control as measured by significant reductions from baseline in FPG, HbA1c, fructosamine and blood glucose response (see 14 CLINICAL TRIALS).

The minimum effective dose of each drug should be identified. With concomitant METFORMIN ER and sulfonylurea therapy, there is risk of hypoglycemia. Appropriate precautions should be taken. If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of METFORMIN ER and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin.

4 Administration Tablets should be taken whole, with a glass of water. During treatment initiation and dose METFORMIN ER (Metformin Hydrochloride Extended- Release Tablets) Page 8 of 46 titration, […]

5 Post-Market Adverse Reactions). Some of these cases were reported without association with lactic acidosis, hypoglycemia, or renal impairment. Peri-operative Considerations Metformin therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids).

Metformin should be discontinued 2 days before surgical intervention and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Radiological studies involving the use of intravascular iodinated contrast materials Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast material) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see 2 CONTRAINDICATIONS).

Therefore, in patients in whom any such study is planned, METFORMIN ER should be temporarily discontinued at the time of or prior to the procedure, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been re-evaluated and found to be normal.

Renal Metformin hydrochloride is excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. 73 m2 (see 2 CONTRAINDICATIONS). 73 m2. In patients with advanced age, metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function.

2 Recommended Dose and Dose Adjustment). 73 m2 (see 2 CONTRAINDICATIONS) Special caution should be exercised in situations where renal function may become impaired, for example in the elderly, in the case of dehydration, when initiating antihypertensive therapy or diuretic therapy, or when starting therapy with an NSAID.

METFORMIN ER (Metformin Hydrochloride Extended- Release Tablets) Page 15 of 46 Radiologic studies involving the use of iodinated contrast materials can lead to acute renal failure and have been associated with lactic acidosis in patients receiving metformin.

Metformin should be discontinued 2 days before radiologic studies and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. 4 Drug-Drug Interactions), should be used with caution.

1 Pregnant Women METFORMIN ER are contraindicated during pregnancy (see 2 CONTRAINDICATIONS). Safety of metformin in pregnant women has not been established. There are no adequate and well- controlled studies in pregnant women. Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities.

It is recommended that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. The combined fertility and developmental toxicity study in rats, (0, 150, 450, or 900 mg/kg/day orally) showed no adverse effects on fertility or embryofetal development, although a decrease in male reproductive organ weights was observed at a dose of 900 mg/kg/day.

An embryofetal development study in rabbits revealed no effects on gross external, soft tissue, or skeletal malformation or variations at dose up to 90 mg/kg/day (see 16 NON-CLINICAL TOXICOLOGY). 2 Breast-feeding METFORMIN ER are contraindicated in breast-feeding women (see 2 CONTRAINDICATIONS).

Studies in lactating rats have shown that metformin is excreted into milk and reaches levels comparable to those in plasma. Metformin hydrochloride is also excreted into human breast milk in very small amounts. 3 Pediatrics (< 18 years of age) No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

4 Geriatrics). Care should be taken in dose selection which should be based on careful and more frequent monitoring of renal function. 3 Pharmacokinetics and Special Populations). 2 Recommended Dose and Dosage Adjustment). 1 Adverse Reaction Overview Lactic acidosis is a rare, but serious adverse reaction […]

METFORMIN ER (metformin hydrochloride) extended-release tablets are contraindicated for patients: • Who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medical ingredient or component of the container.

For a complete listing see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the Product Monograph. METFORMIN ER (Metformin Hydrochloride Extended- Release Tablets) Page 5 of 46 • With unstable and/or Type 1 (insulin-dependent) diabetes mellitus.

• With acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; history of ketoacidosis with or without coma. Diabetic ketoacidosis should be treated with insulin. • With a history of lactic acidosis, irrespective of precipitating factors.

73 m2)], end-stage renal disease, in patients on dialysis or when renal function is not known (see 7 WARNINGS AND PRECAUTIONS). • With excessive alcohol intake, acute or chronic. • Suffering from severe hepatic dysfunction. Since severe hepatic dysfunction has been associated with some cases of lactic acidosis, metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

• Undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. Metformin should be temporarily discontinued during period around administration of iodinated contrast materials (see 7 WARNINGS AND PRECAUTIONS).

• In cases of cardiovascular collapse and in disease states associated with hypoxemia such as cardiorespiratory insufficiency, which are often associated with hyperlactacidemia. • During stressful conditions, such as severe infections, trauma or surgery and the recovery phase thereafter.

• Suffering from severe dehydration. 2 breastfeeding).