Taro-Metformin XR (Taro Pharmaceuticals, 500 mg, 1000 mg) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................ 2

PART 1: HEALTH PROFESSIONAL INFORMATION ..................................................... 4

1. 1.

   INDICATIONS ...................................................................................................... 4

   1.1 Pediatrics ................................................................................................... 4

   1.2 Geriatrics .................................................................................................... 4

2. 2. CONTRAINDICATIONS ....................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................ 6

4 DOSAGE AND ADMINISTRATION ...................................................................... 6

4.1 Dosing Considerations ............................................................................... 6

4.2 Recommended Dose and Dose Adjustment ............................................... 7

4.4 Administration ............................................................................................. 9

4.5 Missed Dose .............................................................................................. 9

5 OVERDOSAGE ................................................................................................... 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ..............10

7 WARNINGS AND PRECAUTIONS .....................................................................10

7.1 Special Populations ...................................................................................15

7.1.1 Pregnant Women ......................................................................................15

7.1.2 Breast-feeding ...........................................................................................16

7.1.3 Pediatrics ..................................................................................................16

7.1.4 Geriatrics ...................................................................................................16

1. 8.

   ADVERSE REACTIONS .....................................................................................16

   8.1 Adverse Drug Reaction Overview ..............................................................16

   8.2 Clinical Trial Adverse Drug Reactions ........................................................17

   8.3 Less Common Clinical Trial Adverse Drug Reactions .................................18

   8.5 Post-Market Adverse Reactions ................................................................19

9 DRUG INTERACTIONS ......................................................................................19

9.2 Drug Interactions Overview........................................................................19

9.3 Drug-Behavioural Interactions ....................................................................19

9.4 Drug-Drug Interactions ...............................................................................20

9.5 Drug-Food Interactions ..............................................................................21

9.6 Drug-Herb Interactions ...............................................................................21

9.7 Drug-Laboratory Interactions ......................................................................22

1. 10.

   CLINICAL PHARMACOLOGY ...........................................................................23

   10.1 Mechanism of Action .................................................................................23

   10.2 Pharmacodynamics ...................................................................................25

   10.3 Pharmacokinetics ......................................................................................25

2. 11. STORAGE, STABILITY AND DISPOSAL ...........................................................28

PART II: SCIENTIFIC INFORMATION ...........................................................................29

13 PHARMACEUTICAL INFORMATION .................................................................29

14 CLINICAL TRIALS .............................................................................................30

14.1 Trial Design and Study Demographics .......................................................30

14.2 Study Results ............................................................................................31

14.3 Comparative Bioavailability Studies ...........................................................34

1. 15. MICROBIOLOGY ...............................................................................................37
2. 16. NON-CLINICAL TOXICOLOGY ..........................................................................37
3. 17. SUPPORTTING PRODUCT MONOGRAPHS ....................................................39

PATIENT MEDICATION INFORMATION .......................................................................40

PART 1: HEALTH PROFESSIONAL INFORMATION

1. INDICATIONS

TARO-METFORMIN XR & METFORMIN XR (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.

1.1 Pediatrics (< 18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Controlled clinical studies of metformin hydrochloride did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged and Cmax is increased, compared to healthy young subjects (see 10 CLINICAL PHARMACOLOGY, 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). More careful and frequent monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis (see 4.1 Dosing considerations, 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Lactic Acidosis, 7.1.4 Geriatrics)

2. CONTRAINDICATIONS

TARO-METFORMIN XR & METFORMIN XR (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.
• 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.
• In the presence of severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 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.
• During pregnancy and breast feeding (see 7.1.1 Pregnant Women and 7.1.2 breastfeeding).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 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. TARO-METFORMIN XR & METFORMIN XR treatment should not be initiated in patients older than 80 years of age, unless their renal function is not significantly reduced (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, 7.1.4 Geriatrics).

TARO-METFORMIN XR & METFORMIN XR extended-release tablets must be taken once daily with food to ensure optimum delivery of the metformin dose to the systemic circulation. (see 10 Clinical Pharmacology, Pharmacokinetics). In adult type 2 diabetic patients, individual determination of the minimum TARO-METFORMIN XR & METFORMIN XR 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 TARO-METFORMIN XR & METFORMIN XR, 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. TARO-METFORMIN XR & METFORMIN XR is contraindicated in patients with severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2)], end-stage renal disease, in patients on dialysis or when renal function is not known (see 2 CONTRAINDICATIONS).” Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of TARO-METFORMIN XR & METFORMIN XR 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. Consideration for TARO-

METFORMIN XR & METFORMIN XR dosage adjustment, as necessary, should be made when TARO-METFORMIN XR & METFORMIN XR is simultaneously administered with cationic drugs or with drugs that produce hyperglycemia or hypoglycaemia, especially at the initiation of treatment with the interfering drug and upon its discontinuation (see 9.4 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.

4.2 Recommended Dose and Dose Adjustment

TARO-METFORMIN XR & METFORMIN XR therapy should usually be initiated at 1000 mg once daily, taken with the evening meal. TARO-METFORMIN XR & METFORMIN XR 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.

Renal function must be assessed prior to initiation of TARO-METFORMIN XR & METFORMIN XR and periodically thereafter, at least once a year in patients with normal renal function, and more frequent monitoring in patients with renal impairment (eGFR<60 mL/min/1.73m2) and in elderly patients (see 7 WARNINGS AND PRECAUTIONS, Renal). The maximum daily dose of TARO-METFORMIN XR & METFORMIN XR in patients with an eGFR ≥30 mL/min/1.73 m2 to <45 mL/min/1.73 m2 is 1000 mg.

Transfer Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents, other than chlorpropamide, to TARO-METFORMIN XR & METFORMIN XR, no transition period generally is necessary. Patients treated with immediate release metformin have been switched to TARO-METFORMIN XR & METFORMIN XR once daily without incident (see 14 CLINICAL TRIALS) Following switching, from the IR formulation to TARO-METFORMIN XR & METFORMIN XR, 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 TARO-METFORMIN XR & METFORMIN XR and Oral Sulfonylurea Therapy in Adult Patients

If patients have not responded to four weeks of the maximum dose of TARO-METFORMIN XR & METFORMIN XR monotherapy, consideration should be given to gradual addition of oral sulfonylurea while continuing TARO-METFORMIN XR & METFORMIN XR 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 TARO-METFORMIN XR & METFORMIN XR 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 TARO-METFORMIN XR & METFORMIN XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin.

4.4 Administration

Tablets should be taken whole, with a glass of water. During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to TARO-METFORMIN XR & METFORMIN XR, and to identify the minimum effective dose for the patients TARO-METFORMIN XR & METFORMIN XR extended-release tablets must be taken once daily with food, and should be taken whole, with a glass of water. Do not break or crush tablets.

4.5 Missed Dose

If a dose of TARO-METFORMIN XR & METFORMIN XR is missed, it should be taken as soon as possible, with food. However, if it is less than ten hours before the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses. If patients do not feel well, or home glucose testing shows elevated levels, a physician should be contacted.

5 OVERDOSAGE

Overdose with metformin hydrochloride has not been reported. It would be expected that adverse reactions of a more intense character, including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, the presence of lactic acidosis should be excluded. The drug should be discontinued and proper supportive therapy should be instituted.

Overdose of metformin hydrochloride has been reported, 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 (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Lactic Acidosis). Metformin is dialyzable with 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.

Pancreatitis may occur in the context of a metformin overdose (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Summary Product Information

METFORMIN XR 500 mg: White to off white, oval shaped, biconvex coated tablets with beveled edge, debossed with '94' on one side and 'Plain' on the other side.

The tablets are supplied in bottle of 500 tablets and bottle of 1000 tablets

TARO-METFORMIN XR 1000 mg: White to off white, capsule shaped, biconvex coated tablets with beveled edge, debossed with '95' on one side and 'Plain' on the other side.

The tablets are supplied in bottle of 100 tablets and bottle of 500 tablets

7 WARNINGS AND PRECAUTIONS

General

Use of TARO-METFORMIN XR & METFORMIN XR must be considered as treatment in addition to proper dietary and exercise regimen, and not as a substitute for either. Care should be taken to ensure that TARO-METFORMIN XR & METFORMIN XR is not given when a contraindication exists. If during metformin therapy the patient develops acute intercurrent disease such as clinically significant hepatic dysfunction, cardiovascular collapse, congestive heart failure, acute myocardial infarction, or other conditions complicated by hypoxemia which may also cause prerenal azotemia, the drug should be discontinued. If vomiting occurs, withdraw drug temporarily, exclude lactic acidosis, and then resume dosage cautiously.

Cardiovascular

Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on TARO-METFORMIN XR & METFORMIN XR therapy, the drug should be promptly discontinued.

Driving and Operating Machinery

Patients should be warned about driving or operating a vehicle or potentially dangerous machinery under conditions where a risk of hypoglycemia is present (see 7 WARNINGS AND PRECAUTIONS). When TARO-METFORMIN XR & METFORMIN XR is used in combination with a sulfonylurea or in combination with insulin patients should be advised to take precautions to avoid hypoglycaemia while driving or operating a vehicle or potentially dangerous machinery.

Endocrine and Metabolism

Change in clinical status of previously controlled type 2 diabetes patient:

A diabetic patient previously well controlled on TARO-METFORMIN XR & METFORMIN XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs TARO-METFORMIN XR & METFORMIN XR must be stopped immediately and appropriate corrective measures initiated (see 7 WARNINGS AND PRECAUTIONS).

Hypoglycemia

Hypoglycemia does not occur in patients receiving metformin hydrochloride alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose - lowering agents or alcohol.

Elderly debilitated or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to hypoglycemic effect.

Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta- adrenergic blocking drugs.

Hypothyroidism

Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism (see, Post Market Adverse Drug Reactions). Regular monitoring of TSH levels is recommended in patients with hypothyroidism (see Monitoring and Laboratory Tests). Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with Levothyroxine. The metformin- induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion.

Levothyroxine can reduce the hypoglycemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with Levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped

(see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and 9.4 Drug-Drug Interactions, Levothyroxine).

Lactic Acidosis

Lactic Acidosis is a rare, but serious, metabolic complication that may occur during treatment with metformin hydrochloride. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic Acidosis is characterized by elevated blood lactate levels, deceased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin has been implicated in lactic acidosis, metformin plasma levels > 5ug/mL have been generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (0.03 cases/1000 patient years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion. Patients with congestive heart failure requiring pharmacologic management are at increased risk of lactic acidosis. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin hydrochloride, and by use of the minimum effective dose of metformin hydrochloride. In addition, TARO-METFORMIN XR & METFORMIN XR should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, TARO-METFORMIN XR & METFORMIN XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake when taking TARO-METFORMIN XR & METFORMIN XR, since alcohol intake potentiates the effect of metformin hydrochloride on lactate metabolism. The onset of lactic acidosis often is subtle, and accompanied only by non- specific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and non-specific abdominal distress. Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking TARO-METFORMIN XR & METFORMIN XR, the drug should be discontinued immediately. Because metformin hydrochloride is dialysable, prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin.

Physicians should instruct their patients to recognize the symptoms which could be signal onset of lactic acidosis. If acidosis of any kind develops, TARO-METFORMIN XR & METFORMIN XR should be discontinued immediately and the patient should be immediately hospitalized.

Loss of control of blood glucose

When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold TARO-METFORMIN XR & METFORMIN XR and temporarily administer insulin. TARO-METFORMIN XR & METFORMIN XR be reinstituted after the acute episode is resolved.

Vitamin B12 levels

Impairment of vitamin B12 absorption has been reported in some patients. Therefore, measurements of serum vitamin B12 are advisable at least every one to two years in patients on long-term treatment with TARO-METFORMIN XR & METFORMIN XR.

A decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, is observed in approximately 7% of patients receiving metformin in controlled clinical trials of 28 weeks duration. Such decrease, possibly due to interference with B12 absorption from B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Long-term treatment with metformin has been associated with a decrease in serum vitamin B12 levels which may cause peripheral neuropathy. Serious cases of peripheral neuropathy have been reported with metformin treatment in the context of vitamin B12 deficiency. Monitoring of serum vitamin B12 levels is recommended.

Hematologic

Serious cases of metformin-induced hemolytic anemia, some with a fatal outcome, have been reported. Two mechanisms were described for the metformin-induced immune hemolytic anemia; formation of an antibody against the erythrocyte-metformin complex and autoantibody formation.

Monitoring of hematologic parameters is recommended (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Hepatic/Biliary/Pancreatic

Since impaired hepatic function has been associated with some cases of lactic acidosis, TARO-METFORMIN XR & METFORMIN XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. TARO-METFORMIN XR & METFORMIN XR is contraindicated in patients suffering from severe hepatic dysfunction (see 2 CONTRAINDICATIONS).

Serious cases of pancreatitis have been reported in patients receiving metformin. The reported pancreatitis cases occurred either in the context of an acute metformin overdose (see 5 OVERDOSAGE, 8.5 Post-Market Adverse Reactions) or in patients receiving therapeutic doses of metformin with concurrent renal failure and/or lactic acidosis, indicating metformin accumulation.

Monitoring and Laboratory Tests

Response to TARO-METFORMIN XR & METFORMIN XR should be monitored by periodic measurement of fasting blood glucose and glycosylated hemoglobin levels with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic dose response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control.

More frequent glucose monitoring should be considered when TARO-METFORMIN XR & METFORMIN XR is simultaneously administered with cationic drugs that are excreted via renal tubular secretion, or with drugs that produce hyperglycemia or hypoglycaemia, especially at the initiation of treatment with the interfering drug(s) (see 9.4 Drug-Drug Interactions, Cationic

Drugs and Other)

Renal function must be assessed prior to initiation of TARO-METFORMIN XR & METFORMIN XR and periodically thereafter, at least once a year in patients with normal renal function, and more frequent monitoring in patients with renal impairment (eGFR<60 mL/min/1.73 m2) and in elderly patients.

In patients with eGFR less than 60 mL/min/1.73 m2, more intensive monitoring for glycemic and renal biomarkers and signs and symptoms of renal dysfunction is recommended, especially if the eGFR is less than 45 mL/min/1.73 m2 (see 4.2 Recommended Dose and Dose Adjustment, 7 WARNINGS AND PRECAUTIONS, Renal). TARO-METFORMIN XR & METFORMIN XR must be discontinued if the eGFR decreased to ≤ 30mL/min/1.73 m2 (see 2 CONTRAINDICATIONS).

Initial and periodic monitoring of hematologic parameters (e.g. hemoglobin/hematocrit and red blood cell indices). While megaloblastic anemia has rarely been seen with metformin hydrochloride therapy, if this is suspected, vitamin B12 deficiency should be excluded (see 7 WARNINGS AND PRECAUTIONS, Hematologic)

Particular attention should be paid to short range and long-range complications which are peculiar to diabetes. Periodic cardiovascular, ophthalmic, hepatic and are advisable (see 7 WARNINGS AND PRECAUTIONS).

Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism (see 7 WARNINGS AND PRECAUTIONS, Hypothyroidism).

For hypothyroid patients treated with Levothyroxine, careful monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped (see 7 WARNINGS AND PRECAUTIONS, Hypothyroidism and 9.4 DRUG-DRUG INTERACTIONS, Levothyroxine).

For patients concurrently administering TARO-METFORMIN XR & METFORMIN XR and phenprocoumon or other antivitamin K anticoagulants, a close monitoring of the International Normalized Ratio (INR) is recommended (see 9.4 DRUG-DRUG INTERACTIONS).

Neurologic

Serious cases of metformin-induced encephalopathy have been reported (see 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Drug Reactions). Some of these cases were reported without association with lactic acidosis, hypoglycemia, or renal impairment.

Peri-operative Considerations

TARO-METFORMIN XR & METFORMIN XR 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 hydrochloride (see 2 CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, TARO-METFORMIN XR & METFORMIN XR 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. TARO-METFORMIN XR & METFORMIN XR is contraindicated in patients with severe renal impairment; eGFR <30 mL/min/1.73 m2 (see 2 CONTRAINDICATIONS). Renal function must be assessed prior to initiation of TARO-METFORMIN XR & METFORMIN XR and periodically thereafter, with more frequent monitoring in patients whose eGFR decreases to less than 60 mL/min/1.73 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. In elderly patients, renal function should be monitored more frequently and generally TARO-METFORMIN XR & METFORMIN XR should not be titrated to the maximum dose (see 4.1 Dosing Considerations and 4.2 Recommended Dose and Dose Adjustment). In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and TARO-METFORMIN XR & METFORMIN XR discontinued if the eGFR decreased to ≤ 30 mL/min/1.73 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.

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.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see 9.4 Drug-Drug Interactions), should be used with caution.

7.1 Special Populations

7.1.1 Pregnant Women

TARO-METFORMIN XR & METFORMIN XR is 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 TOXICOLOGY).

7.1.2 Breast-feeding

TARO-METFORMIN XR & METFORMIN XR is 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.

7.1.3 Pediatrics: (< 18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics: (> 80 years of age)

Metformin treatment should not be initiated in patients greater than 80 years of age, unless their renal function is not significantly reduced as elderly patients are more susceptible to developing lactic acidosis (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Lactic Acidosis, 7.1.4 Geriatrics). Care should be taken in dose selection which should be based on careful and more frequent monitoring of renal function. In patients with advance age, metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function (See 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics and Special Populations). Generally, elderly patients should not be titrated to the maximum dose of TARO-METFORMIN XR & METFORMIN XR (see 4.1 Dosing Considerations, 4.2 Recommended Dose and Dosage Adjustment).

8. ADVERSE REACTIONS

8.1 Adverse Drug Reaction Overview

Lactic acidosis is a rare, but serious adverse reaction associated with metformin hydrochloride treatment. Lactic acidosis is fatal in approximately 50% of cases (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Lactic Acidosis).

Gastrointestinal symptoms (GI) (diarrhea, nausea, vomiting, abdominal pain, abdominal distention, dyspepsia, and flatulence.) are common reactions to metformin hydrochloride treatment. These symptoms are generally transient and resolve spontaneously during continued treatment.

Additionally, as GI symptoms during therapy initiation appear to be dose-related, they may be decreased by gradual dose escalation and by having patients take their medication with meals.

8.2 Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with Metformin Hydrochloride 1500 – 2000 mg/day in active-controlled and placebo-controlled studies.

Gastrointestinal disorders were the most frequently occurring events in all trials. Table 2 shows the combined incidence of gastrointestinal adverse events occurring in one Phase 2 study and one Phase 3 study comparing metformin hydrochloride to immediate- release metformin, coupled with the open label extension of the Phase 3 study.

Table 2 Combined Gastrointestinal Adverse Events Occurring in at least 5% of Patients, in Three Clinical Trials*

* Combined data is from one Phase 2 study and one Phase 3 study comparing metformin hydrochloride to immediate- release metformin coupled with the open label extension of the Phase 3 study.

In the Phase 3 trial comparing the safety and efficacy of metformin hydrochloride to metformin immediate- release tablets, all four treatment regimens (metformin hydrochloride at 1500 mg QD, 1500 mg BID, 2000 mg QD and Metformin IR 1500 mg BID) had comparable safety profiles. Patients in the once -daily treatment groups did not report any higher occurrence of adverse events than the twice daily treatment groups. The occurrence of GI adverse events was comparable between all treatment groups. All metformin hydrochloride treatment groups reported fewer occurrences of diarrhea and nausea than did the immediate-release treatment group during the first week of the titration period [1000 mg dose].

In the placebo-controlled study, patients receiving background glyburide (SU; sulfonylurea) therapy were randomized to receive add-on treatment of either one of three different regimens of metformin hydrochloride or placebo. In total, 431 patients received metformin hydrochloride + SU and 144 patients placebo + SU. Adverse events reported in greater than 5% of patients treated with metformin hydrochloride, that were more common in the combined metformin hydrochloride + SU group, than in the placebo + SU group, are shown in Table 3.

In 0.7% of patients treated with metformin hydrochloride + SU, diarrhea was responsible for discontinuation of study medication compared to zero in the placebo + SU group.

Table 3 Treatment-Emergent Adverse Events Reported By >5%* of Patients for the Combined Metformin Hydrochloride Group Versus Placebo Group

*AE’s that were more common in the Metformin Hydrochloride-treated than in the placebo-treated patients.

In the same study, the following adverse events were reported by 1-5% of patients for the combined metformin hydrochloride group and these events occurred more commonly in the metformin hydrochloride-treated than in the placebo-treated patients:

• Ear and labyrinth disorders: ear pain
• Gastrointestinal disorders: vomiting, dyspepsia, flatulence, abdominal pain upper, abdominal distension, abdominal pain, toothache, loose stools
• General disorders and administration site conditions: asthenia, chest pain
• Immune system disorders: seasonal allergy
• Infections and infestations: gastroenteritis viral, tooth abscess, tonsillitis, fungal infection
• Injury, poisoning and procedural complications: muscle strain
• Musculoskeletal and connective tissue disorders: pain in limb, myalgia, muscle cramp Nervous system disorders: dizziness, tremor, sinus headache, hypoaesthesia Respiratory, thoracic and mediastinal disorders: nasal congestion
• Skin and subcutaneous tissue disorders: contusion
• Vascular disorders: hypertension

8.3 Less common Clinical Trial Adverse Drug Reactions (< 1%)

The following adverse drug reactions were reported with <1% incidence in patients in any metformin hydrochloride treatment group in the placebo-controlled trial:

• Blood Disorders: thrombocytopenia, neutropenia
• Eye disorders: vision blurred
• Gastrointestinal disorders: flatulence, gastric, gastrointestinal upset, loose stools, vomiting
• General disorders and administration site conditions: adverse drug reaction, asthenia, chest pain, fatigue, lethargy, oedema aggravated, oedema peripheral, rigors
• Infection and Infestations: gastroenteritis viral
• Investigations: blood glucose decreased, liver function test abnormal, muscle cramp, white blood cell count increased
• Metabolism and Nutrition Disorders: hyperglycemia.
• Nervous System Disorders: dizziness, migraine, parasthesia, syncope, tremor
• Reproductive System and Breast Disorders: sexual dysfunction
• Respiratory Disorders: rhinorrhea, sinus congestion

8.5 Post-Market Adverse Reactions

Post Market Adverse Reaction as per GLUCOPHAGE include the following:

• Blood and Lymphatic System Disorders: Hemolytic anemia, some with a fatal outcome
• Gastrointestinal Disorders: Abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper, constipation, diarrhea, dry mouth, dyspepsia, flatulence, gastric disorder, gastric ulcer, gastrointestinal disorder, nausea, vomiting.
• Hepatobiliary Disorders: Liver function tests abnormalities or hepatitis resolving upon metformin discontinuation, autoimmune hepatitis, drug-induced liver injury, hepatitis, pancreatitis.
• Investigations: Blood lactic acid increased, hypomagnesemia in the context of diarrhea, reduction of thyrotropin level in patients with treated or untreated hypothyroidism.
• Metabolism and Nutrition Disorders: Lactic acidosis, decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin, weight decreased, decreased appetite.
• Nervous System Disorders: Encephalopathy, Peripheral neuropathy in patients with vitamin B12 deficiency.
• Skin and Subcutaneous Tissue Disorders: Photosensitivity, erythema, pruritus, rash, skin lesion, and urticaria.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Certain drugs may potentiate the effect of metformin in the treatment of diabetes, particularly sulfonylureas. The simultaneous administration of TARO-METFORMIN XR & METFORMIN XR with sulfonylureas must be carefully monitored to prevent hypoglycemic reaction, especially if they are given to patients also receiving other drugs which can potentiate their effect. For example, the effect of sulfonylureas can be potentiated by long-acting sulfonamides, tuberculostatics, phenylbutazone, clofibrate, monoamine oxidase inhibitors, salicylates, probenecid and propranolol.

9.3 Drug-Behavioural Interactions

Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking TARO-METFORMIN XR & METFORMIN XR, since alcohol intake potentiates the effect of metformin hydrochloride on lactate metabolism (see 2 CONTRAINDICATIONS).

9.4 Drug-Drug Interactions

Metformin Hydrochloride and sulfonylurea: With concomitant Metformin Hydrochloride and sulfonylurea (SU) therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. The influence of glyburide on Metformin Hydrochloride pharmacokinetics was assessed in a single -dose interaction study in healthy subjects. Co-administration of Metformin Hydrochloride and glyburide did not result in any changes in metformin pharmacokinetics, as AUC, Cmax, and Tmax, were unchanged. Changes in pharmacodynamics were not evaluated in this study (see 4 DOSAGE AND ADMINISTRATION, Concomitant TARO-METFORMIN XR & METFORMIN XR and Oral Sulphonylurea Therapy). In a clinical trial of patients with type 2 diabetes and prior treatment with glyburide, Metformin Hydrochloride plus glyburide combined therapy yielded a significant decrease from baseline to endpoint in mean HbA1c, relative to SU treatment alone (see 10 CLINICAL PHARMACOLOGY, 14 CLINICAL TRIALS). With concomitant TARO-METFORMIN XR & METFORMIN XR and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy exists. Appropriate precautions should be taken. If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of TARO-METFORMIN XR & METFORMIN XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to sulfonylureas, which are extensively bound to serum proteins.

In healthy volunteers, the pharmacokinetics of propranolol and ibuprofen were not affected by metformin when co-administered in single-dose interaction studies.

Drugs that have a tendency to produce hyperglycemia and may lead to a loss of blood sugar control include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, estrogen plus proestrogen, oral contraceptive, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to patients receiving TARO-METFORMIN XR & METFORMIN XR, the patient should be closely observed to maintain adequate glycemic control.

Furosemide

A single dose metformin - furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin when co -administered chronically.

Nifedipine

A single dose metformin - nifedipine drug interaction study in healthy subjects demonstrated that co- administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, and increased the amount excreted in the urine. Tmax and half-life were unaffected.

Cationic Drugs

(amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin) These drugs theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction has been observed between metformin and oral cimetidine in normal healthy volunteers in both single and multiple - dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC was observed. The H2-blocker cimetidine competitively inhibits renal tubular secretion of metformin, significantly decreasing its clearance and increasing its bioavailability. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Therefore, careful patient monitoring and dose adjustment of metformin or the interfering drug is recommended in patients who are taking cationic medications that are excreted via renal tubular secretion (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests)

Levothyroxine:

Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), and TARO-METFORMIN XR & METFORMIN XR dosage adjusted as necessary.

Anticoagulant phenprocoumon: Elimination rate of the anticoagulant phenprocoumon has been reported to be increased by 20% when used concurrently with metformin. Patients receiving phenprocoumon or other antivitamin K anticoagulants should be monitored carefully when both types of drugs are used simultaneously. In such cases, an important increase of prothrombin time may occur upon cessation of metformin therapy, with an increased risk of hemorrhage (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

9.5 Drug-Food Interactions

Metformin hydrochloride extended-release tablets have been formulated to be dosed with food. Metformin Hydrochloride extended-release tablets must be taken with food to ensure complete release and absorption of the metformin dose. In a single-dose study with the 500 mg tablet, when the product was given to healthy volunteers while fasting or with a high fat, or a AHA 30% low fat meal, AUC was increased significantly and a delay in Tmax was observed when compared to the fasted state. The increase in AUC was significantly greater when the product was given with the high fat meal. There was no significant difference in Cmax. In an open label pharmacoscintigraphic pharmacokinetic study in healthy volunteers, metformin hydrochloride 500 mg dosed with different fat content meals was evaluated. Both the gastric retention time and the systemic exposure of metformin were higher following the high fat meal than following the AHA 30% fat meal, demonstrating that prolonged gastric retention enables extended delivery of metformin (see 4 DOSAGE AND ADMINISTRATION).

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Interactions

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see 2._CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Renal).

10. CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, (see 7 WARNINGS AND PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

At therapeutic doses, metformin does not lower plasma glucose levels in non-diabetic animals or humans. Oral administration of metformin was demonstrated to effectively lower plasma glucose levels in streptozocine-induced diabetic mice, genetically diabetic KK mice, obese female fa/fa rats, and alloxan-induced diabetic rats. In addition to its antihyperglycemic effects, metformin has been shown to have hypolipidemic effects and to significantly improve the progression and regression of atherosclerotic lesions. Metformin has also been shown to reduce blood pressure in spontaneously hypertensive rats, either through sympathoinhibitory effects, a direct effect on vascular smooth muscle responsiveness to norepinephrine, and/or attenuation of hyperinsulinemia.

The antihyperglycemic effect of metformin does not appear to be due to effects on plasma insulin or glucagon concentrations. While some studies have demonstrated that metformin produces an increase in insulin receptor binding or an increase in low-affinity receptor number, it is generally accepted that the antihyperglycemic effects of metformin are poorly correlated with insulin binding and its effects on receptor binding and number are not directly related to its metabolic and clinical effects. A direct effect of metformin on insulin secretion has been ruled out as a mechanism for the antihyperglycemic effects because metformin does not increase circulating levels of insulin nor has it been shown experimentally to stimulate insulin secretion. Although the precise mechanism of hypoglycemic action of metformin remains unclear, it likely interrupts mitochondrial oxidative processes in the liver and corrects abnormalities of intracellular calcium metabolism in insulin- sensitive tissues (liver, skeletal muscle, and adipocytes) and cardiovascular tissues from specific studies.

DETAILED PHARMACOLOGY

The mechanism of the antihyperglycemic effect of metformin is not completely understood and probably several actions are involved. The following mechanisms of action have been suggested:

1. 1) increased insulin receptor binding; 2) decreased intestinal glucose absorption; 3) increased cellular glucose uptake; 4) decreased hepatic gluconeogenesis; 5) stimulation of anaerobic glycolysis; and 6) potentiation of insulin action at the receptor or post-receptor level.

At therapeutic doses, metformin does not lower plasma glucose levels in non-diabetic animals or humans. However, oral administration of metformin was shown to effectively lower plasma glucose levels in several different animal models of hyperglycemia, including streptozotocin - induced diabetic mice, genetically diabetic KK mice, obese female fa/fa rats, and alloxan- induced diabetic rats. Metformin does not reduce basal glucose concentrations below the normal physiological range, either in diabetic animals or humans.

The antihyperglycemic effect of metformin does not appear to be due to effects on plasma insulin or glucagon concentrations. While some studies have demonstrated that metformin produces an increase in insulin receptor binding or an increase in low-affinity receptor number, it is generally accepted that the antihyperglycemic effects of metformin are poorly correlated with insulin binding, and its effects on receptor binding and number are not directly related to its metabolic and clinical effects. A direct effect of metformin on insulin secretion has been ruled out as a mechanism for the antihyperglycemic effects because metformin does not increase circulating levels of insulin nor has it been shown experimentally to stimulate insulin secretion.

Animal studies have demonstrated that metformin inhibits intestinal glucose absorption in both normal and diabetic animals, although the concentrations necessary to produce this effect are usually higher than the therapeutic range. The inhibition of intestinal glucose absorption does not appear to account for the full ability of metformin to reduce glycemia, indicating that other mechanisms of action play a role. The effect of metformin on glucose absorption has not been confirmed in diabetic patients.

Several studies have been conducted, both in vitro and in vivo, to determine the effects of metformin on glucose uptake into tissues, glucose oxidation, and glycogen synthesis. In general, metformin potentiates insulin-mediated glucose uptake into tissues, with the skeletal muscle being the most important site. This effect of metformin appears to be due to facilitation of a post- receptor sensitivity to insulin. Metformin was shown to have no effect on basal or insulin- stimulated glucose oxidation in muscle from non-diabetic mice but potentiated glucose oxidation in muscle from streptozotocin-diabetic mice in the presence of insulin. Metformin also increased basal glucose oxidation in adipocytes from non-diabetic rats. The results of studies on glycogen synthesis have been less consistent, with metformin producing either no effect or an increase in insulin-stimulated glycogen synthesis in skeletal muscle of non-diabetic and diabetic animals.

Many studies in diabetic animals and human diabetic patients have demonstrated that metformin improves glucose tolerance, an effect that is less pronounced or absent in non- diabetic individuals. Studies at the cellular level indicate that metformin potentiates insulin action and results from in vitro studies support a post-receptor mechanism of action.

In addition to antihyperglycemic effects, metformin has been shown to have hypolipidemic effects and to significantly improve the progression and regression of atherosclerotic lesions. Metformin has been shown to be effective in inhibiting fructose- and fat-induced hypertriglyceridemia; it appears that metformin inhibits the transfer of dietary triglyceride from the gastrointestinal tract into plasma and reduces the uptake of the absorbed lipid by adipose tissue.

Several studies were conducted to determine the effects of metformin on the lipoprotein composition of VLDL from normal and cholesterol-fed animals. The results indicated that metformin produced changes in the lipoprotein composition in cholesterol-fed animals toward a more normal composition. In addition, it produced structural modifications of VLDL that led to a rapid turnover and a decreased interaction with arterial wall binding components.

Metformin also altered lipid metabolism in the aortic wall, inhibiting intramural lipid biosynthesis.

Metformin has been shown to reduce blood pressure in spontaneously hypertensive rats. The suggested mechanisms involved in this effect include a sympathoinhibitory effect, a direct effect on vascular smooth muscle responsiveness to norepinephrine, and attenuation of hyperinsulinemia.

Several drug interaction studies with metformin were available in the scientific literature. Metformin was shown to enhance the elimination of phenprocoumon in diabetic patients. Because studies in rats did not demonstrate any effect of metformin on liver microsomal enzymes, it was postulated that an increase in liver blood flow might explain the drug interaction between metformin and phenprocoumon. Metformin was also shown to counteract the hyperglycemic effects of diazepam and nifedipine.

10.2 Pharmacodynamics

The TARO-METFORMIN XR & METFORMIN XR tablet utilises a delivery technology, non-aqueous-coating Opadry 21 K580032 White version of the extended-release tablet formulation. Since the tablet coating controls the release of metformin, the tablet does not need to dissolve or break down in order to deliver the specified dose of metformin. Therefore, the tablet coating may be retrieved in the stool.

Metformin hydrochloride is a biguanide anti-hyperglycemic agent, which is widely used for the treatment of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus [NIDDM]. Metformin improves glycemic control by enhancing insulin sensitivity in liver and muscle and reducing gastrointestinal glucose absorption and hepatic glucose production. However, it does not stimulate insulin secretion and, therefore, is not associated with hypoglycemia. Improved metabolic control with metformin does not induce weight gain and may cause weight loss. It has been demonstrated that the favorable effects of metformin also include improvements in factors associated with cardiovascular risk including lipids, fibrinolysis and body weight.

The TARO- Metformin XR tablet utilises a delivery technology, a non-aqueous-coating Opadry 21 K580032 White version of the extended-release tablet formulation. Since the tablet coating controls the release of metformin, the tablet does not need to dissolve or break down in order to deliver the specified dose of metformin. Therefore, the tablet coating may be retrieved in the stool.

10.3 Pharmacokinetics

Metformin hydrochloride pharmacokinetics have been characterized after oral administration of single and multiple doses to adult healthy volunteers, in eleven separate studies.

Table 4: Summary of Mean Pharmacokinetic Parameters

Absorption

Following a single oral dose of 1000 mg metformin hydrochloride extended-release tablets once-daily after a meal, the time to reach maximum plasma metformin concentration (Tmax) is approximately 7 - 8 hours. In both single and multiple dose studies in healthy subjects, once daily 1000 mg dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), of metformin relative to the immediate release given as 500 mg twice daily.

Once daily oral doses of metformin hydrochloride 500 mg to 2500 mg doses resulted in less than proportional increases in both AUC and Cmax. The mean Cmax values were 473 ± 145, 868 ± 223, 1171 ± 297, and 1630 ± 399 ng/mL for once daily doses of 500, 1000, 1500, and 2500 mg, respectively. For AUC, the mean values were 3501 ± 796, 6705 ± 1918, 9299 ± 2833, and 14161 ± 4432 ng.hr/mL for once daily doses of 500, 1000, 1500, and 2500 mg, respectively.

Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin hydrochloride extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours, but Cmax was not affected. In an open label pharmacoscintigraphic pharmacokinetic study in healthy volunteers, metformin hydrochloride extended-release tablets 500 mg dosed with different fat content meals was evaluated. Both the gastric retention time and the systemic exposure of metformin were higher following the high fat meal than following the AHA 30% fat meal, demonstrating that extended gastric retention enables extended delivery of metformin. For transit times less than 7 hours as sometimes seen in AHA 30% fat meal administration, absorption of metformin may be decreased almost linearly with decreasing upper GI transit time.

Distribution

The apparent volume of distribution (V/F) of metformin, following single oral doses of 850 mg immediate- release metformin hydrochloride averaged 654 ± 358 L. At doses of 500 to 1500 mg, metformin has an absolute oral bioavailability of 50% to 60%. The drug is not protein bound and therefore has a wide volume of distribution, with maximal accumulation in the small intestine wall. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 mcg/mL.

Metabolism

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half -life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Elimination

Metformin undergoes no modifications in the body and is secreted unchanged by rapid kidney excretion (through glomerular filtration and, possibly, tubular secretion). Impaired kidney function slows elimination and may cause metformin accumulation.

The apparent plasma elimination half-life of metformin following a single dose of metformin hydrochloride is approximately 8 hours. Results from a dose proportionality study involving once daily oral doses of metformin hydrochloride 500 mg to 2500 mg, indicate a lack of dose proportionality with increasing doses, as both AUC and Cmax increased nonlinearly within the investigated dose range.

Concomitant administration with glyburide (DIAΒETA®) does not lead to a change in the peak and systemic exposures of metformin. (PART II: SCIENTIFIC INFORMATION, CLINICAL TRIALS)

Special Populations and Conditions

Pediatrics

No pharmacokinetic studies of metformin hydrochloride in pediatric subjects were conducted.

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half -life is prolonged and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see 7 WARNINGS AND PRECAUTIONS, Special Populations).

Sex

In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC (males = 268, females = 293) and t1/2(males = 229, females = 260). However, Cmax for metformin were somewhat higher in female subjects (Female/Male Cmax Ratio = 1.4). The gender differences for Cmax are unlikely to be clinically important.

Race and Ethnic Origin

There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin hydrochloride extended-release tablets because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important.

Hepatic Insufficiency

No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted in patients with hepatic insufficiency.

Renal Insufficiency

In patients with decreased renal function (based on measured serum creatinine) the blood half-life of metformin is prolonged, and the renal clearance is decreased in proportion to the decrease in creatinine clearance.

11. STORAGE, STABILITY AND DISPOSAL

TARO-METFORMIN XR & METFORMIN XR (metformin hydrochloride extended release) tablets are to be stored at room temperature (15°C - 30˚C).

Protect from moisture. Keep out of reach and sight of children.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: metformin hydrochloride

Chemical Name: Imidodicarbonimidic diamide, N,N-dimethyl-, monohydrochloride

1,1-dimethylbigunide monohydrochloride

3-( diaminomethylidene)-1, 1-dimethylguanidine; hydrochloride

Molecular Formula: C₄H₁₁N₅•HCl

Molecular Mass: 165.6 g/mol

Structural formula:

Physiochemical Properties

Description: Metformin hydrochloride is a white crystalline powder with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.6 g/mol.

Solubility: Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol and is practically insoluble in acetone, and methylene chloride.

pH: The pH of 10% solution of Metformin Hydrochloride in purified water is 6.89 (~ 7.0), at the temperature 25°C

METFORMIN XR & TARO-METFORMIN XR tablets are extended release dosage forms that contain 500 mg and 1000 mg of metformin hydrochloride respectively.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Four clinical studies were conducted in patients with type 2 diabetes, to establish the safety and efficacy of metformin hydrochloride extended-release tablets, as shown in the following Table 5.

Table 5 Metformin Hydrochloride Safety and Efficacy Trials

14.2 Study results

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study of metformin hydrochloride 1500 mg once a day, metformin hydrochloride 1500 per day in divided doses (500 mg in the morning and 1000 mg in the evening), and metformin hydrochloride 2000 mg once a day were compared to immediate release (IR) metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening) (Table 6). Metformin IR treatment was initiated as 500 mg BID for 1 week followed by 500 mg with breakfast and 1000 mg with dinner from the second week. The 3-week titration period was followed by an additional 21-week period at the randomized dose. Each of the metformin hydrochloride regimens, were at least as effective as metformin IR in all measures of glycemic control. Once daily dosing of metformin hydrochloride was as effective as the commonly prescribed twice daily dosing of the immediate-release product.

Table 6 Mean±SE Changes from Baseline to Final Visit in HbA1c, Fasting Plasma Glucose and Body Weight for the Metformin Hydrochloride and Metformin IR Treatment Groups (24-Week Study)

Patients who completed this 24-week study were placed on metformin hydrochloride 2000 mg/day treatment during a 24-week open-label trial in order to evaluate the long-term safety and duration of effectiveness of metformin hydrochloride. This resulted in the exposure of 158 patients to continuous treatment with metformin hydrochloride 1500-2000 mg/day (56 on 2000 mg/day) for a cumulative period of 48 weeks. metformin hydrochloride treatment maintained steady levels of HbA1c, FPG and plasma fructosamine over the 24-week period from the open-label baseline to the open-label endpoint. All treatment groups irrespective of previous treatment in the double-blind study, showed similar decreases in HbA1c, FPG and plasma fructosamine levels over the cumulative 48-week period from the double-blind baseline to the open-label phase.

In a double-blind, randomized, placebo-controlled (add-on), multicentre study, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise, or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides, or treated with combination therapy consisting of metformin/glyburide at doses up to 1000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) were enrolled. They were stabilized on glyburide for a 6 -week period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); metformin hydrochloride 1500 mg once a day + glyburide, metformin hydrochloride 2000 mg once a day + glyburide, or metformin hydrochloride 1000 mg twice a day + glyburide. A 3-week metformin hydrochloride titration phase was followed by a 21-week maintenance treatment phase. There was a decrease from Baseline to Endpoint in mean HbA1c levels in the metformin hydrochloride + glyburide groups (mean change, -0.74%; 95% CI, -0.85, -0.64), but almost no change in the glyburide only group (mean change 0.08%; 95% CI, -0.08, 0.25). (See Table 6). The difference in the change from Baseline in HbA1c levels between the combined M-ER+ SU groups and the SU only group was statistically significant (p<0.001). The changes in glycemic control across the three metformin hydrochloride + glyburide groups were comparable.

Table 7 Mean ± SE Changes from Baseline to Final Visit in HbA1c, Fasting Plasma Glucose and Body Weight for the Combined Metformin Hydrochloride/Glyburide and Placebo/Glyburide Treatment Groups (24-Week Study)

* Glyburide was administered as 10 mg at breakfast and 5 mg at dinner.

14.3 Comparative Bioavailability Studies

A randomized, two-treatment, two-period, two-sequence, crossover, single dose (1 x 500 mg), oral comparative bioavailability study of METFORMIN XR 500 mg extended-release tablets and GLUMETZA^® 500 mg extended-release tablets was conducted in 48 healthy, adult, subjects under fasted conditions. Comparative bioavailability data from 44 subjects (38 male and 6 female) that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ METFORMIN XR (metformin hydrochloride) extended-release tablets, 500 mg (Taro Pharmaceuticals Inc.)

^{2 Pr}GLUMETZA^® (metformin hydrochloride) extended-release tablets, 500 mg (Valeant Canada)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

A randomized, two-treatment, two-period, two-sequence, crossover, single dose (1 x 500 mg), oral comparative bioavailability study of METFORMIN XR 500 mg extended-release tablets and GLUMETZA^® 500 mg extended-release tablets was conducted in 48 healthy, adult, subjects under fed conditions. Comparative bioavailability data from 45 subjects (42 male and 3 female) that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ METFORMIN XR (metformin hydrochloride) extended-release tablets, 500 mg (Taro Pharmaceuticals Inc.)

^{2 Pr}GLUMETZA^® (metformin hydrochloride) extended-release tablets, 500 mg (Valeant Canada)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

A randomized, two-treatment, two-period, two-sequence, crossover, single dose (1 x 1000 mg), oral comparative bioavailability study of TARO-METFORMIN XR 1000 mg extended-release tablets and GLUMETZA^® 1000 mg extended-release tablets was conducted in 48 healthy, adult, subjects under fasted conditions. Comparative bioavailability data from 46 male subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TARO-METFORMIN XR (metformin hydrochloride) extended-release tablets, 1000 mg (Taro Pharmaceuticals Inc.)

^{2 Pr}GLUMETZA^® (metformin hydrochloride) extended-release tablets, 1000 mg (Valeant Canada)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

A randomized, two-treatment, two-period, two-sequence, crossover, single dose (1 x 1000 mg), oral comparative bioavailability study of TARO-METFORMIN XR 1000 mg extended-release tablets and GLUMETZA^® 1000 mg extended-release tablets was conducted in 48 healthy, adult, subjects under fed conditions. Comparative bioavailability data from 47 subjects (42 male and 5 female) that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TARO-METFORMIN XR (metformin hydrochloride) extended-release tablets, 1000 mg (Taro Pharmaceuticals Inc.)

^{2 Pr}GLUMETZA^® (metformin hydrochloride) extended-release tablets, 1000 mg (Valeant Canada)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV %) only

15. MICROBIOLOGY

No microbiological information is required for this drug product.

16. NON-CLINICAL TOXICOLOGY

A comprehensive nonclinical toxicology program was conducted with metformin, including repeat-dose toxicity studies in rats and dogs, a battery of genotoxicity studies, two carcinogenicity studies, and a full assessment of reproductive toxicity studies.

General Toxicology:

Chronic Toxicity

In a 26-week oral/gavage toxicity study, 160 Sprague-Dawley rats were administered with 150, 450, 900 mg/kg/day. The No-observed-effect level in this study was 150 mg/kg/day. Decrease in body weight gains at 450 and 900 mg/kg/day, changes in clinical laboratory parameters (decreased total leukocyte, lymphocyte and neutrophil count) and in some organ weights at 900 mg/kg/day have been observed.

In another 39-week oral toxicity study, 32 Beagle dogs were administered with 20, 40, 60, 80 mg/kg/day. Only at 80 mg/kg/day, treatment-related effects in food consumption have been observed in females.

Carcinogenicity

In 26-week dermal carcinogenicity study in transgenic mice. 150 mice were administered with 500, 1000, 2000 mg/kg/day. There is no findings and none of papillomas at treatment sites. No evidence of carcinogenicity was observed in male or female mice.

In a 104-week oral/gavage carcinogenicity study in rats, 400 rats / Sprague-Dawley were administered 150, 300, 450 mg/kg/day for males and 150, 450, 900, 1200 mg/kg/day for females. These doses are approximately two and five times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons.

The No-observed- effect level in this study was 450 mg/kg/day. No evidence of carcinogenicity with metformin was found in either male or female rats. There was, however, an increased incidence of adenomas and diffuse hyperplasia in the parathyroids of treated males. Parathyroid hyperplasia was noted in males at all doses, and not noted for females.

Non-neoplastic findings seen in females and not with males, no tumorigenicity has been observed and increase in female kidney weights at 900 and 1200 mg/kg/day.

Genotoxicity

AMES Assay has been performed, doses at 100, 333, 1000, 5000 mcg/plate with Salmonella /E. coli strain. Results were all negatives.

In vitro cytogenetics – mouse lymphoma assay, doses at 1000, 2000, 3000, 4000, 5000 mcg/plate with mice /Lymphoma cells strains. Results obtained were all negatives.

In vivo cytogenetics – mouse micronucleus assay, 70 ICR mice were oral administered 500, 1000, 2000 mg/kg. Results were also all negatives.

Reproductive Toxicity

Fertility of male and female rats was unaffected by metformin when administered at doses as high as 900 mg/kg/day, which is approximately four times the recommended human daily dose based on body surface area comparisons (see 16 NON- CLINICAL TOXICOLOGY)

In rats Segment I/II toxicity study (Fertility & developmental toxicity), 200 Sprague-Dawley rats

(100 males and 100 females) were orally administered 150, 450, 900 mg/kg/day. Decrease in male reproductive organ weights at 900 mg/kg/day has been noted.

In a second rats Segment III toxicity study (Pre-and postnatal toxicity), 100 mated females Sprague-Dawley rats were orally administered 150, 300, 600 mg/kg/day. The No-observed- effect level in this study was 150 mg/kg/day in this study and decrease in F1 female body weight and feed consumption at 300 and 600 mg/kg/day were observed.

In a third Segment II toxicity study in rabbits (Developmental toxicity in rabbits), 80 New Zealand white Time Pregnant females Rabbits were Orally/ Stomach tube administered 30, 60, 90 mg/kg/day. The No-observed-effect level in this study was higher than 90 mg/kg/day and no effects on gross external, soft tissue or skeletal malformation were noted.

Bridging Study

Bridging study in dogs has been performed, 70 Beagle dogs were orally administered 250, 500, 1000 mg/day. The No-observed-effect level in this study was 250 mg/kg/day and severe weight loss and clinical signs at doses 500 mg/day and higher have been observed.

1. 17.

   SUPPORTTING PRODUCT MONOGRAPHS

   1. 1. ^PrGLUMETZA^® (Metformin Hydrochloride Extended- Release Tablets, Mfr. Std. 500 mg and 1000 mg) and ^PrGLUMETZA^® (SB) (Metformin Hydrochloride Extended- Release Tablets, Mfr. Std. 1000 mg), Submission Control: 264310, Product Monograph, Bausch Health, Canada Inc. [FEB 14, 2023]