METFORMIN HYDROCHLORIDE: Package Insert and Label Information

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, extended release
Ascend Laboratories, LLC

1 INDICATIONS AND USAGE

Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

Metformin Hydrochloride Extended-Release Tablets:

• Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.
• The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg orally once daily with the evening meal.
• Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal.
• If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2000 mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride extended-release tablets at total daily doses up to 2550 mg administered in divided daily doses, as described above.
• Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily.

2.3 Recommendations for Use in Renal Impairment

• Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter.
• Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m ².
• Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m ² is not recommended.
• In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m ² , assess the benefit risk of continuing therapy.
• Discontinue metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m ² [ see Warnings and Precautions (5.1) ].

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/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 extended-release tablets if renal function is stable.

3 DOSAGE FORMS AND STRENGTHS

Metformin hydrochloride extended-release tablets USP, 500 mg are available as white to off white capsule shaped, biconvex, beveled edge tablet, with occasionally mottled appearance, debossed with ” 001″ on one side and plain on other side.

4 CONTRAINDICATIONS

Metformin hydrochloride extended-release tablets are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m ²) [ see Warnings and Precautions (5.1) ].
• Hypersensitivity to metformin.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride extended-release tablets. In metformin hydrochloride extended-release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

• Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [ see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]:

• Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
• Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [ see Contraindications (4) ].
• Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m ².
• Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45 mL/min/1.73 m ² , assess the benefit and risk of continuing therapy.

• Drug interactions – The concomitant use of metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
• Age 65 or greater – The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
• Radiologic studies with contrast – Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m ² ; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal function is stable.
• Surgery and other procedures — Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
• Hypoxic states — Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended-release tablets.
• Excessive alcohol intake – Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.
• Hepatic impairment – Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B12 Deficiency

In metformin hydrochloride tablets 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. Such decrease, possibly due to interference with B ₁₂ absorption from the B ₁₂ -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B ₁₂ supplementation. Certain individuals (those with inadequate vitamin B ₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B ₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B ₁₂ at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [ see Adverse Reactions (6.1)].

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets [ see Drug Interactions (7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

6 ADVERSE REACTIONS

The following adverse reactions are also discussed elsewhere in the labeling:

• Lactic Acidosis [ see Boxed Warning and Warnings and Precautions (5.1)]
• Vitamin B ₁₂ Deficiency [ see Warnings and Precautions (5.2)]
• Hypoglycemia [ see Warnings and Precautions (5.3)]

6.1 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.

Metformin Hydrochloride Extended-Release Tablets:

In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablets- than placebo-treated patients, are listed in Table 2.

Table 2: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

	Metformin Hydrochloride Extended-Release Tablets (n=781)	Placebo (n=195)
Diarrhea	10%	3%
Nausea/Vomiting	7%	2%

Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

6.2 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.

7 DRUG INTERACTIONS

Table 3 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets.

Table 3: Clinically Significant Drug Interactions with metformin hydrochloride extended-release tablets

Carbonic Anhydrase Inhibitors
Clinical Impact:	Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.
Intervention:	Consider more frequent monitoring of these patients.
Examples:	Topiramate, zonisamide, acetazolamide or dichlorphenamide.
Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance
Clinical Impact:	Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)].
Intervention:	Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets.
Examples:	Ranolazine, vandetanib, dolutegravir, and cimetidine.
Alcohol
Clinical Impact:	Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention:	Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.
Insulin Secretagogues or Insulin
Clinical Impact:	Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
Intervention:	Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
Drugs Affecting Glycemic Control
Clinical Impact:	Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention:	When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.
Examples:	Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.