Metformin: uses, appearance and warnings

Metformin hydrochloride oral solution is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. Metformin hydrochloride is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. ( 1 )

Oral solution: 500 mg per 5 mL (100 mg/mL) clear, colorless solution having cherry flavor. Oral Solution: 500 mg per 5 mL (100 mg/mL) in cherry flavor ( 3 )

How Supplied Metformin hydrochloride oral solution 500 mg per 5 mL (100 mg/mL) oral solution is supplied in bottles with child-resistant caps and a dosing cup as follows: Flavor Appearance Size NDC Cherry clear, colorless solution 16 ounce (473 mL) 31722-042-47 Storage Store at 15° to 30°C (59° to 86°F) [see USP controlled room temperature].

Metformin hydrochloride oral solution is 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. • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 , 5.1 ) • Hypersensitivity to metformin ( 4 ) • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. ( 4 )

• Lactic acidosis: See boxed warning. ( 5.1 ) • Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.2 ) • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required ( 5.3 ) 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 (> 5mmol/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. In metformin hydrochloride 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 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 ( 2.3 ), Clinical Pharmacology ( 12.3 ) ]: o Before initiating metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR). o Metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) ]. o Initiation of metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . o Obtain an eGFR at least annually in all patients taking metformin hydrochloride. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. o In patients taking metformin hydrochloride 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 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 [ see Drug Interactions ( 7 ) ]. • 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 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 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 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. • Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride. • 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. …

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 )] The most common adverse reactions are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 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. In a U.S. …

Table 2 presents clinically significant drug interactions with metformin hydrochloride. Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride 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 may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. …