Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 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].; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Metformin Hydrochloride Oral Solution 500 mg/5 mL-Container Label Metformin Hydrochloride Oral Solution 500 mg/5 mL-Carton Label containerlabel cartonlabel
- 16 HOW SUPPLIED/STORAGE AND HANDLING 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].
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Metformin Hydrochloride Oral Solution 500 mg/5 mL-Container Label Metformin Hydrochloride Oral Solution 500 mg/5 mL-Carton Label containerlabel cartonlabel
Overview
Metformin hydrochloride oral solution contains the biguanidine antihyperglycemic agent metformin in the form of monohydrochloride salt. Metformin hydrochloride, is N,N -dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is shown as: Metformin hydrochloride USP, is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin hydrochloride, USP 2.0 g is soluble in 20 mL of water. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. It is freely soluble in water; slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride. Metformin hydrochloride (Cherry Flavor) contains 500 mg of metformin hydrochloride USP (the equivalent of 389.93 mg metformin) per 5 mL and the following inactive ingredients: artificial cherry flavor, hydrochloric acid, potassium bicarbonate, purified water, sucralose, and xylitol. chemicalstructure
Indications & Usage
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 )
Dosage & Administration
Adult Dosage for Metformin Hydrochloride Oral Solution: • Starting dose: 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, with meals ( 2.1 ) • Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks, up to a maximum dose of 2,550 mg (25.5 mL) per day, given in divided doses ( 2.1 ) • Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals ( 2.1 ) Pediatric Dosage for Metformin Hydrochloride Oral Solution: • Starting dose: 500 mg (5 mL) orally twice a day, with meals ( 2.2 ) • Increase dosage in increments of 500 mg (5 mL) weekly up to a maximum of 2,000 mg (20 mL) per day, given in divided doses twice daily ( 2.2 ) Renal Impairment: • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.3 ) o Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 ( 2.3 ) o Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 ( 2.3 ) o Assess risk/benefit of continuing metformin hydrochloride oral solution if eGFR falls below 45 mL/minute/1.73 m 2 ( 2.3 ) o Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 ( 2.3 ) Discontinuation for Iodinated Contrast Imaging Procedures: • Metformin hydrochloride oral solution may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.4 ) 2.1 Adult Dosage • Measure the metformin hydrochloride oral solution dose in the metformin hydrochloride oral solution specific dosing cup. • The recommended starting dose of metformin hydrochloride oral solution is 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, given with meals. • Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2,550 mg (25.5 mL) per day, given in divided doses. • Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals. 2.2 Pediatric Dosage • Measure the metformin hydrochloride oral solution dose in the metformin hydrochloride oral solution specific dosing cup. • The recommended starting dose of metformin hydrochloride oral solution for pediatric patients 10 years of age and older is 500 mg (5 mL) orally twice a day, given with meals. • Increase dosage in increments of 500 mg (5 mL) weekly on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg (20 mL) per day, given in divided doses twice daily. 2.3 Recommendations for Use in Renal Impairment • Assess renal function prior to initiation of metformin hydrochloride oral solution and periodically thereafter. • Metformin hydrochloride oral solution is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . • Initiation of metformin hydrochloride oral solution in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. • In patients taking metformin hydrochloride oral solution whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. • Discontinue metformin hydrochloride oral solution 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 oral solution 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 oral solution if renal function is stable.
Warnings & Precautions
• 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. Therefore, avoid use of metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency In clinical trials of 29-week duration with metformin hydrochloride (HCl) tablets, 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 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 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 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 [see Drug Interactions ( 7 )]. 5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride.
Boxed Warning
LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1 ) ]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride oral solution and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 ) ]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL. ( 5.1 ) • Risk factors include renal impairment, concomitant use of certain drugs, age ≥ 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1) • If lactic acidosis is suspected, discontinue metformin hydrochloride oral solution and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )
Contraindications
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 )
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 )] 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. clinical trial of metformin HCl tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin HCl tablets up to 2,550 mg per day. Adverse reactions reported in greater than 5% of patients treated with metformin HCl tablets and that were more common than in placebo-treated patients, are listed in Table 1. Table 1: Adverse Reactions from a Clinical Trial of Metformin HCl Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin HCl Tablets (n = 141) Placebo (n = 145) Diarrhea 53% 12% Nausea/Vomiting 26% 8% Flatulence 12% 6% Asthenia 9% 6% Indigestion 7% 4% Abdominal Discomfort 6% 5% Headache 6% 5% Diarrhea led to discontinuation of metformin HCl tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥ 1% to ≤ 5% of patients treated with metformin HCl tablets and were more commonly reported than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Pediatric Patients In clinical trials with metformin HCl tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. Laboratory Tests Vitamin B 12 Concentrations In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 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.
Drug Interactions
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. Drugs that Reduce Metformin Hydrochloride 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 [OCT 2 ] / 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. 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. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride 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, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride, 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. • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7 ) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use ( 7 ) • Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake ( 7 )
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