Metformin Hydrochloride

Boxed Warning 6/2026 Warnings and Precautions, Lactic Acidosis (5.1) 6/2026

1 INDICATIONS AND 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 )

2 DOSAGE AND 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.

3 DOSAGE FORMS AND STRENGTHS Oral solution: 500 mg per 5 mL (100 mg/mL) clear to light yellow solution in cherry flavor Oral Solution: 500 mg per 5 mL (100 mg/mL) in cherry flavor ( 3 )

4 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 )

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 )] 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.

7 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 )

8 USE IN SPECIFIC POPULATIONS • Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) • Geriatric Use: Assess renal function more frequently. ( 8.5 ) • Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 8.2 Lactation Risk Summary Limited published studies report that metformin is present in human milk [see Data] . However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride and any potential adverse effects on the breastfed child from metformin hydrochloride or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride may result in ovulation in some anovulatory women. 8.4 Pediatric Use The s …

12.1 Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

11 DESCRIPTION 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 oral solution (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

10 OVERDOSAGE Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions ( 5.1 ) ]. Metformin is dialyzable with a 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Metformin hydrochloride oral solution 500 mg per 5 mL (100 mg/mL) is supplied in bottles with child-resistant caps and a dosing cup as follows: Flavor Appearance Size NDC Cherry clear, colorless to light yellow solution 16 ounce (473 mL) 66689-318-16 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].