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TABLETS safely and effectively. See full prescribing information for METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS. METFORMIN HYDROCHLORIDE extended-release tablets, for oral useInitial U.S. Approval: 1995 · Viona Pharmaceuticals Inc

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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, hepatic impairment, and mitochondrial diseases [see Warnings and Precautions (5.1)].

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration (2.4), (2.7), Contraindications (4), Warnings and Precautions (5.1)].

If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

Metformin hydrochloride extended-release tablets are 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.

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.

Risk Summary

Limited data with metformin hydrochloride extended-release tablets 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 times 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 postmarketing 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 times 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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Lactic Acidosis

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Hypoglycemia

Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)].

Vitamin B₁₂ Deficiency

Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Females of Reproductive Age

Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].

Metformin hydrochloride extended-release tablets Administration Information

Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

What it looks like

Photos of the product and/or packaging supplied by the manufacturer.

Package codes (NDC)

72578-035-01
72578-035-05
72578-036-01
72578-036-05

Full prescribing information (for healthcare professionals)

12 CLINICAL PHARMACOLOGY

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.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of metformin hydrochloride tablets, 500 mg given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1,500 mg and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 hours to 48 hours and are generally <1 μg/mL.

Following a single oral dose of metformin hydrochloride extended-release tablets, C_max is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride tablets.

At steady state, the AUC and C_max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2,000 mg administered once daily. Peak plasma levels are approximately 0.6 mcg/mL, 1.1 mcg/mL, 1.4 mcg/mL and 1.8 mcg/mL for 500 mg, 1,000 mg, 1,500 mg and 2,000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2,000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1,000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.

Effect of food:

Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C_max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T_max) following administration of a single 850 mg tablet of metformin hydrochloride tablets with food, compared to the same tablet strength administered fasting.

Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C_max and T_max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

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.

Elimination

Renal clearance (see Table 4) 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.

Specific Populations

Patients with Renal Impairment

In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [See Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [See Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatric Patients

Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C_max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4). [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Table 4 Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

^a All doses given fasting except the first 18 doses of the multiple dose studies
^b Peak plasma concentration
^c Time to peak plasma concentration
^d Combined results (average means) of five studies: mean age 32 years (range 23 years to59 years)
^e Kinetic study done following dose 19, given fasting
^f Elderly subjects, mean age 71 years (range 65 years to 81 years)
^g CL_cr= creatinine clearance normalized to body surface area of 1.73 m²
Subject Groups: Metformin Hydrochloride Tablets dose^a (number of subjects)	C _max ^b (mcg/mL)	T _max ^c (hrs)	Renal Clearance (mL/min)
Healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74)^d 850 mg three times daily for 19 doses^e (9)	1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42)	2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94)	600 (±132) 552 (±139) 642 (±173)
Adults with type 2 diabetes mellitus: 850 mg single dose (23) 850 mg three times daily for 19 doses^e (9)	1.48 (±0.5) 1.90 (±0.62)	3.32 (±1.08) 2.01 (±1.22)	491 (±138) 550 (±160)
Elderly ^f , healthy nondiabetic adults: 850 mg single dose (12)	2.45 (±0.70)	2.71 (±1.05)	412 (±98)
Renal-impaired adults: 850 mg single dose Mild (CL_cr ^g61 mL/min to 90 mL/min) (5) Moderate (CL_cr 31 mL/min to 60 mL/min) (4) Severe (CL_cr10 mL/min to 30 mL/min) (6)	1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92)	3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10)	384 (±122) 108 (±57) 130 (±90)

Pediatric Patients

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C_max and AUC differed less than 5% between pediatric patients (12 years to 16 years of age) with type 2 diabetic mellitus and sex- and weight-matched healthy adults (20 years to 45 years of age), all with normal renal function.

Sex

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to sex (males=19, females=16).

Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interaction Studies

In Vivo Assessment of Drug Interactions

Table 5 Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

^* All metformin and coadministered drugs were given as single doses
^† AUC = AUC(INF)
^‡ Ratio of arithmetic means
^§ At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC_{0 to 12h}
Coadministered Drug	Dose of Coadministered Drug^*	Dose of Metformin^*	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
	AUC ^†	C _max
No dosing adjustments required for the following:
Glyburide	5 mg	850 mg	metformin	0.91^‡	0.93^‡
Furosemide	40 mg	850 mg	metformin	1.09^‡	1.22^‡
Nifedipine	10 mg	850 mg	metformin	1.16	1.21
Propranolol	40 mg	850 mg	metformin	0.90	0.94
Ibuprofen	400 mg	850 mg	metformin	1.05^‡	1.07^‡
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See W arnings and Precautions (5.9) and Drug Interactions (7.2). ]
Cimetidine	400 mg	850 mg	metformin	1.40	1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7.1). ]
Topiramate	100 mg^§	500 mg^§	metformin	1.25^§	1.17

Table 6 Effect of Metformin on Coadministered Drug Systemic Exposure

^* All metformin and coadministered drugs were given as single doses
^† AUC = AUC(INF) unless otherwise noted
^‡ Ratio of arithmetic means, p-value of difference <0.05
^§ AUC(0 hr to 24 hr) reported
^¶ Ratio of arithmetic means
C o a dministered D rug	Do se of C o a dministered Drug ^*	Do se of Metformin ^*	Geometric Mean Ratio (ratio with/without metformin) N o Effect = 1
	A U C ^†	C_max
N o dosing adjustments required for the following:
Glyburide	5 mg	850 mg	glyburide	0.78^‡	0.63^‡
Furosemide	40 mg	850 mg	furosemide	0.87^‡	0.69^‡
Nifedipine	10 mg	850 mg	nifedipine	1.10^§	1.08
Propranolol	40 mg	850 mg	propranolol	1.01^§	1.02
Ibuprofen	400 mg	850 mg	ibuprofen	0.97^¶	1.01^¶
Cimetidine	400 mg	850 mg	cimetidine	0.95^§	1.01

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2,550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2,550 mg based on body surface area comparisons.

14 CLINICAL STUDIES

SPL UNCLASSIFIED SECTION

Manufactured by:

Zydus Lifesciences Ltd.

Ahmedabad, India

Distributed by:

Viona Pharmaceuticals Inc.

Cranford, NJ 07016

Rev.: 04/26

SPL UNCLASSIFIED SECTION

Manufactured by:

Zydus Lifesciences Ltd.

Ahmedabad, India

Distributed by:

Viona Pharmaceuticals Inc.

Cranford, NJ 07016

Rev.: 04/26

Serious warning (boxed)Boxed warningThe FDA's most prominent safety warning.

What this medicine is forThe uses this medicine is approved for.

How to take itDosage and administration instructions.

Available doses and formsMetformin Hydrochloride Extended-release Tablets, USP Metformin Hydrochloride Extended-release Tablets USP, 500 mg are white to off-white, capsule shaped, uncoated tablets, debossed with "63" on one side and "Z" on the o…

Do not use if…Contraindications.Metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)] . Hypersensitivity to metformin. Acute or…

Drug interactionsTable 3 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 3 Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets Carb…

Important warnings and precautions

Possible side effectsThe following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)] Vitamin B12Deficiency [see Warnings and Precautions (5.2)] Hypoglycemia…

Use during pregnancyRisk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metf…

Use in childrenSafety and effectiveness of metformin hydrochloride extended-release tablets as an adjunct to diet and exercise to improve glycemic control in pediatric patients 10 years of age and older with type 2 diabetes mellitus ha…

Use in older adultsControlled clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose…

Use in specific groups

If you take too much (overdose)In the event of an overdose with metformin hydrochloride extended-release tablets, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.…

Patient informationAdvise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients t…

What's in this medicineMetformin hydrochloride extended-release tablets contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N-dimethylimidodic…

Package labelMetformin Hydrochloride Extended-release Tablets USP, 500 mg NDC 72578-035-01 100 tablets Rx only Metformin Hydrochloride Extended-release Tablets USP, 750 mg NDC 72578-036-01 100 tablets Rx only

How it's supplied

How it's suppliedMetformin Hydrochloride Extended-release Tablets, USP Metformin Hydrochloride Extended-release Tablets USP, 500 mg are white to off-white, capsule shaped, uncoated tablets, debossed with "63" on one side and "Z" on the o…

What it looks like

Package codes (NDC)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION