METFORMIN HYDROCHLORIDE (Page 3 of 6)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 3 and 1 times, respectively, a 2,000 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 pregestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with an 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 HCl was not teratogenic or embyrolethal when administered to rats prior to pregnancy through the period of organogenesis at doses up to 900 mg/kg, or when administered to rabbits during the period of organogenesis at doses up to 90 mg/kg.

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 extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets 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 extended-release tablets may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

10 OVERDOSAGE

Overdose of metformin HCl 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/minute under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION

Metformin Hydrochloride Extended-Release Tablets, USP contains the biguanide antihyperglycemic agent metformin in the form of monohydrochloride salt. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown:

http://medlibrary.org/lib/images-rx/metformin-hydrochloride-167/structure.jpg

Metformin hydrochloride is a white crystalline powder with a molecular formula of C4 H11 N5 •HCl and a molecular weight of 165.62 g/mol. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride. The pKa of metformin is 2.8 and 11.5 at 32°C. The pH of a 5% aqueous solution of metformin hydrochloride is 6 to 7.

Metformin Hydrochloride Extended-Release Tablets, USP contain 500 mg or 1,000 mg of metformin hydrochloride, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. Each 500 mg and 1,000 mg tablet contains ammonio methacrylate copolymer dispersion type A, ammonio methacrylate copolymer dispersion type B, hypromellose, magnesium stearate, povidone K 30, talc, titanium dioxide, and triethyl citrate. The tablets are imprinted using a water-soluble black ink which contains shellac, black iron oxide, propylene glycol and ammonium hydroxide.

Meets USP Dissolution Test 12.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, 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

Following a single oral dose of 1,000 mg (2×500 mg tablets) metformin hydrochloride extended-release tablets after a meal, the time to reach maximum plasma metformin concentration (Tmax ) is achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2×500 mg tablets) dosing provides equivalent systemic exposure, as measured by area under the curve (AUC), and up to 35% higher Cmax , of metformin relative to the immediate-release given as 500 mg twice daily. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL.

In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be similar to two 500 mg tablets under fed conditions based on equivalent Cmax and AUCs for the two formulations.

Single oral doses of metformin hydrochloride extended-release tablets from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and Cmax .

Effect of food: Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin hydrochloride extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl 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 healthy 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.

Excretion

Renal clearance 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.

Special Populations

Renal Impairment

Following a single-dose administration of metformin hydrochloride extended-release tablets 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36‑fold greater in subjects with moderate renal impairment as compared to healthy subjects [see Dosage and Administration (2.2), Contraindications (4), and Warnings and Precautions (5.1)].

Hepatic Impairment

No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and Cmax is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

Gender

In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2 . However, Cmax for metformin was 40% higher in female subjects as compared to males. In controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females. The gender differences for Cmax are unlikely to be clinically important.

Race

A trend towards 10% higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24).

Pediatrics

There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in pediatric patients.

Drug Interactions

Specific pharmacokinetic drug interaction studies with metformin hydrochloride extended-release tablets have not been performed except for one with glyburide. However, such studies have been performed on metformin HCl tablets.

Table 3: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug

Dose of Coadministered Drug1

Dose of Metformin HCl1

Geometric Mean Ratio (ratio with/without coadministered drug)

No Effect=1.00

AUC2

Cmax

No dosing adjustments required for the following:

Glyburide

5 mg

500 mg4

0.983

0.993

Furosemide

40 mg

850 mg

1.093

1.223

Nifedipine

10 mg

850 mg

1.16

1.21

Propranolol

40 mg

850 mg

0.90

0.94

Ibuprofen

400 mg

850 mg

1.053

1.073

Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Cimetidine

400 mg

850 mg

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis:
[see Warnings and Precautions (5.1) and Drug Interactions (7)].

Topiramate

100 mg5

500 mg5

1.255

1.17

1 All metformin HCl and coadministered drugs were given as single doses
2 AUC = AUC0 to inf
3 Ratio of arithmetic means
4 Metformin hydrochloride extended-release tablets 500 mg
5 At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0 to 12h
Table 1: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug

Dose of Coadministered Drug1

Dose of Metformin HCl1

Geometric Mean Ratio (ratio with/without coadministered drug)

No effect=1.00

AUC2

Cmax

No dosing adjustments required for the following:

Glyburide

5 mg

500 mg 4

0.783

0.633

Furosemide

40 mg

850 mg

0.873

0.693

Nifedipine

10 mg

850 mg

1.104

1.08

Propranolol

40 mg

850 mg

1.014

0.94

Ibuprofen

400 mg

850 mg

0.975

1.015

Cimetidine

400 mg

850 mg

0.954

1.01

1 All metformin HCl and coadministered drugs were given as single doses
2 AUC = AUC0 to inf unless otherwise noted
3 Ratio of arithmetic means, p-value of difference <0.05
4 AUC0 to 24hr reported
5 Ratio of arithmetic means

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