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 2- and 5­ times, respectively, a 2550 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 HCl 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 2550 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 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

Controlled 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 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 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/min/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/min 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 contain the biguanidine antihyperglycemic agent, metformin, in the form of monohydrochloride salt. The chemical name of metformin HCl is N, N-dimethylimidodicarbonimidic diamide hydrochloride with a molecular formula of C4 H11 N5 •HCl and a molecular weight of 165.63. Its structural formula is:

structure

Metformin HCl is a white to off-white crystalline powder that is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68.

Metformin Hydrochloride Extended-Release Tablets deliver 500 mg or 1,000 mg of metformin HCl, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. In addition to the active ingredient metformin HCl, each tablet contains the following inactive ingredients: candelilla wax, cellulose acetate, hypromellose, magnesium stearate, polyethylene glycols (PEG 400, PEG 8000), polysorbate 80, povidone, sodium lauryl sulfate, synthetic black iron oxides, titanium dioxide, and triacetin.

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

In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either metformin hydrochloride extended-release tablets 2,000 mg once a day (after dinner) or metformin HCl tablets 1,000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (Tmax ), and maximum concentration (Cmax ) were evaluated. The appearance of metformin in plasma from metformin hydrochloride extended-release tablets are slower and more prolonged compared to metformin HCl tablets. Results are presented in Table 3.

Table 3 M etformin Hydrochloride Extended-Release Tablets vs. Metformin HCl Tablets Steady-State Pharmacokinetic Parameters at 4 Weeks

Pharmacokinetic Parameters (mean ± SD)

M etformin Hydrochloride Extended-Release Tablets 2,000 mg (administered q.d. after dinner)

Metformin HCl tablets* 2,000 mg (1,000 mg b.i.d.)

AUC0-24hr (ng•hr/mL)

26,811 ± 7055

27,371 ± 5,781

Tmax (hr)

6 (3-10)

3 (1-8)

Cmax (ng/mL)

2849 ± 797

1820 ± 370

*Immediate-release metformin HCl tablets

In four single-dose studies and one multiple-dose study, the bioavailability of metformin hydrochloride extended-release tablets 2,000 mg given once daily, in the evening, under fed conditions [as measured by AUC] was similar to the same total daily dose administered as metformin HCl tablets 1,000 mg given twice daily. The geometric mean ratios (metformin hydrochloride extended-release tablets / metformin HCL tablets) of AUC0-24hr , AUC0-72hr , and AUC0-inf for these five studies ranged from 0.96 to 1.08.

In a single-dose, four-period replicate crossover design study, comparing two 500 mg metformin hydrochloride extended-release tablets to one 1,000 mg metformin hydrochloride extended-release tablet administered in the evening with food to 29 healthy male subjects, two 500 mg metformin hydrochloride extended-release tablets were found to be equivalent to one 1,000 mg metformin hydrochloride extended-release tablet.

In a study carried out with metformin hydrochloride extended-release tablets, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1,000, 1,500, 2,000, and 2,500 mg.

In three studies with metformin hydrochloride extended-release tablets using different treatment regimens (2,000 mg after dinner; 1,000 mg after breakfast and after dinner; and 2,500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration.

Effect of food: The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets increased by approximately 60% when given with food. When metformin hydrochloride extended-release tablets were administered with food, Cmax was increased by approximately 30% and Tmax was more prolonged compared with the fasting state (6.1 versus 4.0 hours).

Distribution

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

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 4) [See Dosage and Administration (2.2), Contraindications (4), and Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

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)].

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax 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 HCl Tablets

Subject Groups: Metformin HCl dosea

(number of subjects)

Cmax b

(mcg/mL)

Tmax c

(hrs)

Renal Clearance (mL/min)

Healthy, nondiabetic adults:

500 mg single dose (24)

1.03 (±0.33)

2.75 (±0.81)

600 (±132)

850 mg single dose (74)d

1.60 (±0.38)

2.64 (±0.82)

552 (±139)

850 mg three times daily for 19 dosese (9)

2.01 (±0.42)

1.79 (±0.94)

642 (±173)

Adults with type 2 diabetes mellitus:

850 mg single dose (23)

1.48 (±0.5)

3.32 (±1.08)

491 (±138)

850 mg three times daily for 19 dosese (9)

1.90 (±0.62)

2.01 (±1.22)

550 (±160

Elderlyf , 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 (CLcrg 61 to 90 mL/min) (5)

1.86 (±0.52)

3.20 (±0.45)

384 (±122)

Moderate (CLcr 31 to 60 mL/min) (4)

4.12 (±1.83)

3.75 (±0.50)

108 (±57)

Severe (CLcr 10 to 30 mL/min) (6)

3.93 (±0.92)

4.01 (±1.10)

130 (±90)

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 to 59 years)

e Kinetic study done following dose 19, given fasting

f Elderly subjects, mean age 71 years (range 65 to 81 years)

g CLcr = creatinine clearance normalized to body surface area of 1.73 m2

Pediatrics

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

Gender

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

Race

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

Drug Interactions

In Vivo Assessment of Drug Interactions

Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug

Dose of

Coadministered Drug*

Dose of

Metformin HCl*

Geometric Mean Ratio

(ratio with/without coadministered drug)

No Effect = 1.00

AUC

Cmax

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 Warnings and Precautions (5.1) and Drug Interactions (7). ]

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).]

Topiramate

100 mg§

500 mg§

metformin

1.25§

1.17

* All metformin HCl and coadministered drugs were given as single doses

AUC = AUCinf

Ratio of arithmetic means

§ At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug

Dose of Coadministered Drug*

Dose of Metformin HCl*

Geometric Mean Ratio

(ratio with/without metformin)

No Effect = 1.00

AUC

Cmax

No 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

* All metformin HCl and coadministered drugs were given as single doses

AUC = AUCinf unless otherwise noted

Ratio of arithmetic means, p-value of difference <0.05

§ AUC0-24 hr reported

Ratio of arithmetic means

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