Prescription Drug Information: Metformin Hydrochloride (Page 3 of 6)

8.5 Geriatric Use

Controlled clinical studies of metformin hydrochloride 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 is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.3), 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 is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

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.

11 DESCRIPTION

Metformin hydrochloride tablets, USP contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N -dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below:

Chemical Structure
(click image for full-size original)

Metformin hydrochloride, USP is a white to off-white crystalline compound with a molecular formula of C4 H11 N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride, USP 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 hydrochloride is 6.68.

Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride USP. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg, 850 mg, and 1000 mg contains hypromellose and polyethylene glycol.

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 a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride 500 to 1500 mg and 850 to 2550 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, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL.

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 (Cmax ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax ) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 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 3) [see Dosage and Administration (2.3), Contraindications (4), 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 hydrochloride 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 Hydrochloride Tablets
a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentrationc Time to peak plasma concentrationd Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)e Kinetic study done following dose 19, given fastingf Elderly subjects, mean age 71 years (range 65 to 81 years)g CLcr = creatinine clearance normalized to body surface area of 1.73 m2
Subject Groups: Metformin Hydrochloride Tablets dosea (number of subjects) Cmax b (mcg/mL) Tmax 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 dosese (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 dosese (9) 1.48 (±0.5)1.90 (±0.62) 3.32 (±1.08)2.01 (±1.22) 491 (±138)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)Moderate (CLcr 31 to 60 mL/min) (4)Severe (CLcr 10 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)

Pediatrics

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

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
* 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 = AUC0-12h
Coadministered Drug Dose of Coadministered Drug * Dose of Metformin * 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
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(0-24 hr) reported Ratio of arithmetic means
Coadministered Drug Dose of Coadministered Drug * Dose of Metformin * 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

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