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

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

Metformin Hydrochloride Extended-Release Tablets

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 m ² [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 extended-release tablets are 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 extended-release 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:

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C ₄ H ₁₁ N ₅ ∙ HCl and a molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK _a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 584.90 mg metformin base, respectively.

Metformin hydrochloride extended-release tablets USP, 500 mg and 750 mg contain the inactive ingredients carboxymethylcellulose sodium, copovidone, hypromellose, magnesium stearate and microcrystalline cellulose.

The USP dissolution test is pending.

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

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 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, 1.1, 1.4 and 1.8 mcg/mL for 500, 1,000, 1,500, 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 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 3) 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 2) [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 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 3) . [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)] .

Table 3: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

Subject Groups: Metformin Hydrochloride Tablets Dose * (number of subjects)	C max †(mcg/mL)	T max ‡(hrs)	Renal Clearance (mL/min)
* All doses given fasting except the first 18 doses of the multiple dose studies † Peak plasma concentration ‡ Time to peak plasma concentration § Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years) ¶ Kinetic study done following dose 19, given fasting # Elderly subjects, mean age 71 years (range 65 to 81 years) Þ CLcr = creatinine clearance normalized to body surface area of 1.73 m 2
Healthy, nondiabetic adults:
500 mg single dose (24)	1.03 (± 0.33)	2.75 (± 0.81)	600 (± 132)
850 mg single dose (74) §	1.60 (± 0.38)	2.64 (± 0.82)	552 (± 139)
850 mg three times daily for 19 doses ¶ (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 doses ¶ (9)	1.90 (± 0.62)	2.01 (± 1.22)	550 (± 160)
Elderly #, 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 Þ 61 to 90 mL/min) (5)	1.86 (± 0.52)	3.20 (± 0.45)	384 (± 122)
Moderate (CL cr 31 to 60 mL/min) (4)	4.12 (± 1.83)	3.75 (± 0.50)	108 (± 57)
Severe (CL cr 10 to 30 mL/min) (6)	3.93 (± 0.92)	4.01 (± 1.10)	130 (± 90)

Pediatrics

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 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 4: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug	Dose of Coadministered Drug *	Dose of Metformin *	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUC †	C max
* 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 0-12 h
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 5: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug	Dose of Coadministered Drug *	Dose of Metformin *	Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00
				AUC †	C max
* 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
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