Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450mg/kg/day in males and 150, 450, 900, and 1200mg/kg/day in females. These doses are approximately 2, 4, and 8times in males, and 3, 7, 12, and 16times in females of the maximum recommended human daily dose of 2000mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2000mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lyhpocytes) and invivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at dose up to 600mg/kg/day, which is approximately 3times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy
Teratogenic Effects: Pregnancy Category B

Metformin was not teratogenic in rats and rabbits at doses up to 600mg/kg/day, which represent 3 and 6times the maximum recommended human daily dose of 2000mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed.

Nursing Mothers
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin HCl Oral Solution may exist.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

Geriatric Use
Clinical studies of GLUMETZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and 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.

This drug may be known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
(SeeWARNINGS: Lactic Acidosis)

ADVERSE REACTIONS
In clinical trials conducted in the U.S., over 1000patients with type2 diabetes mellitus have been treated with GLUMETZA 1500-2000mg/day in active-controlled and placebo-controlled studies with the 500mg dosage form.

In the 24-week active-controlled monotherapy trial, serious adverse events were reported in 3.6% (19/528) of the GLUMETZA-treated patients compared to 2.9% (5/174) of the patients treated with immediate-r