METFORMIN HYDROCHLORIDE EXTENDED-RELEASE

Metformin Hydrochloride Extended-Release Tablets
• Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.
• The recommended starting dose of metformin hydrochloride extended-release tablets are 500 mg orally once daily with the evening meal.
• Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal.
• If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2000 mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride tablets at total daily doses up to 2550 mg administered in divided daily doses, as described above.
• Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily.

• Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter.
• Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m ².
• Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/ 1.73 m ² is not recommended.
• In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m ², assess the benefit risk of continuing therapy.
• Discontinue metformin hydrochloride extended- release tablets if the patient's eGFR later falls below 30 mL/minute/1.73 m ² [see Warnings and Precautions (5.1) ].

Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m ²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable.

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B ₁₂ levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B ₁₂ absorption from the B ₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B ₁₂ supplementation. Certain individuals (those with inadequate vitamin B ₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B ₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B ₁₂ at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [see Adverse Reactions (6.1) .

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets [see Drug Interactions (7) ].

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Metformin Hydrochloride Extended-Release Tablets

In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended release tablets patients, and that were more common in metformin hydrochloride extended-release tablets-than placebo-treated patients, are listed in Table 2.

Table 2: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

	Metformin Hydrochloride Extended-Release Tablets (n=781)	Placebo (n=195)
Diarrhea	10%	3%
Nausea/Vomiting	7%	2%

Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

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)].

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.

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 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 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 tablets 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 tablet 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 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 tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C _maxis 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

Subject Groups: Metformin Hydrochloride Tablets dose a (number of subjects)	C maxb (mcg/mL)	T maxc (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 doses e(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 doses e(9)	1.48 (±0.5) 1.90 (±0.62)	3.32 (±1.08) 2.01 (±1.22)	491 (±138) 550 (±160)
Elderly f, 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 g 61 to 90 mL/min) (5) Moderate (CL cr 31 to 60 mL/min) (4) Severe (CL cr 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)
aAll doses given fasting except the first 18 doses of the multiple dose studies bPeak plasma concentration cTime to peak plasma concentration dCombined results (average means) of five studies: mean age 32 years (range 23 to 59 years) eKinetic study done following dose 19, given fasting fElderly subjects, mean age 71 years (range 65 to 81 years) gCLcr = creatinine clearance normalized to body surface area of 1.73 m 2

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*	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
	AUC †	C max
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	0.9	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 (5.9) and Drug Interactions (7.2).]
Cimetidine	400 mg	850 mg	metformin	1.4	1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5.1) and Drug Interactions (7.1). ]
Topiramate	100 mg §	500 mg §	metformin	1.25 §	1.17
* 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 0-12h

Table 6: 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
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 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

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a mean baseline HbA of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg 1c once daily if at Week 12 HbA1c was ≥7.0% but <8.0% (patients with HbA ≥8.0% were discontinued from 1c the study). At the final visit (24-week), mean HbA had increased 0.2% from baseline in placebo patients 1c and decreased 0.6% with metformin hydrochloride extended-release tablets.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 10.

Table 10: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 16 Comparing Metformin Hydrochloride Extended-Release Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus

	Metformin Hydrochloride Extended-Release Tablets	Placebo
500 mg Once Daily	1000 mg Once Daily	1500 mg Once Daily	2000 mg Once Daily	1000 mg Once Daily
Hemoglobin A1 C (%) Baseline Change at FINAL VISIT p-value a	(n=115) 8.2 –0.4 <0.001	(n=115) 8.4 –0.6 <0.001	(n=111) 8.3 –0.9 <0.001	(n=125) 8.4 –0.8 <0.001	(n=112) 8.4 –1.1 <0.001	(n=111) 8.4 0.1 –
FPG (mg/dL) Baseline Change at FINAL VISIT p-value a	(n=126) 182.7 –15.2 <0.001	(n=118) 183.7 –19.3 <0.001	(n=120) 178.9 –28.5 <0.001	(n=132) 181.0 –29.9 <0.001	(n=122) 181.6 –33.6 <0.001	(n=113) 179.6 7.6 –

^aAll comparisons versus Placebo

Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the metformin hydrochloride extended-release tablets 500 mg , 1000 mg, 1500 mg, and 2000 mg once daily, 1000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively.

A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 11.

Table 11: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 24 Comparing Metformin Hydrochloride Extended-Release Tablets vs Metformin Hydrochloride Tablets in Patients with Type 2 Diabetes Mellitus

	Metformin Hydrochloride Tablets 500 mg Twice Daily	Metformin Hydrochloride Extended–Release Tablets
1000 mg Once Daily	1500 mg Once Daily
Hemoglobin A1 c (%) Baseline Change at FINAL VISIT (95% CI)	(n=67) 7.06 0.14a (-0.04, 0.31)	(n=72) 6.99 0.27 (0.11, 0.43)	(n=66) 7.02 0.13 (-0.02, 0.28)
FPG (mg/dL) Baseline Change at FINAL VISIT (95% CI)	(n=69) 127.2 14.0 (7.0, 21.0)	(n=72) 131.0 11.5 (4.4, 18.6)	(n=70) 131.4 7.6 (1.0, 14.2)

^†a n=68

Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500 mg twice daily, and metformin hydrochloride extended-release tablets 1000 mg and 1500 mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.

Table 13: Metformin Hydrochloride Extended-Release Tablets, USP Available Strengths, Units, and Appearance

Metformin Hydrochloride Extended-Release Tablets, USP
500 mg	Bottles of 1000	NDC 82009-117-10	White to off white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on other side.
750 mg	Bottles of 100	NDC 82009-118-01	White to off white uncoated modified capsule shaped tablets dedossed with “G8” on one side and plain on other side.

Store at 20° to 25°C (68° to 77°F); excursions permitted within 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

Dispense in light-resistant container.