metformin er 500mg

Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

Following a single oral dose of metformin hydrochloride extended-release tablet, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours.

At steady state, the AUC and Cmax are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/mL for 500 mg, 1000 mg, 1500 mg, 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.

Within-subject variability in Cmax and AUC of metformin from metformin hydrochloride extended-release tablets is comparable to that with metformin hydrochloride tablets.

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 Cmax and Tmax 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, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism and Elimination

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. Renal clearance (see Table 1) 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.

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

The pharmacokinetics of metformin hydrochloride extended-release tablets in patients with type 2 diabetes are comparable to those in healthy normal adults.

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 1; also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS).

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 Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1; also see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

*
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
CL cr = creatinine clearance normalized to body surface area of 1.73 m 2

Subject Groups: Metformin Hydrochloride Tablets dose*(number of subjects)
Cmax†
(mcg/mL)
Tmax‡
(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)§ 1.6 (±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:



850 mg single dose (23)
1.48 (±0.5)
3.32 (±1.08)
491 (±138)
850 mg three times daily for 19 doses¶ (9)
1.9 (±0.62)
2.01 (±1.22)
550 (±160)
Elderly#, healthy nondiabetic adults:



850 mg single dose (12)
2.45 (±0.7)
2.71 (±1.05)
412 (±98)
Renal-impaired adults:



850 mg single dose



Mild (CLcrÞ 61 to 90 mL/min) (5)
1.86 (±0.52)
3.2 (±0.45)
384 (±122)
Moderate (CLcr 31 to 60 mL/min) (4)
4.12 (±1.83)
3.75 (±0.5)
108 (±57)
Severe (CLcr 10 to 30 mL/min) (6)
3.93 (±0.92)
4.01 (±1.1)
130 (±90)

Pediatrics

No pharmacokinetic data from studies of pediatric patients are currently available

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride tablets in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies

METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS

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 who had failed to achieve glycemic control with diet and exercise (HbA1c 7% to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin hydrochloride extended-release tablets 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7% but <8% (patients with HbA1c ≥8% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients 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 who had failed to achieve glycemic control with diet and exercise (HbA1c 7% to 11%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 2.

Table 2: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study)

*
All patients on diet therapy at Baseline
†
All comparisons versus Placebo
‡
Not statistically significant

Metformin Hydrochloride Extended-Release Tablets

Placebo

500 mg
Once
Daily
1000 mg
Once
Daily
1500 mg
Once
Daily
2000 mg
Once
Daily
1000 mg
Twice
Daily
Hemoglobin A1c (%)
Baseline
Change at FINAL VISIT
p–value†
(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†
(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
-29.9
<0.001
(n=122)
181.6
-33.6
<0.001
(n = 113)
179.6
7.6
-
Body Weight (lbs)
Baseline
Change at FINAL VISIT
p–value†
(n = 125)
192.9
-1.3
NS‡
(n = 119)
191.8
-1.3
NS‡
(n = 117)
188.3
-0.7
NS‡
(n = 131)
195.4
-1.5
NS‡
(n =119)
192.5
-2.2
NS‡
(n = 113)
194.3
-1.8
-

Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin hydrochloride extended-release tablets).

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 who had been treated with metformin hydrochloride tablets, 500 mg twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablets dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 3.

Table 3: Summary of Mean Changes from Baseline in HbA1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study)

Metformin Hydrochloride Extended-Release Tablets
1000 mg
Once Daily
1500 mg
Once Daily
Hemoglobin A1c (%)
(n = 72)
(n = 66)
Baseline
6.99
7.02
Change at 12 Weeks
0.23
0.04
(95% CI)
(0.1, 0.36)
(-0.08, 0.15)
Change at FINAL VISIT
0.27
0.13
(95% CI)
(0.11, 0.43)
(-0.02, 0.28)
FPG (mg/dL)
(n = 72)
(n = 70)
Baseline
131
131.4
Change at 12 Weeks
9.5
3.7
(95% CI)
(4.4, 14.6)
(-0.4, 7.8)
Change at FINAL VISIT
11.5
7.6
(95% CI)
(4.4, 18.6)
(1, 14.2)
Body Weight (lbs)
(n = 74)
(n = 71)
Baseline
202.8
192.7
Change at 12 Weeks
0.9
0.7
(95% CI)
(0, 2)
(-0.4, 1.8)
Change at FINAL VISIT
1.1
0.9
(95% CI)
(-0.2, 2.4)
(-0.4, 2)

After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the metformin hydrochloride extended-release tablets 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).

Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended-release tablets are shown in Table 4.

Table 4: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study)

Metformin Hydrochloride Extended-Release Tablets

500 mg
Once
Daily
1000 mg
Once
Daily
1500 mg
Once
Daily
2000 mg
Once
Daily
1000 mg
Twice
Daily
Placebo
Total Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 120)
210.3
1%
(n = 113)
218.1
1.7%
(n = 110)
214.6
0.7%
(n = 126)
204.4
- 1.6%
(n = 117)
208.2
- 2.6%
(n = 110)
208.6
2.6%
Total Triglycerides (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 120)
220.2
14.5%
(n = 113)
211.9
9.4%
(n = 110)
198
15.1%
(n = 126)
194.2
14.9%
(n = 117)
179
9.4%
(n = 110)
211.7
10.9%
LDL–Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 119)
131
-1.4%
(n = 113)
134.9
-1.6%
(n = 109)
135.8
-3.5%
(n = 126)
125.8
-3.3%
(n = 117)
131.4
-5.5%
(n = 107)
131.9
3.2%
HDL–Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 120)
40.8
6.2%
(n = 108)
41.6
8.6%
(n = 108)
40.6
5.5%
(n = 125)
40.2
6.1%
(n = 117)
42.4
7.1%
(n = 108)
39.4
5.8%

Changes in lipid parameters in the previously described study of metformin hydrochloride extended-release tablets are shown in Table 5.

Table 5: Summary of Mean Percent Changes from Baseline in Major Lipid Variables at Final Visit (24-week study)

Metformin Hydrochloride Extended-Release Tablets
1000 mg
Once Daily
1500 mg
Once Daily
Total Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 70)
201.9
1.3%
(n = 66)
201.6
0.1%
Total Triglycerides (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 70)
169.2
25.3%
(n = 66)
206.8
33.4%
LDL–Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 70)
126.2
-3.3%
(n = 66)
115.7
-3.7%
HDL–Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
(n = 70)
41.7
1%
(n = 65)
44.6
-2.1%

Metformin Hydrochloride Extended-Release Tablets, USP

(met-FOR-min HYE-droe-KLOR-ide)

Read this information carefully before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of your doctor's advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.

What are Metformin Hydrochloride Extended-Release Tablets?

Metformin hydrochloride extended-release tablets are used to treat type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take metformin hydrochloride extended-release tablets, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness.

This medicine helps control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin hydrochloride extended-release tablets do not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain.

Tell your doctor if you are pregnant or plan to become pregnant. Metformin hydrochloride extended-release tablets may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child.

Can Metformin Hydrochloride Extended-Release Tablets be used in children?

Metformin hydrochloride extended-release tablets have not been studied in children.

How should I take Metformin Hydrochloride Extended-Release Tablets?

Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metformin hydrochloride extended-release tablets with meals.

Your doctor may have you take other medicines along with metformin hydrochloride extended-release tablets to control your blood sugar. These medicines may include insulin shots. Taking metformin hydrochloride extended-release tablets with insulin may help you better control your blood sugar while reducing the insulin dose.

Continue your exercise and diet program and test your blood sugar regularly while taking metformin hydrochloride extended-release tablets. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that metformin hydrochloride extended-release tablets cause harm to the liver or kidneys.

Tell your doctor if you:

have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking metformin hydrochloride extended-release tablets for a short time.
plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin hydrochloride extended-release tablets for a short time.
start to take other medicines or change how you take a medicine. Metformin hydrochloride extended-release tablets can affect how well other drugs work, and some drugs can affect how well metformin hydrochloride extended-release tablets work. Some medicines may cause high blood sugar.

Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way metformin hydrochloride extended-release tablets work to control your diabetes.

What should I avoid while taking Metformin Hydrochloride Extended-Release Tablets?

Do not drink a lot of alcoholic drinks while taking metformin hydrochloride extended-release tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.

What are the side effects of Metformin Hydrochloride Extended-Release Tablets?

Lactic acidosis. Metformin, the active ingredient in metformin hydrochloride extended-release tablets, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

you feel cold in your hands or feet
you feel dizzy or lightheaded
you have a slow or irregular heartbeat
you feel very weak or tired
you have unusual (not normal) muscle pain
you have trouble breathing
you feel sleepy or drowsy
you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with metformin hydrochloride extended-release tablets if you:

have severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye
have liver problems
drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking
get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids
have surgery
have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your metformin hydrochloride extended-release tablets for a while if you have any of these things.

Other Side Effects. Common side effects of metformin hydrochloride extended-release tablets include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they've gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good.

About 3 out of every 100 people who take metformin hydrochloride extended-release tablets have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

Metformin hydrochloride extended-release tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.

General advice about prescription medicines

If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin hydrochloride extended-release tablets that is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not share your medicine with other people.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

* All trademark names are the property of their respective owners.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Industries Limited

Halol-Baroda Highway,

Halol-389 350, Gujarat, India.

PJPI0125D

ISS. 06/2017