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These highlights do not include all the information needed to use METFORMIN HYDROCHLORIDE EXTENDED-RELEASE
TABLETS safely and effectively. See full prescribing information for METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS. METFORMIN HYDROCHLORIDE extended-release tablets, for oral use Initial U.S. Approval: 1995 · Ascend Laboratories, LLC
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin- associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1)].
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological s tudy with contrast, surgery and other procedures, hypoxic s tates (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration ( 2.3), Contraindications ( 4), Warnings and Precautions ( 5.1)].
If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1)]
Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.
Metformin hydrochloride extended-release tablets USP, 500 mg are available as:
White to off white capsule shaped, biconvex, beveled edge tablet, with occasionally mottled appearance, debossed with " [image: IMGID271] " 001" on one side and plain on other side.
Metformin hydrochloride extended-release tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m 2) [ see Warnings and Precautions ( 5.1) ].
- Hypersensitivity to metformin.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets.
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Carbonic Anhydrase Inhibitors
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Clinical
Impact:
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Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended- release tablets may increase the risk for lactic acidosis.
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Intervention:
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Consider more frequent monitoring of these patients.
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Examples:
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Topiramate, zonisamide, acetazolamide or dichlorphenamide.
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Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance
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Clinical
Impact:
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Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
[see Clinical Pharmacology (12.3)].
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Intervention:
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Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets.
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Examples:
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Ranolazine, vandetanib, dolutegravir, and cimetidine.
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Alcohol
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Clinical
Impact:
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Alcohol is known to potentiate the effect of metformin on lactate metabolism.
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Intervention:
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Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.
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Insulin Secretagogues or Insulin
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Clinical
Impact:
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Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
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Intervention:
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Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
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Drugs Affecting Glycemic Control
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Clinical
Impact:
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Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
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Intervention:
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When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.
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Examples:
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Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.
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Risk Summary
Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data].There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5 times, respectively, a 2550 mg clinical dose, based on body surface area [see Data].
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human Data
Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin- associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data
Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively.
Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Safety and effectiveness of metformin hydrochloride extended-release tablets as an adjunct to diet and exercise to improve glycemic control in pediatric patients 10 years of age and older with type 2 diabetes mellitus have been established. Use of metformin hydrochloride extended-release tablets for this indication is supported by evidence from adequate and well controlled trials of metformin hydrochloride immediate-release tablets in adults with additional data from a controlled clinical trial of metformin hydrochloride immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus.
The safety and effectiveness of metformin extended-release tablets for glycemic control in pediatric patients less than 10 years of age with type 2 diabetes mellitus have not been established.
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) ].
In the event of an overdose with metformin hydrochloride extended-release tablets, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
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.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Lactic Acidosis:
Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions ( 5.1)].
Hypoglycemia
Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions ( 5.3)].
Vitamin B 12 Deficiency:
Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.2)] .
Females of Reproductive Age:
Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations ( 8.6)].
Metformin Hydrochloride Extended-Release Tablets Administration Information:
Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Manufactured By:
Inventia Healthcare Limited
F1-F1/1-F75/1, Additional Ambernath M.I.D.C.,
Ambernath (East), Thane 421506, Maharashtra State, India
Manufactured for:
Ascend Laboratories, LLC
Bedminster, NJ 07921
PATIENT INFORMATION
Metformin hydrochloride (met-FOR-min HYE-droe-KLOR-ide) Extended-Release Tablets
Read the Patient Information that comes with metformin hydrochloride extended-release tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.
What is the most important information I should know about metformin hydrochloride extended- release tablets?
Serious s ide effects can happen in people taking metformin hydrochloride extended-release tablets, including:
Lactic Acidosis.Metformin hydrochloride, the medicine in metformin hydrochloride extended-release tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital.
Stop taking metformin hydrochloride extended-release tablets and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis:
- feel very weak and tired
- have unusual (not normal) muscle pain have trouble breathing
- have unusual sleepiness or sleep longer than usual
- have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea feel cold, especially in your arms and legs
- feel dizzy or lightheaded
- have a slow or irregular heartbeat
You have a higher chance of getting lactic acidosis if you:
- have kidney problems. People whose kidneys are not working properly should not take metformin hydrochloride extended-release tablets.
- have liver problems.
- have congestive heart failure that requires treatment with medicines. drink a lot of alcohol (very often or 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 certain x-ray tests with injectable dyes or contrast agents. have surgery.
- have a heart attack, severe infection, or stroke.
- are 80 years of age or older and have not had your kidney function tested.
What are metformin hydrochloride extended-release tablets?
- Metformin hydrochloride extended-release tablets are prescription medicines that contain metformin hydrochloride. Metformin hydrochloride extended-release tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults and children 10 years of age and older with type 2 diabetes.
- Metformin hydrochloride extended-release tablets are not for people with type 1 diabetes. Metformin hydrochloride extended-release tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).
- It is not known if metformin hydrochloride extended-release tablets are safe and effective in children under 10 years of age.
Metformin hydrochloride extended-release tablets works longer in your body. 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.
Who should not take metformin hydrochloride extended-release tablets?
Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. Most of the conditions listed below can increase your chance of getting lactic acidosis.
Do not take metformin hydrochloride extended-release tablets if you:
- have kidney problems
- are allergic to the metformin hydrochloride in metformin hydrochloride extended-release tablets or any of the ingredients in metformin hydrochloride extended-release tablets. See the end of this leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets.
- are going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and not able to eat or drink much. In these situations, metformin hydrochloride extended-release tablets will need to be stopped for a short time. Talk to your healthcare provider about when you should stop metformin hydrochloride extended-release tablets and when you should start metformin hydrochloride extended-release tablets again. See " What is the most important information I should know about metformin hydrochloride extended-release tablets? "
What should I tell my healthcare provider before taking metformin hydrochloride extended- release tablets?
- Before taking metformin hydrochloride extended-release tablets, tell your healthcare provider if you: have type 1 diabetes. Metformin hydrochloride extended-release tablets should not be used to treat people with type 1 diabetes.
- have a history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). Metformin hydrochloride extended-release tablets should not be used for the
- treatment of diabetic ketoacidosis. have kidney problems.
- have liver problems.
- have heart problems, including congestive heart failure.
- are older than 80 years. If you are over 80 years old you should not take metformin hydrochloride extended-release tablets unless your kidneys have been checked and they are normal.
- drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking. are taking insulin.
- have any other medical conditions.
- are pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended- release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.
- are breast-feeding or plan to breast-feed. It is not known if metformin hydrochloride passes into
- your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take metformin hydrochloride extended-release tablets.
Tell your healthcare provider about all the medicines you take,including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
- Metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended-release tablets works.
Can metformin hydrochloride e x t e nd e d - r e l e a s e tablets be used in children?Metformin hydrochloride extended-release tablets has not been studied in children. How should I take metformin hydrochloride extended-release tablets?
- Take metformin hydrochloride extended-release tablets exactly as your healthcare provider tells you.
- Metformin hydrochloride extended-release tablets should be taken with meals to help lessen an upset stomach side effect.
- Swallow metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew metformin hydrochloride extended-release tablets.
- You may sometimes pass a soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended-release tablets. This is not harmful and will not affect the way metformin hydrochloride extended-release tablets works to control your diabetes.
- When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems.
- Your healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended-release tablets.
- Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.
- Follow your healthcare provider's instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is a problem for you. See " What are the possible s ide effects of metformin hydrochloride extended-release tablets? "Check your blood sugar as your healthcare provider tells you to.
- Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended- release tablets.
- If you miss a dose of metformin hydrochloride extended-release tablets, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take an extra dose the next day.
- If you take too much metformin hydrochloride extended-release tablets, call your healthcare
- provider, local Poison Control Center, or go to the nearest hospital emergency room right away.
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 s ide 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 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
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.
How should I s tore metformin hydrochloride extended-release tablets?
Store metformin hydrochloride extended-release tablets at 680 to 770F (200 to 250C).
Keep metformin hydrochloride extended-release tablets and all medicines out of the reach of children.
General information about the use of metformin hydrochloride extended-release tablets
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.
For more information, call Ascend Laboratories, LLC at 1-877-ASCRX01 (877-272-7901).
What are the ingredients of metformin hydrochloride extended-release tablets?
Active ingredients of metformin hydrochloride extended-release tablets: metformin hydrochloride.
Inactive ingredients in each tablet of metformin hydrochloride extended-release tablets, 500 mg: carboxymethylcellulose sodium, hypromellose and magnesium stearate.
What is type 2 diabetes?
Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that
your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.
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, and by certain medicines when necessary.
Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.
The brands listed are trademarks of their respective owners.
Manufactured By:
Inventia Healthcare Limited
F1-F1/1-F75/1, Additional Ambernath M.I.D.C.,
Ambernath (East), Thane 421506, Maharashtra State, India
Manufactured for:
Ascend Laboratories, LLC
Bedminster, NJ 07921.
Revision Date: 07/2026
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:
[image: MM1]Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4H 11N 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 aof metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Metformin hydrochloride extended-release tablets, USP contains 500 mg of metformin hydrochloride, which is equivalent to 389.93 mg metformin base.
Metformin hydrochloride extended-release tablets USP, 500 mg contain the inactive ingredients carboxymethylcellulose sodium, hypromellose and magnesium stearate.
Metformin Hydrochloride Extended-Release Tablets, USP meets USP Dissolution Test 3
[image: MM2]
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Metformin Hydrochloride Extended-Release Tablets, USP
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| 500 mg
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Bottles of 100
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NDC 67877-159-01
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White to off white capsule shaped, biconvex, beveled edge tablet, with occasionally mottled appearance,
debossed with " [image: IMGID1091]001" on one side and plain on other side. |
| Bottles of 500
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NDC 67877-159-05
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| Bottles of 1000
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NDC 67877-159-10
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What it looks like
Photos of the product and/or packaging supplied by the manufacturer.
Package codes (NDC)
- 67877-159-01
- 67877-159-05
- 67877-159-10
Full prescribing information (for healthcare professionals)
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 extended-release 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride extended-release tablets 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 extended-release tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.
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 of metformin hydrochloride extended-release 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 tablets increased by approximately 50% when given with food, there was no effect of food on C maxand T maxof 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
Patients With 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 ( 2.4), Contraindications (4), Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.6) ].
Patients With 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) ] .
Geriatric Patients
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) ].
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aAll doses given fasting except the first 18 doses of the multiple dose studies |
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bPeak plasma concentration |
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cTime to peak plasma concentration |
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dCombined results (average means) of five studies: mean age 32 years (range 23 to 59 years) |
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eKinetic study done following dose 19, given fasting |
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fElderly subjects, mean age 71 years (range 65 to 81 years) |
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gCLcr = creatinine clearance normalized to body surface area of 1.73 m 2 |
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| Subject Groups: Metformin Hydrochloride Tablets dose a(number of subjects) | C max b(mcg/mL) |
T max
c
(hrs) |
Renal Clearance (mL/min) |
| Healthy, nondiabetic adults: |
1.03 (±0.33) |
2.75 (±0.81) |
600 (±132) |
| 500 mg single dose (24) | |||
| 850 mg single dose (74) d | 1.60 (±0.38) | 2.64 (±0.82) | 552 (±139) |
| 850 mg three times daily for 19 doses e | 2.01 (±0.42) | 1.79 (±0.94) | 642 (±173) |
| (9) | |||
| Adults with type 2 diabetes mellitus: |
1.48 (±0.5) |
3.32 (±1.08) |
491 (±138) |
| 850 mg single dose (23) | |||
| 850 mg three times daily for 19 doses e | 1.90 (±0.62) | 2.01 (±1.22) | 550 (±160) |
| (9) | |||
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Elderly
f, healthy nondiabetic adults:
850 mg single dose (12) |
2.45 (±0.70) |
2.71 (±1.05) |
412 (±98) |
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Renal-impaired adults: 850 mg single
dose |
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Mild(CLcr
g61 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) |
P e d i a t r i c Patients
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 patients (12 to 16 years of age) with type 2 diabetes mellitus and sex and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.
Sex
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to sex (males=19, females=16).
Race
No studies of metformin pharmacokinetic parameters according to race have been performed.
Drug Interaction Studies
In Vivo Assessment of Drug Interactions
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Coadministered Drug |
Dose of Coadministered Drug |
Dose of Metformin |
Geometric Mean Ratio
(ratio with/without coadministered drug) No Effect = 1.00 |
||
| AUC |
C
m a x |
||||
| 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 |
|
Coadministered Drug |
Dose of Coadministered Drug |
Dose of Metformin |
Geometric
Mean
Ratio
(ratio
with/without metformin)
No Effect = 1.00 |
||
| AUC | C m a x | ||||
| 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 |
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 vitrotests: Ames test ( S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivomouse 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.