Metformin Hydrochloride Extended-Release Tablets 500 mg and 750 mg

DESCRIPTION

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displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Metformin Hydrochloride Extended-Release Tablets, USP Metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride, USP (N,N-dimethyl-monohydrochloride,Imidodicarbonimidic diamide) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

Metformin hydrochloride, USP is a white or almost white, crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in Methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.35.

Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride as the active ingredient.

Metformin hydrochloride extended-release tablets, USP 500 mg and 750 mg tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone.

Dissolution Method: Test 10

System Components and Performance – Metformin hydrochloride extended-release tablets, USP comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride, USP is combined with a drug release controlling polymer to form an “inner” phase, which is then incorporated as discrete particles into an “external” phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.

INDICATIONS & USAGE

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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Metformin hydrochloride extended-release tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

CONTRAINDICATIONS

id: 67e94bca-dc15-e996-e053-2991aa0a6b6d
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Metformin hydrochloride extended-release tablets, USP are contraindicated in patients with: 1. Severe Renal Impairment (eGFR below 30mL/min/1.73m2) (see
WARNINGS and
PRECAUTIONS ). 2.Known hypersensitivity to metformin hydrochloride, USP. 3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

WARNINGS

id: 67e94bca-dc16-e996-e053-2991aa0a6b6d
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

LACTIC ACIDOSIS:

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 evidenceof ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see
PRECAUTIONS
).

Risk factors for metformin associated lactic acidosis include renal impairment, concamitent use of certain drugs (e.g carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (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 ,
CONTRAINDICATIONS , AND
PRECAUTIONS ).

If metformin associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extend release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see
PRECAUTIONS ).

ADVERSE REACTIONS

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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

In a US double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablets therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablets patients, and that were more common in metformin hydrochloride tablets – than placebo-treated patients, are listed in
Table 6.                                                       

Table 6:	Most Common Adverse Reactions (>5 Percent) in a Placebo- Controlled Clinical Study of Metformin Hydrochloride Tablets Monotherapy*
	Metformin Hydrochloride Tablets	Placebo
Adverse Reaction	(n=141)	(n=145)
	% of Patients
Diarrhea	53.2	11.7
Nausea/Vomiting	25.5	8.3
Flatulence	12.1	5.5
Asthenia	9.2	5.5
Indigestion	7.1	4.1
Abdominal Discomfort	6.4	4.8
Headache	5.7	4.8

* Reactions that were more common in metformin hydrochloride tablets-than placebo-treated patients. Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥1 -≤5% of metformin hydrochloride tablets patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. 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 7.                           

Table  7: Most  C om mon  Adv erse  Reactions  (>5   P er c e n t)  in   Pl a c e b o- Controlled Studies of Metformin Hydrochloride Extended-Release Tablets*
	Metformin Hydrochloride Extended-Release Tablets ( N= 781)	Placebo   N=195
Adverse Reaction	% of Patients
Diarrhea	9.6	2.6
Nausea/Vomiting	6.5	1.5

* Reactions that were more common in metformin hydrochloride extended-release tablets- than placebo-treated patients.  Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in ≥1% to ≤5% 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.

OVERDOSAGE

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displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

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 hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see
WARNINGS ). 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.

DOSAGE & ADMINISTRATION

id: 67e94bca-dc23-e996-e053-2991aa0a6b6d
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride extended-release tablets, USP or any other pharmacologic agent. Dosage of metformin hydrochloride extended-release tablets, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin hydrochloride extended-release tablets, USP in adults is 2000 mg. Metformin hydrochloride extended-release tablets, USP should generally be given once daily with the evening meal. Metformin hydrochloride extended-release tablets, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin hydrochloride extended-release tablets, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months.
The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin hydrochloride extended-release tablets, USP either  when used as monotherapy or in combination with sulfonylurea or insulin. Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication,   and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Short-term administration of metformin hydrochloride extended-release tablets, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Metformin hydrochloride extended-release tablets, USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets, USP will be eliminated in the feces as a soft, hydrated mass. (See Patient Informationprinted below.)

HOW SUPPLIED

id: 67e94bca-dc2a-e996-e053-2991aa0a6b6d
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Metformin Hydrochloride Extended-Release Tablets, USP 500 mg              Bottles of    30               NDC 62207-491-54 500 mg              Bottles of   1000            NDC 62207-491-49 750 mg              Bottles of   30                NDC 62207-492-54 750 mg              Bottles of  1000              NDC 62207-492-49 Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side. Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side.

Storage
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 containers.

Manufactured by: Granules India Limited Hyderabad-500 081, India

Manufactured for: Granules USA, Inc. Parsipanny, NJ 07054 Toll-free: 1-877-770-3183

Revision date:
May 2017

SPL PATIENT PACKAGE INSERT

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displayName: SPL PATIENT PACKAGE INSERT SECTION
FDA Article Code: 42230-3

Patient Information

Metformin Hydrochloride Extended-Release Tablets, USP

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.

Metformin hydrochloride and Metformin hydrochloride extended-release tablets have the same active ingredient. However, metformin hydrochloride extended-release tablets works longer in your body. Both of these medicines help 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 has 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 causes 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 works 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. Distributed by:

Granules India Limited

Hyderabad-500 081, India

Revision Date:  May 2017

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

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FDA Article Code: 51945-4