Metformin Hydrochloride Information
Metformin hydrochloride (Metformin hydrochloride)
Metformin hydrochloride (Metformin hydrochloride) Description
Metformin hydrochloride (Metformin hydrochloride) Tablets, USP and Metformin hydrochloride (Metformin hydrochloride) Extended-Release Tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (Metformin hydrochloride) (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
Metformin hydrochloride (Metformin hydrochloride) is a white to off-white crystalline compound with a molecular formula of CHN•HCI and a molecular weight of 165.63. Metformin hydrochloride (Metformin hydrochloride) is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of Metformin hydrochloride (Metformin hydrochloride) is 6.68.
Each Metformin hydrochloride (Metformin hydrochloride) Tablet, for oral administration, contains 500 mg, 850 mg or 1000 mg of Metformin hydrochloride (Metformin hydrochloride) . In addition, each film-coated tablet also contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol and titanium dioxide.
Each 500 mg Metformin hydrochloride (Metformin hydrochloride) Extended-Release Tablet, for oral administration, contains 500 mg of Metformin hydrochloride (Metformin hydrochloride) . In addition, each 500 mg tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate and methylcellulose.
Each 750 mg Metformin hydrochloride (Metformin hydrochloride) Extended-Release Tablet, for oral administration, contains 750 mg of Metformin hydrochloride (Metformin hydrochloride) . In addition, each 750 mg tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose and magnesium stearate.
Metformin Extended-Release Tablets meet USP Dissolution Test 6.
Metformin hydrochloride (Metformin hydrochloride) Indications And Usage
Metformin hydrochloride (Metformin hydrochloride) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
Metformin hydrochloride (Metformin hydrochloride) extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Metformin hydrochloride (Metformin hydrochloride) Contraindications
Metformin hydrochloride (Metformin hydrochloride) and Metformin hydrochloride (Metformin hydrochloride) extended-release tablets are contraindicated in patients with:
Metformin hydrochloride (Metformin hydrochloride) and Metformin hydrochloride (Metformin hydrochloride) extended-release tablets should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also .)
Metformin hydrochloride (Metformin hydrochloride) Precautions
Macrovascular outcomes:
Before initiation of metformin therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and metformin discontinued if evidence of renal impairment is present.
Hypoxic states:
Surgical procedures:
Alcohol intake:
Impaired hepatic function:
Certain individuals (those with inadequate vitamin B or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B levels. In these patients, routine serum vitamin B measurements at two- to three-year intervals may be useful.
Hypoglycemia:
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Loss of control of blood glucose:
The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either metformin or sulfonylurea monotherapy, combined therapy with metformin and sulfonylurea may result in a response. Should secondary failure occur with combined metformin/ sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.
Patients should be informed of the potential risks and benefits of metformin and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the and sections, should be explained to patients. Patients should be advised to discontinue metformin immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving metformin.
Metformin alone does not usually cause hypoglycemia, although it may occur when metformin is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)
Patients should be informed that Metformin hydrochloride (Metformin hydrochloride) extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also ).
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin hydrochloride (Metformin hydrochloride) tablets therapy, if this is suspected, vitamin B12 deficiency should be excluded.
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 four times the maximum recommended human daily dose of 2000 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 tests: Ames test (), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the 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 three times the maximum recommended human daily dose based on body surface area comparisons.
The safety and effectiveness of Metformin hydrochloride (Metformin hydrochloride) tablets for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin hydrochloride (Metformin hydrochloride) tablets in this age group is supported by evidence from adequate and well-controlled studies of Metformin hydrochloride (Metformin hydrochloride) tablets in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults (see ). In this study, adverse effects were similar to those described in adults (see ). A maximum daily dose of 2000 mg is recommended (see ).
Safety and effectiveness of Metformin hydrochloride (Metformin hydrochloride) extended-release tablets in pediatric patients have not been established.
Metformin hydrochloride (Metformin hydrochloride) Adverse Reactions
In a U.S. double-blind clinical study of Metformin hydrochloride (Metformin hydrochloride) tablets in patients with type 2 diabetes, a total of 141 patients received Metformin hydrochloride (Metformin hydrochloride) tablet therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin- than placebo-treated patients, are listed in Table 11.
Diarrhea led to discontinuation of study medication in 6% of patients treated with Metformin hydrochloride (Metformin hydrochloride) tablets. Additionally, the following adverse reactions were reported in ≥1 - ≤5% of Metformin hydrochloride (Metformin hydrochloride) tablet patients and were more commonly reported with Metformin hydrochloride (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 (Metformin hydrochloride) extended-release tablets in placebo and active-controlled studies. In placebo-controlled trials, 781 patients were administered Metformin hydrochloride (Metformin hydrochloride) extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin hydrochloride (Metformin hydrochloride) extended-release tablet patients, and that were more common in Metformin hydrochloride (Metformin hydrochloride) extended-release tablet- than placebo-treated patients, are listed in Table 12.
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Metformin hydrochloride (Metformin hydrochloride) extended-release tablets. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of Metformin hydrochloride (Metformin hydrochloride) extended-release tablet patients and were more commonly reported with Metformin hydrochloride (Metformin hydrochloride) extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Metformin hydrochloride (Metformin hydrochloride) Overdosage
Overdose of Metformin hydrochloride (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 (Metformin hydrochloride) has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see ). 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.
Metformin hydrochloride (Metformin hydrochloride) Dosage And Administration
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin or any other pharmacologic agent. Dosage of metformin 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 (Metformin hydrochloride) tablets is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age); the maximum recommended daily dose of Metformin hydrochloride (Metformin hydrochloride) extended-release tablets in adults is 2000 mg.
Metformin hydrochloride (Metformin hydrochloride) tablets should be given in divided doses with meals while Metformin hydrochloride (Metformin hydrochloride) extended release tablets should generally be given once daily with the evening meal. Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets 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 ), fasting plasma glucose should be used to determine the therapeutic response to Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months.
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 may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Metformin hydrochloride (Metformin hydrochloride) How Supplied
Metformin hydrochloride (Metformin hydrochloride) Tablets, USP 500 mg are available for oral administration as white to off-white, capsule shaped, unscored, film-coated tablets, imprinted “APO 500” on one side and “MET” on the other side. They are supplied as follows:
Bottles of 100 (NDC 60505-0190-0)Bottles of 500 (NDC 60505-0190-1)Bottles of 1,000 (NDC 60505-0190-8)Bottles of 4,500 (NDC 60505-0190-4)
Metformin hydrochloride (Metformin hydrochloride) Tablets, USP 850 mg are available for oral administration as white to off-white, capsule shaped, unscored, film-coated tablets, imprinted “APO 850” on one side and plain on the other side. They are supplied as follows:
Bottles of 100 (NDC 60505-0191-0)Bottles of 500 (NDC 60505-0191-1)Bottles of 1,000 (NDC 60505-0191-8)Bottles of 2,500 (NDC 60505-0191-4)
Metformin hydrochloride (Metformin hydrochloride) Tablets, USP 1000 mg are available for oral administration as white to off-white, oval, scored, film-coated tablets, imprinted “APO 1000” on one side and plain with a full bisect on the other side. They are supplied as follows:
Bottles of 100 (NDC 60505-0192-0)Bottles of 500 (NDC 60505-0192-1)Bottles of 1,000 (NDC 60505-0192-8)Bottles of 2,000 (NDC 60505-0192-4)
Metformin hydrochloride (Metformin hydrochloride) Extended-Release Tablets, USP 500 mg are available for oral administration as white to off-white, capsule shaped, unscored tablets, imprinted “APO” on one side and “XR500” on the other side. They are supplied as follows:
Bottles of 100 (NDC 60505-0260-1)Bottles of 500 (NDC 60505-0260-2)Bottles of 2500 (NDC 60505-0260-7)
Metformin hydrochloride (Metformin hydrochloride) Extended-Release Tablets, USP 750 mg are available for oral administration as white to off-white, capsule shaped, unscored tablets, imprinted “APO” on one side and “XR750” on the other side. They are supplied as follows:
Bottles of 30 (NDC 60505-1329-3)Bottles of 100 (NDC 60505-1329-1)Bottles of 500 (NDC 60505-1329-5)
Metformin hydrochloride (Metformin hydrochloride) Patient Information
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.
Metformin hydrochloride (Metformin hydrochloride) tablets and Metformin hydrochloride (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 (Metformin hydrochloride) tablets or Metformin hydrochloride (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 (Metformin hydrochloride) tablets and Metformin hydrochloride (Metformin hydrochloride) extended release tablets have the same active ingredient. However, Metformin hydrochloride (Metformin hydrochloride) extended release tablets work 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 (Metformin hydrochloride) tablets and Metformin hydrochloride (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 does 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.
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.
• have kidney problems • have liver problems • have heart failure that is treated with medicines, such as Lanoxin® (digoxin) or Lasix® (furosemide) • drink a lot of alcohol. This means you binge drink for short periods or drink all the time • are seriously dehydrated (have lost a lot of water from your body) • are going to have an x-ray procedure with injection of dyes (contrast agents) • are going to have surgery • develop a serious condition, such as heart attack, severe infection, or a stroke • are 80 years or older and you have NOT had your kidney function tested
Tell your doctor if you are pregnant or plan to become pregnant. Metformin hydrochloride (Metformin hydrochloride) tablets and Metformin hydrochloride (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.
Metformin hydrochloride (Metformin hydrochloride) tablets have been shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. Metformin hydrochloride (Metformin hydrochloride) tablets have not been studied in children younger than 10 years old. Metformin hydrochloride (Metformin hydrochloride) tablets have not been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of Metformin hydrochloride (Metformin hydrochloride) tablets in children, talk with your doctor or other healthcare provider.
Metformin hydrochloride (Metformin hydrochloride) extended-release tablets have not been studied in children.
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 (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets with meals.
Your doctor may have you take other medicines along with Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets to control your blood sugar. These medicines may include insulin shots. Taking Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (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 (Metformin hydrochloride) tablets or Metformin hydrochloride (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 (Metformin hydrochloride) tablets or Metformin hydrochloride (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 (Metformin hydrochloride) tablets or Metformin hydrochloride (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 (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets for a short time. • start to take other medicines or change how you take a medicine. Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets can affect how well other drugs work, and some drugs can affect how well Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets work. Some medicines may cause high blood sugar.
Occasionally, the inactive ingredients of Metformin hydrochloride (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 (Metformin hydrochloride) extended-release tablets work to control your diabetes.
Do not drink a lot of alcoholic drinks while taking Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (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.
It is also important for your liver to be working normally when you take Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets Your liver helps remove lactic acid from your blood.
Make sure you tell your doctor before you use Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets if you have kidney or liver problems. You should also
Signs of lactic acidosis are: • feeling very weak, tired, or uncomfortable • unusual muscle pain • trouble breathing • unusual or unexpected stomach discomfort • feeling cold • feeling dizzy or lightheaded • suddenly developing a slow or irregular heartbeat
If your medical condition suddenly changes, stop taking Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect.
About 3 out of every 100 people who take Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.
Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets rarely cause hypoglycemia (low blood sugar) by itself. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.
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 (Metformin hydrochloride) tablets and Metformin hydrochloride (Metformin hydrochloride) extended release tablets that is written for health care professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Metformin hydrochloride (Metformin hydrochloride) tablets or Metformin hydrochloride (Metformin hydrochloride) extended release tablets for a condition for which they were not prescribed. Do not share your medicine with other people.
Manufactured by: Manufactured for:
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, Florida
Canada M9L 1T9 33326
Revised: January 2011
Rev. 6
Metformin hydrochloride (Metformin hydrochloride)
Metformin hydrochloride (Metformin hydrochloride)
Metformin hydrochloride (Metformin hydrochloride)
Metformin hydrochloride (Metformin hydrochloride)
Metformin hydrochloride (Metformin hydrochloride)
