Glucophage XR Extended Release tablets, a once daily version of metformin, is available. Also, metformin is available as part of combination products with two different sulfonylureas (glyburide and glipizide), called Glucovance and Metaglip, respectively. And, on September 15, 2003, a liquid version was announced (Ranbaxy Gains FDA Approval for Commercialization of Riomet™ (Metformin HCl) Oral Solution 100 mg/mL).

As part of the approval process, Bristol-Myers Squibb Company, the pharmaceutical company that sells Glucophage in the U.S., developed a patient information insert. We include the text of the April 2003 version of the insert (below), and the original version (below).

Revised labeling for use when radiologic studies are planned "is based on the experience of leading radiologists, the short half-life of Glucophage (6 hours), and its relatively rapid clearance by the kidneys. The labeling now recommends that:

• Glucophage should be stopped at the time of or prior to the procedure.
• Glucophage should then be withheld for 48 hours after the procedure. Once renal function is found to be normal, Glucophage therapy can be started again."

PATIENT INFORMATION (Revised April 2003)

(metformin hydrochloride tablets) and

GLUCOPHAGE® XR

(metformin hydrochloride extended-release tablets)

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 GLUCOPHAGE and GLUCOPHAGE XR?

GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, 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.

GLUCOPHAGE and GLUCOPHAGE XR have the same active ingredient. However,

GLUCOPHAGE XR 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. GLUCOPHAGE and GLUCOPHAGE XR 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.

WARNING: A small number of people who have taken GLUCOPHAGE have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most people with kidney problems should not take GLUCOPHAGE or GLUCOPHAGE XR. (See "What are the side effects of GLUCOPHAGE and GLUCOPHAGE XR?")

Who should not take GLUCOPHAGE or GLUCOPHAGE XR?

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 GLUCOPHAGE or GLUCOPHAGE XR if you:

• 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. GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR be used in children?

GLUCOPHAGE has been shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. GLUCOPHAGE has not been studied in children younger than 10 years old.

GLUCOPHAGE has not been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of GLUCOPHAGE in children, talk with your doctor or other healthcare provider.

GLUCOPHAGE XR has not been studied in children.

How should I take GLUCOPHAGE or GLUCOPHAGE XR?

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 GLUCOPHAGE or GLUCOPHAGE XR with meals.

Your doctor may have you take other medicines along with GLUCOPHAGE or GLUCOPHAGE XR to control your blood sugar. These medicines may include insulin shots. Taking GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR. 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 GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE (metformin hydrochloride tablets) or GLUCOPHAGE XR (metformin hydrochloride extended-release tablets) for a short time.
• start to take other medicines or change how you take a medicine. GLUCOPHAGE and GLUCOPHAGE XR can affect how well other drugs work, and some drugs can affect how well GLUCOPHAGE and GLUCOPHAGE XR work. Some medicines may cause high blood sugar.

GLUCOPHAGE XR must be swallowed whole and never crushed or chewed. Occasionally, the inactive of GLUCOPHAGE XR 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 GLUCOPHAGE XR works to control your diabetes.

What should I avoid while taking GLUCOPHAGE or GLUCOPHAGE XR?

Do not drink a lot of alcoholic drinks while taking GLUCOPHAGE or GLUCOPHAGE XR. 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 GLUCOPHAGE and GLUCOPHAGE XR?

Lactic Acidosis. In rare cases, GLUCOPHAGE and GLUCOPHAGE XR can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This build-up can cause serious damage. Lactic acidosis caused by GLUCOPHAGE (metformin hydrochloride tablets) and GLUCOPHAGE XR (metformin hydrochloride extended release tablets) is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking GLUCOPHAGE over the course of a year.

Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it.

It is also important for your liver to be working normally when you take GLUCOPHAGE or GLUCOPHAGE XR. Your liver helps remove lactic acid from your blood.

Make sure you tell your doctor before you use GLUCOPHAGE or GLUCOPHAGE XR if you have kidney or liver problems. You should also stop using GLUCOPHAGE or GLUCOPHAGE XR and

call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital.

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 GLUCOPHAGE or GLUCOPHAGE XR and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect.

Other Side Effects. Common side effects of GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR for a condition for which it was not prescribed. Do not share your medicine with other people.

GLUCOPHAGE® is a registered trademark of Merck Santé S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.

6060DIM-14 F5-B057-04-03

Original Patient Information About Glucophage® (metformin hydrochloride tablets)

500 mg and 850 mg

WARNING: A small number of people who have taken GLUCOPHAGE have developed a serious condition called lactic acidosis. Properly functioning kidneys are needed to help prevent lactic acidosis. Most people with kidney problems should not take Glucophage. (See Question Nos. 7-11)

Q1. Why do I need to take GLUCOPHAGE?

Your doctor has prescribed GLUCOPHAGE (GLUE-coe-fahj) to treat your type II diabetes. This is also known as non-insulin-dependent diabetes mellitus (NIDDM).

Q2. What is type II diabetes?

People with diabetes are not able to make enough insulin and/or respond normally to the insulin their body does 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.

Q3. How is type II diabetes usually controlled?

High blood sugar can be lowered by diet and exercise, by a number of oral medications and by insulin injections. Before taking GLUCOPHAGE you should first try to control your diabetes by exercise and weight loss. Even if you are taking GLUCOPHAGE, you should still exercise and follow the diet recommended for your diabetes.

Q4. Does GLUCOPHAGE work differently from other glucose-control medications?

Yes it does. Until GLUCOPHAGE was introduced, all the available oral glucose-control medications were from the same chemical group called sulfonylureas. These drugs lower blood sugar primarily by causing more of the body's own insulin to be released. GLUCOPHAGE (metformin hydrochloride tablets) lowers the amount of sugar in your blood by helping your body respond better to its own insulin. GLUCOPHAGE does not cause your body to produce more insulin. Therefore, GLUCOPHAGE rarely causes hypoglycemia (low blood sugar) and it doesn't usually cause weight gain.

Q5. What happens if my blood sugar is still too high?

When blood sugar cannot be lowered enough by either GLUCOPHAGE (metformin hydrochloride tablets) or a sulfonylurea, the two medications may be effective taken together. However, if you are unable to maintain your blood sugar with diet, exercise, and glucose-control medication taken orally, then your doctor may prescribe injectable insulin to control your diabetes.

Q6. Can GLUCOPHAGE cause side effects?

GLUCOPHAGE, like all blood-sugar lowering medications, can cause side effects in some patients. Most of these side effects are minor and will go away after you've taken GLUCOPHAGE for a while. However, there are also serious, but rare side effects related to GLUCOPHAGE (see below).

Q7. What kind of side effects can GLUCOPHAGE cause?

If side effects occur, they usually occur during the first few weeks of therapy. They are normally minor ones such as diarrhea, nausea and upset stomach. Taking your GLUCOPHAGE with meals can help reduce these side effects.

Although these side effects are likely to go away, call your doctor if you have severe discomfort or if these effects last for more than a few weeks. Some patients may need to have their dose lowered or stop taking GLUCOPHAGE, either temporarily or permanently. Although these problems occur in up to one-third of patients when they first start taking GLUCOPHAGE, you should tell your doctor if the problems come back or start later on during the therapy.

About three out of one hundred people report having a temporary unpleasant or metallic taste when they start taking GLUCOPHAGE.

Q8. Are there any serious side effects that GLUCOPHAGE can cause?

GLUCOPHAGE rarely causes serious side effects. The most serious side effect that GLUCOPHAGE can cause is called lactic acidosis.

Q9. What is lactic acidosis and can it happen to me?

Lactic acidosis is caused by a buildup of lactic acid in the blood. Lactic acidosis associated with GLUCOPHAGE is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking GLUCOPHAGE over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.

It's also important for your liver to be working normally when you take GLUCOPHAGE. Your liver helps remove lactic acid from your bloodstream.

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 GLUCOPHAGE causes harm to the kidneys or liver.

Q10. Are there other risk factors for lactic acidosis?

Your risk of developing lactic acidosis from taking GLUCOPHAGE is very low as long as your kidneys and liver are healthy. However some factors can increase your risk because they can affect kidney and liver function. You should not take GLUCOPHAGE if:

• You have chronic kidney or liver problems.
• You drink alcohol excessively (all the time or short-term "binge" drinking)
• You are seriously dehydrated (have lost a large amount of body fluids)
• You are going to have certain x-ray procedures with injectable contrast agents.
• You are going to have surgery.
• You develop a serious condition such as a heart attack, severe infection, or a stroke.

Q11. What are the symptoms of lactic acidosis?

Some of the symptoms include: feeling very weak, tired or uncomfortable; unusual muscle pain, trouble breathing, unusual or unexpected stomach discomfort, feeling cold, feeling dizzy or lightheaded, or suddenly developing a slow or irregular heartbeat.

If you notice these symptoms, or if your medical condition has suddenly changed, stop taking GLUCOPHAGE and call your doctor right away. Lactic acidosis is a medical emergency that must be treated in a hospital.

Q12. What does my doctor need to know to decrease my risk of lactic acidosis?

Tell your doctor if you have an illness that results in severe vomiting, diarrhea and/or fever, or if your intake of fluids is significantly reduced. These situations can lead to severe dehydration, and it may be necessary to stop taking GLUCOPHAGE temporarily.

You should let your doctor know if your are going to have any surgery or specialized x-ray procedures that require injection of contrast agents. GLUCOPHAGE therapy will need to be stopped temporarily in such instances.

Q13. Can I take GLUCOPHAGE with other medications?

Remind your doctor that you are taking GLUCOPHAGE when any new drug is prescribed or a change is made in how you take a drug already prescribed. GLUCOPHAGE my interfere with the way some drugs work and some drugs may interfere with the action of GLUCOPHAGE.

Q14. What if I become pregnant while taking GLUCOPHAGE?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take GLUCOPHAGE during pregnancy.

Usually your doctor will prescribe insulin while you are pregnant. As with all medications, you and your doctor should discuss the use of GLUCOPHAGE if you are nursing a child.

Q15. Are there other risks associated with GLUCOPHAGE?

There is some evidence that any oral diabetes drug may increase the risk of heart problems. Experts are not sure what the real risk is for heart problems, if any, from taking oral diabetes medicine.

Q16. How do I take GLUCOPHAGE?

Your doctor will tell you how many GLUCOPHAGE tablets to take and how often. This should also be printed on the label of your prescription. You will probably be started on a low dose of GLUCOPHAGE and your dosage will be increased gradually until your blood sugar is controlled.

Q17. Where can I get more information about GLUCOPHAGE?

This leaflet is a summary of the most important information about GLUCOPHAGE. IF you have any questions or problems, you should talk to your doctor or other healthcare provider about type II diabetes as well as GLUCOPHAGE and its side effects. There is also a leaflet (package insert) written for health professional that your pharmacist can let you read.

Glucophage is a registered trademark of LIPHA s.a.
Licensed to Bristol-Myers Squibb Company.

Issued: February 1995
P8330-00 F5-B001-3-95