WARNINGS

What is the most important information I should know about ACTOPLUS MET XR?

ACTOPLUS MET XR can cause serious side effects, including new or worse heart failure.

•     Pioglitazone, one of the medicines in ACTOPLUS MET XR, can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.

•     If you have severe heart failure, you cannot start ACTOPLUS MET XR.

•     If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, ACTOPLUS MET XR may not be right for you.

Call your doctor right away if you have any of the following:

•     swelling or fluid retention, especially in the ankles or legs.

•     shortness of breath or trouble breathing, especially when you lie down.

•     an unusually fast increase in weight.

•     unusual tiredness.

Metformin, one of the medicines in ACTOPLUS MET XR, 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.

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 ACTOPLUS MET XR if you:

•     have kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. People whose kidneys are not working properly should not take ACTOPLUS MET XR.

•     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.

•     are 80 years of age or older, and your kidneys are not working properly.

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 ACTOPLUS MET XR for a while if you have any of these things.

Lactic acidosis can be hard to diagnose early, because the early symptoms could seem like the symptoms of many other health problems besides lactic acidosis. You should call your doctor right away if you get the following symptoms, which could be signs of lactic acidosis:

•     You feel very weak or tired.

•     You have unusual (not normal) muscle pain.

•     You have stomach pains, nausea or vomiting.

•     You have trouble breathing.

•     You feel dizzy or lightheaded.

•     You have a slow or irregular heartbeat.

ACTOPLUS MET XR can have other serious side effects. See the section  SIDE EFFECTS below.

USES

What is ACTOPLUS MET XR?

ACTOPLUS MET XR is a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

ACTOPLUS MET XR contains 2 prescription diabetes medicines called pioglitazone hydrochloride (ACTOS) and metformin hydrochloride extended-release (FORTAMET). Your doctor will decide if you should take ACTOPLUS MET XR.

ACTOPLUS MET XR can be used for adults with type 2 diabetes who:

•     are taking pioglitazone alone and do not have good enough blood sugar control,

•     are taking metformin alone and do not have good enough blood sugar control, or

•     are already taking both pioglitazone and metformin

If you are taking pioglitazone or metformin, check with your healthcare provider and make sure you understand exactly how your healthcare provider wants you to switch over to ACTOPLUS MET XR.

It is important to eat the right foods, lose weight if needed, and exercise regularly in order to manage your type 2 diabetes. Diet, weight loss, and exercise are the main treatment for type 2 diabetes and they also help your diabetes medicines work better for you.

ACTOPLUS MET XR has not been studied in children and is not recommended for children under the age of 18. The risks of giving ACTOPLUS MET XR to a child are not known. See “What are some other possible side effects of ACTOPLUS MET XR?”

HOW TO USE

How should I take ACTOPLUS MET XR?

•     Take ACTOPLUS MET XR exactly as prescribed. Your doctor may need to change your dose of ACTOPLUS MET XR to control your blood glucose. Do not change your dose unless told to do so by your doctor.

•     Take ACTOPLUS MET XR once a day with the evening meal to lower your chance of an upset stomach.

•     Take ACTOPLUS MET XR tablets whole. Do not chew, cut, or crush the tablets. If you cannot swallow ACTOPLUS MET XR whole, tell your doctor. You may need a different medicine.

•     If you take ACTOPLUS MET XR, you may see something that looks like the ACTOPLUS MET XR tablet in your stools. This is normal.

•     If you miss a dose of ACTOPLUS MET XR, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day.

•     If you take too much ACTOPLUS MET XR, call your doctor or poison control center right away.

•     If your body is under stress, for example: due to fever, infection, trauma (such as a car accident), or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away.

•     Stay on your diet and exercise programs and test your blood sugar regularly while taking ACTOPLUS MET XR.

•     Your doctor should do blood tests before starting ACTOPLUS MET XR and from time to time to check your liver, kidneys, and blood cells.

•     Your doctor should also do regular blood tests (for example, hemoglobin A1C) to check how well your blood sugar is controlled with ACTOPLUS MET XR.

•     Your doctor should check your eyes regularly. Some people have had vision changes due to swelling in the back of the eye, called macular edema, while taking ACTOPLUS MET XR.

•      It may take 2-3 months to see the full effect on your blood sugar level.

You may need to stop ACTOPLUS MET XR for a short time. Call your doctor for instructions if you:

•     are sick with severe vomiting, diarrhea, or fever or if you drink a much lower amount of liquid than normal.

•      plan to have surgery.

•      are having an x-ray procedure with injection of dye.

What are other possible side effects of ACTOPLUS MET XR? ACTOPLUS MET XR can cause other serious side effects including:

•     Weight gain. Pioglitazone, one of the medicines in ACTOPLUS MET XR, can cause weight gain that may be due to fluid retention or extra body fat. Weight gain due to fluid retention can be a serious problem for people with certain conditions, including heart problems. See “What is the most important information I should know about ACTOPLUS MET XR?”

•     Liver problems.

It is important for your liver to be working normally when you take ACTOPLUS MET XR. Your doctor should do blood tests to check your liver before you start taking ACTOPLUS MET XR and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:

o    nausea or vomiting.

o    stomach pain.

o    unusual or unexplained tiredness.

o    loss of appetite.

o    dark urine.

o    yellowing of your skin or the whites of your eyes.

•     Macular edema   (diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes

regularly.

•     Fractures (broken bones), usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthy. It is not known if ACTOPLUS MET XR can affect the bones of children.

•     Low red blood cell count (anemia).

•     Low blood sugar (hypoglycemia).  Lightheadedness, dizziness, shakiness, or hunger may indicate that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.

•     Ovulation (release of an egg from an ovary in a woman) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take ACTOPLUS MET XR. This can increase the chance of pregnancy. See “What should I tell my doctor before taking ACTOPLUS MET XR?”

In studies of pioglitazone (one of the medicines in ACTOPLUS MET XR), bladder cancer occurred in a few more people who were taking pioglitazone than in people who were taking other diabetes medicines. There were too few cases to know if the bladder cancer was related to pioglitazone.

The most common side effects of ACTOPLUS MET XR reported in clinical trials included diarrhea, nausea, and upset stomach. These side effects usually happen during the first few weeks of treatment. Taking ACTOPLUS MET XR with meals can help lessen these side effects. However, if you have unusual or unexpected stomach problems, talk with your doctor. Stomach problems that start up later during treatment may be a sign of something more serious.

Other common side effects of ACTOPLUS MET XR:

o    cold-like symptoms (upper respiratory infection)

o    headache

o    urinary tract infection

o    dizziness

o    sinus infection

o    anemia

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of ACTOPLUS MET XR. For more information, ask your doctor or pharmacist.

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

General information about ACTOPLUS MET XR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ACTOPLUS MET XR for a condition for which it is not prescribed. Do not give ACTOPLUS MET XR to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about ACTOPLUS MET XR. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ACTOPLUS MET XR that is written for healthcare professionals. For more information, go to www.actoplusmetxr.com or call 1-877-825-3327.

What are the ingredients in ACTOPLUS MET XR?

Active Ingredients: pioglitazone hydrochloride and metformin hydrochloride

Inactive Ingredients for ACTOPLUS MET XR: candelilla wax, cellulose acetate, povidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycols (PEG 400, PEG 8000), sodium lauryl sulfate, titanium dioxide, and triacetin. Ink contains shellac, iron-oxide red (15 mg/1000 mg tablet strength), FD&C Blue No. 2 Lake (30 mg/1000 mg tablet strength), propylene glycol, and ammonium hydroxide.

OVERDOSE

If you miss a dose of ACTOPLUS MET XR, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day.

MISSED DOSE

If you take too much ACTOPLUS MET XR, call your doctor or poison control center right away. 

STORAGE

How should I store ACTOPLUS MET XR?

Store ACTOPLUS MET XR at 59-degrees to 86-degrees F (15-degrees to 30-degrees C).

Keep ACTOPLUS MET XR in the original container to protect from light.

Keep the ACTOPLUS MET XR bottle tightly closed and protect from getting wet (away from moisture and humidity).

Keep ACTOPLUS MET XR and all medicines out of the reach of children.

NOTES

Medication Guide: revision date   12/2010

Prescribing Information: revision date 12/2017

DRUG INTERACTIONS

Strong CYP2C8 Inhibitors

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t½) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone.

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ACTOPLUS MET XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs that Reduce Metformin Clearance

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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic. Consider the benefits and risks of concomitant use.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving ACTOPLUS MET XR

Insulin Secretagogues or Insulin

If hypoglycemia occurs in a patient co-administered ACTOPLUS MET XR and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered ACTOPLUS MET XR and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving ACTOPLUS MET XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ACTOPLUS MET XR, the patient should be observed closely for hypoglycemia.

Topiramate

A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate. The clinical relevance of this decrease is unknown; however, when ACTOPLUS MET XR and topiramate are used concomitantly, monitor patients for adequate glycemic control.

WARNINGS

What is the most important information I should know about ACTOPLUS MET XR?

ACTOPLUS MET XR can cause serious side effects, including new or worse heart failure.

•     Pioglitazone, one of the medicines in ACTOPLUS MET XR, can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.

•     If you have severe heart failure, you cannot start ACTOPLUS MET XR.

•     If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, ACTOPLUS MET XR may not be right for you.

Call your doctor right away if you have any of the following:

•     swelling or fluid retention, especially in the ankles or legs.

•     shortness of breath or trouble breathing, especially when you lie down.

•     an unusually fast increase in weight.

•     unusual tiredness.

Metformin, one of the medicines in ACTOPLUS MET XR, 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.

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 ACTOPLUS MET XR if you:

•     have kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. People whose kidneys are not working properly should not take ACTOPLUS MET XR.

•     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.

•     are 80 years of age or older, and your kidneys are not working properly.

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 ACTOPLUS MET XR for a while if you have any of these things.

Lactic acidosis can be hard to diagnose early, because the early symptoms could seem like the symptoms of many other health problems besides lactic acidosis. You should call your doctor right away if you get the following symptoms, which could be signs of lactic acidosis:

•     You feel very weak or tired.

•     You have unusual (not normal) muscle pain.

•     You have stomach pains, nausea or vomiting.

•     You have trouble breathing.

•     You feel dizzy or lightheaded.

•     You have a slow or irregular heartbeat.

ACTOPLUS MET XR can have other serious side effects. See the section  SIDE EFFECTS below.

USES

What is ACTOPLUS MET XR?

ACTOPLUS MET XR is a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

ACTOPLUS MET XR contains 2 prescription diabetes medicines called pioglitazone hydrochloride (ACTOS) and metformin hydrochloride extended-release (FORTAMET). Your doctor will decide if you should take ACTOPLUS MET XR.

ACTOPLUS MET XR can be used for adults with type 2 diabetes who:

•     are taking pioglitazone alone and do not have good enough blood sugar control,

•     are taking metformin alone and do not have good enough blood sugar control, or

•     are already taking both pioglitazone and metformin

If you are taking pioglitazone or metformin, check with your healthcare provider and make sure you understand exactly how your healthcare provider wants you to switch over to ACTOPLUS MET XR.

It is important to eat the right foods, lose weight if needed, and exercise regularly in order to manage your type 2 diabetes. Diet, weight loss, and exercise are the main treatment for type 2 diabetes and they also help your diabetes medicines work better for you.

ACTOPLUS MET XR has not been studied in children and is not recommended for children under the age of 18. The risks of giving ACTOPLUS MET XR to a child are not known. See “What are some other possible side effects of ACTOPLUS MET XR?”

HOW TO USE

How should I take ACTOPLUS MET XR?

•     Take ACTOPLUS MET XR exactly as prescribed. Your doctor may need to change your dose of ACTOPLUS MET XR to control your blood glucose. Do not change your dose unless told to do so by your doctor.

•     Take ACTOPLUS MET XR once a day with the evening meal to lower your chance of an upset stomach.

•     Take ACTOPLUS MET XR tablets whole. Do not chew, cut, or crush the tablets. If you cannot swallow ACTOPLUS MET XR whole, tell your doctor. You may need a different medicine.

•     If you take ACTOPLUS MET XR, you may see something that looks like the ACTOPLUS MET XR tablet in your stools. This is normal.

•     If you miss a dose of ACTOPLUS MET XR, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day.

•     If you take too much ACTOPLUS MET XR, call your doctor or poison control center right away.

•     If your body is under stress, for example: due to fever, infection, trauma (such as a car accident), or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away.

•     Stay on your diet and exercise programs and test your blood sugar regularly while taking ACTOPLUS MET XR.

•     Your doctor should do blood tests before starting ACTOPLUS MET XR and from time to time to check your liver, kidneys, and blood cells.

•     Your doctor should also do regular blood tests (for example, hemoglobin A1C) to check how well your blood sugar is controlled with ACTOPLUS MET XR.

•     Your doctor should check your eyes regularly. Some people have had vision changes due to swelling in the back of the eye, called macular edema, while taking ACTOPLUS MET XR.

•      It may take 2-3 months to see the full effect on your blood sugar level.

You may need to stop ACTOPLUS MET XR for a short time. Call your doctor for instructions if you:

•     are sick with severe vomiting, diarrhea, or fever or if you drink a much lower amount of liquid than normal.

•      plan to have surgery.

•      are having an x-ray procedure with injection of dye.