Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) (pioglitazone hydrochloride and metformin hydrochloride) tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: pioglitazone hydrochloride and metformin hydrochloride. The concomitant use of pioglitazone and metformin has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on metformin. Additional efficacy and safety information about pioglitazone and metformin monotherapies may be found in the prescribing information for each individual drug.

Pioglitazone hydrochloride is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels.

Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, biguanides, or the α-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert . The structural formula is as shown:

Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of CHNOS•HCl and a molecular weight of 392.90. It is soluble in -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Metformin hydrochloride (-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white crystalline powder with a molecular formula of CHN•HCl  and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) is available as a tablet for oral administration containing 15 mg pioglitazone hydrochloride (as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone hydrochloride (as the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following excipients: povidone USP, microcrystalline cellulose NF, croscarmellose sodium NF, magnesium stearate NF, hypromellose 2910 USP, polyethylene glycol 8000 NF, titanium dioxide USP, and talc USP.

Two treatment-randomized, controlled clinical studies in patients with type 2 diabetes were conducted to evaluate the safety and efficacy of pioglitazone plus metformin. Both studies included patients receiving metformin, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. All other antihyperglycemic agents were discontinued prior to starting study treatment. In the first study, 328 patients received either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their established metformin regimen. In the second study, 827 patients received either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their established metformin regimen.

In the first study, the addition of pioglitazone 30 mg once daily to metformin treatment significantly reduced the mean A1C by 0.83% and the mean FPG by 37.7 mg/dL at Week 16 from that observed with metformin alone. In the second study, the mean reductions from Baseline at Week 24 in A1C were 0.80% and 1.01% for the 30 mg and 45 mg doses, respectively. Mean reductions from Baseline in FPG were 38.2 mg/dL and 50.7 mg/dL, respectively. Based on these reductions in A1C and FPG (), the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose.

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) is a thiazolidinedione and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and metformin or who have inadequate glycemic control on a thiazolidinedione alone or metformin alone.

Initiation of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see ).

In addition, Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) is contraindicated in patients with:

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) 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 ).

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, pioglitazone at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%).

In this study two of the 191 patients receiving 15 mg pioglitazone plus insulin (1.1%) and two of the 188 patients receiving 30 mg pioglitazone plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose-controlled study in which pioglitazone was co-administered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event.

Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin.

In type 2 diabetes and congestive heart failure (systolic dysfunction)
A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean A1C 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed.

ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation.

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)
In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg once daily, or placebo (n=2633) (see ). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebo-treated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo.

Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia
In postmarketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.

Ovulation
Hepatic Effects
During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with pioglitazone and 2 of 793 (0.25%) placebo-treated patients had ALT values ≥ 3 times the upper limit of normal. The ALT elevations in patients treated with pioglitazone were reversible and were not clearly related to therapy with pioglitazone.

In postmarketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data on pioglitazone, it is recommended that patients treated with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) undergo periodic monitoring of liver enzymes.

Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) therapy should be discontinued.

Fractures
Macrovascular Outcomes
Before initiation of therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) 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 Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) discontinued if evidence of renal impairment is present.

Hypoxic states
Surgical procedures
Alcohol intake
Impaired hepatic function
Hypoglycemia
Loss of control of blood glucose
FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) .

Liver enzyme monitoring is recommended prior to initiation of therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) in all patients and periodically thereafter per the clinical judgment of the health care professional (see   and ).

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 therapy, if this is suspected, Vitamin Bdeficiency should be excluded.

Patients should be instructed regarding the importance of adhering to dietary instructions, a regular exercise program, and regular testing of blood glucose and A1C. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.

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 Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) immediately and to promptly notify their health care professional if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) therapy; however, patients should consult with their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) .

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should immediately report these symptoms to their physician.

Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.

Patients should be informed about the importance of regular testing of renal function and hematologic parameters when receiving treatment with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) .

Therapy with a thiazolidinedione, which is the active pioglitazone component of the Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) tablet, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) . Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.

Combination antihyperglycemic therapy may cause hypoglycemia. When initiating Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) , the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients.

Patients should be told to take Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) as prescribed and instructed that any change in dosing should only be done if directed by their physician.

Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 years.

The most common adverse events reported in at least 5% of patients in the controlled 16-week clinical trial between placebo plus metformin and pioglitazone 30 mg plus metformin were upper respiratory tract infection (15.6% and 15.5%), diarrhea (6.3% and 4.8%), combined edema/peripheral edema (2.5% and 6.0%) and headache (1.9% and 6.0%), respectively.

The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus metformin and pioglitazone 45 mg plus metformin are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 7.8% and 7.7%, respectively.

Most clinical adverse events were similar between groups treated with pioglitazone in combination with metformin and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical trials between placebo and pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.

In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus metformin (see ).

In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with pioglitazone versus 1.2% of placebo-treated patients. Most of these events were considered mild or moderate in intensity (see ).

In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see ).

In controlled clinical trials of metformin at 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin Blevels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with Babsorption from the B-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin Bsupplementation (see ).

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see ).

During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.

Selecting the starting dose of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should be based on the patient's current regimen of pioglitazone and/or metformin. After initiation of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) or with dose increase, patients should be carefully monitored for adverse events related to fluid retention (see and ). Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should be given in divided daily doses with meals to reduce the gastrointestinal side effects associated with metformin.

Starting dose for patients inadequately controlled on metformin monotherapy
Based on the usual starting dose of pioglitazone (15-30 mg daily), Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) may be initiated at either the 15 mg/500 mg or 15 mg/850 mg tablet strength once or twice daily, and gradually titrated after assessing adequacy of therapeutic response.

Starting dose for patients who initially responded to pioglitazone monotherapy and require additional glycemic control
Based on the usual starting doses of metformin (500 mg twice daily or 850 mg daily), Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) may be initiated at either the 15 mg/500 mg twice daily or 15 mg/850 mg tablet strength once daily, and gradually titrated after assessing adequacy of therapeutic response.

Starting dose for patients switching from combination therapy of pioglitazone plus metformin as separate tablets
Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) may be initiated with either the 15 mg/500 mg or 15 mg/850 mg tablet strengths based on the dose of pioglitazone and metformin already being taken.

No studies have been performed specifically examining the safety and efficacy of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) in patients previously treated with other oral hypoglycemic agents and switched to Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) . Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Sufficient time should be given to assess adequacy of therapeutic response. Ideally, the response to therapy should be evaluated using A1C, which is a better indicator of long-term glycemic control than FPG alone. A1C reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) for a period of time adequate to evaluate change in A1C (8-12 weeks) unless glycemic control as measured by FPG deteriorates.

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) is not recommended for use in pregnancy or for use in pediatric patients.

The initial and maintenance dosing of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) . Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see   and ).

Therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see   and ). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) and periodically thereafter (see   and ).

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) is available in 15 mg pioglitazone hydrochloride (as the base)/500 mg metformin hydrochloride and 15 mg pioglitazone hydrochloride (as the base)/850 mg metformin hydrochloride tablets as follows:

15 mg/500 mg tablet: white to off-white, oblong, film-coated tablet with "4833M" on one side, and "15/500" on the other, available in: Bottles of 60  NDC 64764-155-60 Bottles of 180  NDC 64764-155-18

15 mg/850 mg tablet: white to off-white, oblong, film-coated tablet with "4833M" on one side, and "15/850" on the other, available in: Bottles of 60  NDC 64764-158-60 Bottles of 180  NDC 64764-158-18  

Read this Medication Guide carefully before you start taking Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) , ask your doctor or pharmacist.

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) can cause serious side effects, including

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

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 (Metformin hydrochloride; pioglitazone hydrochloride) if you:

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 (Metformin hydrochloride; pioglitazone hydrochloride) 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:

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) can have other serious side effects. See ""

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) is a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) contains 2 prescription diabetes medicines called pioglitazone hydrochloride (ACTOS) and metformin hydrochloride (GLUCOPHAGE).

Your doctor will decide if you should take Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) .

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) can be used for adults with type 2 diabetes who:

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 (Metformin hydrochloride; pioglitazone hydrochloride) .

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 treatments for type 2 diabetes and they also help your diabetes medicines work better for you.

Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) has not been studied in children and is not recommended for children under the age of 18. The risks of giving Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) to a child are not known. See ""

Do not take Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) if you:

People with severe heart failure should not start taking Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) . See "".

Before starting Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) , ask your doctor about what the choices are for diabetes medicines and what the expected benefits and possible risks are for you in particular.

Tell your doctor about all of your medical conditions, especially if you:

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) and some of your other medicines can affect each other. You may need to have your dose of Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) or certain other medicines adjusted. Certain other medicines can affect your blood sugar (glucose) control.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is okay to take Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) with other medicines.

In studies of pioglitazone (one of the medicines in Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) ), 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 (Metformin hydrochloride; pioglitazone hydrochloride) 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 (Metformin hydrochloride; pioglitazone hydrochloride) 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 (Metformin hydrochloride; pioglitazone hydrochloride) are:

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 (Metformin hydrochloride; pioglitazone hydrochloride) . 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.

Keep Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) for a condition for which it is not prescribed. Do not give Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) 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 (Metformin hydrochloride; pioglitazone hydrochloride) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) that is written for healthcare professionals. For more information, go to www.actoplusmet.com or call 1-877-825-3327.

Active Ingredients: pioglitazone hydrochloride and metformin hydrochloride

Inactive Ingredients: povidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose 2910, polyethylene glycol 8000, titanium dioxide, and talc.

Always check to make sure that the medicine you are taking is the correct one. Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) tablets look like this:

ACTOSand Actoplus met (Metformin hydrochloride; pioglitazone hydrochloride) are registered trademarks of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc.

All other trademarks are the property of their respective owners.

Distributed by: Deerfield, IL 60015

© 2009 Takeda Pharmaceuticals America, Inc.

September 2009APM0509-R1/MG

(pioglitazone HCl 15 mg andmetformin HCl 850 mg) tablets

Contains Approximately 2520 Tablets

Each film-coated tablet containspioglitazone hydrochloride equivalent to 15 mg pioglitazone and 850 mg metformin HCl. 

WARNING: Keep out of reach of children.

(pioglitazone HCl 15 mg andmetformin HCl 850 mg) tablets

Contains Approximately 720 Tablets

Each film-coated tablet containspioglitazone hydrochloride equivalent to 15 mg pioglitazone and 850 mg metformin HCl. 

WARNING: Keep out of reach of children.