Drugs Details

Drugs Info of Actoplus Met, Actoplus Met XR
Drugs Details
  • Drugs Type  : FDA
  • Date : 16th Mar 2015 05:26 am
  • Brand Name :  Actoplus Met, Actoplus Met XR
  • Generic Name : metformin and pioglitazone (Pronunciation: met FOR min and PYE o GLI ta zone)
Descriptions

ACTOPLUS MET® (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 in vivo. The structural formula is as shown:

 

Pioglitazone hydrochloride Structural Formula Illustration

Pioglitazone hydrochloride

Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90. It is soluble in N,N­ dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Metformin hydrochloride (N,N -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 C4H11N5•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:

 

Metformin hydrochloride Structural Formula Illustration

Metformin hydrochloride

ACTOPLUS MET 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.

What are the possible side effects of metformin and pioglitazone (Actoplus Met, Actoplus Met XR)?

This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or irregular heart rate, dizziness, or feeling very weak or tired.

Get emergency medical help if you have any of these signs of an allergic reaction: hives;...

Read All Potential Side Effects and See Pictures of Actoplus MET, Actoplus MET XR »

What are the precautions when taking pioglitazone hcl and metformin hcl (Actoplus MET, Actoplus MET XR)?

See also Warning section.

Before taking this medication, tell your doctor or pharmacist if you are allergic to pioglitazone or metformin; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: severe breathing problems (such as obstructive lung disease, severe asthma), blood problems (such as anemia, vitamin B12 deficiency), kidney disease, liver disease, heart disease (such as congestive heart failure, chest pain), fluid in your lungs, swelling (edema), a certain eye problem (macular edema), bladder cancer.

Before having surgery or any...

Read All Potential Precautions of Actoplus MET, Actoplus MET XR »


This monograph has been modified to include the generic and brand name in many instances.

Indications

ACTOPLUS MET 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.

Dosage Administration

General

The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and metformin 2550 mg.

Dosage Recommendations

Selecting the starting dose of ACTOPLUS MET should be based on the patient's current regimen of pioglitazone and/or metformin. After initiation of ACTOPLUS MET or with dose increase, patients should be carefully monitored for adverse events related to fluid retention (see BOXED WARNING and WARNINGS, Pioglitazone hydrochloride). ACTOPLUS MET 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 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 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 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 in patients previously treated with other oral hypoglycemic agents and switched to ACTOPLUS MET. 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 for a period of time adequate to evaluate change in A1C (8-12 weeks) unless glycemic control as measured by FPG deteriorates.

Special Patient Populations

ACTOPLUS MET is not recommended for use in pregnancy or for use in pediatric patients.

The initial and maintenance dosing of ACTOPLUS MET 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. Monitoring of renal function is necessary to aid in prevention of metformin­associated lactic acidosis, particularly in the elderly (see WARNINGS, Metformin hydrochloride and PRECAUTIONS, General: Metformin hydrochloride).

Therapy with ACTOPLUS MET 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 PRECAUTIONS, General: Pioglitazone hydrochloride and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOPLUS MET and periodically thereafter (see PRECAUTIONS, General: Pioglitazone hydrochloride and PRECAUTIONS, Laboratory Tests).

Maximum Recommended Dose

ACTOPLUS MET tablets are available as a 15 mg pioglitazone plus 500 mg metformin or a 15 mg pioglitazone plus 850 mg metformin formulation for oral administration. The maximum recommended dose for pioglitazone is 45 mg daily. The maximum recommended daily dose for metformin is 2550 mg in adults.

How Supplied

ACTOPLUS MET 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

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity.

Distributed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015. July 2011


This monograph has been modified to include the generic and brand name in many instances.

Side Effects

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.

Table 4: Adverse Events That Occurred in ≥ 5% of Patients in Any Treatment Group During the 24-Week Study

Adverse Event
Preferred Term
Pioglitazone 30 mg + metformin
N=411 n (%)
Pioglitazone 45 mg + metformin
N=416 n (%)
Upper Respiratory Tract Infection 51 (12.4) 56 (13.5)
Diarrhea 24 (5.8) 20 (4.8)
Nausea 24 (5.8) 15 (3.6)
Headache 19 (4.6) 22 (5.3)
Urinary Tract Infection 24 (5.8) 22 (5.3)
Sinusitis 18 (4.4) 21 (5.0)
Dizziness 22 (5.4) 20 (4.8)
Edema Lower Limb 12 (2.9) 47 (11.3)
Weight Increased 12 (2.9) 28 (6.7)

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 PRECAUTIONS, General: Pioglitazone hydrochloride).

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 PRECAUTIONS, General: Pioglitazone hydrochloride).

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 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.

Table 5: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

Cardiovascular Events Placebo
N=2633
ACTOS
N=2605
First Events (N) Total events (N) First Events (N) Total events (N)
Any event 572 900 514 803
All-cause mortality 122 186 110 177
Non-fatal MI 118 157 105 131
Stroke 96 119 76 92
ACS 63 78 42 65
Cardiac intervention 101 240 101 195
(Major leg amputation 15 28 9 28
Leg revascularization 57 92 71 115

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General: Pioglitazone hydrochloride).

Laboratory Abnormalities

Hematologic: Pioglitazone may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with pioglitazone appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and have rarely been associated with any significant hematologic clinical effects (see PRECAUTIONS, General: Pioglitazone hydrochloride).

In controlled clinical trials of metformin at 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation (see PRECAUTIONS, General: Metformin hydrochloride).

Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with pioglitazone had ALT values ≥ 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with pioglitazone were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

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

CPK Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive pioglitazone, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

Read the Actoplus MET, Actoplus MET XR (pioglitazone hcl and metformin hcl) Side Effects Center for a complete guide to possible side effects

Interactions

Pioglitazone hydrochloride

In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP450 isoform 3A4 substrate.

An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions, Pioglitazone hydrochloride).

Metformin hydrochloride

Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co­administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single-and multiple-dose, metformin-cimetidine drug interaction studies with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of ACTOPLUS MET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving ACTOPLUS MET, the patient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol and probenecid.

Read the Actoplus MET, Actoplus MET XR Drug Interactions Center for a complete guide to possible interactions

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This monograph has been modified to include the generic and brand name in many instances.

Warnings

Metformin hydrochloride

Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with ACTOPLUS MET (pioglitazone hydrochloride and metformin hydrochloride) tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see PRECAUTIONS, General: Metformin hydrochloride).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see PRECAUTIONS, General: Metformin hydrochloride). Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling (see PRECAUTIONS, General: Metformin hydrochloride).

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see CONTRAINDICATIONS and PRECAUTIONS, General: Metformin hydrochloride).

Pioglitazone hydrochloride

Cardiac Failure and Other Cardiac Effects: Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antihyperglycemic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered. Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and pioglitazone is not recommended in these patients (see BOXED WARNING and CONTRAINDICATIONS).

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 ADVERSE REACTIONS). 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.

 

Precautions

General

Pioglitazone hydrochloride

Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOPLUS MET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with pioglitazone as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with pioglitazone in combination with insulin (see WARNINGS, Pioglitazone hydrochloride). Patients with NYHA Class III and IV cardiac status were not studied in pre-approval pioglitazone clinical trials. Pioglitazone is not indicated in patients with NYHA Class III or IV cardiac status.

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

Edema: In all U.S. clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOPLUS MET should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see BOXED WARNING, WARNINGS, Pioglitazone hydrochloride, and PATIENT INFORMATION).

Weight Gain: Dose related weight gain was observed with pioglitazone alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 3: Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with Pioglitazone

View Enlarged Table

Urinary Bladder Tumors: Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study (see Carcinogenesis, Mutagenesis and Impairment of Fertility, Pioglitazone hydrochloride). In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a non­significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure, a duration of ACTOS therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking ACTOS longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without ACTOS] to approximately 10 in 10,000 [with ACTOS]).

There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOPLUS MET should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS MET should be considered in patients with a prior history of bladder cancer.

Ovulation: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. Thus, adequate contraception in premenopausal women should be recommended while taking ACTOPLUS MET. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.

Hematologic: Across all clinical studies with pioglitazone, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). ACTOPLUS MET may cause decreases in hemoglobin and hematocrit.

Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with pioglitazone. In U.S. clinical studies, over 4700 patients with type 2 diabetes received pioglitazone. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.

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 undergo periodic monitoring of liver enzymes.

Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOPLUS MET 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 should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Therapy with ACTOPLUS MET 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 should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOPLUS MET 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 therapy should be discontinued.

Macular Edema: Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings (see ADVERSE REACTIONS).

Fractures: In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOPLUS MET or any other anti-diabetic drug.

General

Metformin hydrochloride

Monitoring of renal function: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive ACTOPLUS MET. In patients with advanced age, ACTOPLUS MET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be monitored regularly and, generally, ACTOPLUS MET should not be titrated to the maximum dose of the metformin component (see WARNINGS, Metformin hydrochloride and DOSAGE AND ADMINISTRATION).

Before initiation of therapy with ACTOPLUS MET 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 discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: DRUG INTERACTIONS, Metformin hydrochloride), should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials): Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, ACTOPLUS MET should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving ACTOPLUS MET therapy, the drug should be promptly discontinued.

Surgical procedures: Use of ACTOPLUS MET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving ACTOPLUS MET.

Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, ACTOPLUS MET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels: In controlled clinical trials of metformin at 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on ACTOPLUS MET and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS, General: Metformin hydrochloride and Laboratory Tests). Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two-to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes: A patient with type 2 diabetes previously well-controlled on ACTOPLUS MET who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, ACTOPLUS MET must be stopped immediately and other appropriate corrective measures initiated (see WARNINGS, Metformin hydrochloride).

Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas or insulin) or ethanol. 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: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold ACTOPLUS MET and temporarily administer insulin. ACTOPLUS MET may be reinstituted after the acute episode is resolved.

Laboratory Tests

FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to ACTOPLUS MET.

Liver enzyme monitoring is recommended prior to initiation of therapy with ACTOPLUS MET in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General: Pioglitazone hydrochloride and ADVERSE REACTIONS, Serum Transaminase Levels).

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 B12 deficiency should be excluded.

Information for Patients

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 WARNINGS, Metformin hydrochloride and PRECAUTIONS, General: Metformin hydrochloride sections, should be explained to patients. Patients should be advised to discontinue ACTOPLUS MET 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 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.

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 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.

Therapy with a thiazolidinedione, which is the active pioglitazone component of the ACTOPLUS MET 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. 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, 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 promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Patients should be told to take ACTOPLUS MET as prescribed and instructed that any change in dosing should only be done if directed by their physician.

Carcinogenesis, Mutagenesis, Impairment of Fertility

ACTOPLUS MET

No animal studies have been conducted with ACTOPLUS MET. The following data are based on findings in studies performed with pioglitazone or metformin individually.

Pioglitazone hydrochloride

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ.

Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCl daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²).

Metformin hydrochloride

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 a human daily dose of 2000 mg of the metformin component of ACTOPLUS MET 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 mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo 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 of the metformin component of ACTOPLUS MET based on body surface area comparisons.

Animal Toxicology

Pioglitazone hydrochloride

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with the pioglitazone HCl component of ACTOPLUS MET (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m²). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²).

Pregnancy

Pregnancy Category C

ACTOPLUS MET

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. ACTOPLUS MET should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women with ACTOPLUS MET or its individual components. No animal studies have been conducted with the combined products in ACTOPLUS MET. The following data are based on findings in studies performed with pioglitazone or metformin individually.

Pioglitazone hydrochloride

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²).

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times a human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

No studies have been conducted with the combined components of ACTOPLUS MET. In studies performed with the individual components, both pioglitazone and metformin are secreted in the milk of lactating rats. It is not known whether pioglitazone and/or metformin is secreted in human milk. Because many drugs are excreted in human milk, ACTOPLUS MET should not be administered to a breastfeeding woman. If ACTOPLUS MET is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness of ACTOPLUS MET in pediatric patients have not been established.

Elderly Use

Pioglitazone hydrochloride

Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, ACTOPLUS MET should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, Metformin hydrochloride and CLINICAL PHARMACOLOGY, Special Populations). Because aging is associated with reduced renal function, ACTOPLUS MET should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of ACTOPLUS MET (see WARNINGS, Metformin hydrochloride and DOSAGE AND ADMINISTRATION).


This monograph has been modified to include the generic and brand name in many instances.

OverDose

Pioglitazone hydrochloride

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.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS, Metformin hydrochloride). 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 metformin from patients in whom metformin overdosage is suspected.

ContrainDications

Initiation of ACTOPLUS MET in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING).

In addition, ACTOPLUS MET is contraindicated in patients with:

  1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS, Metformin hydrochloride and PRECAUTIONS, General: Metformin hydrochloride).
  2. Known hypersensitivity to pioglitazone, metformin or any other component of ACTOPLUS MET.
  3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

ACTOPLUS MET 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 PRECAUTIONS, General: Metformin hydrochloride).


This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism of Action

ACTOPLUS MET

ACTOPLUS MET combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone hydrochloride, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone hydrochloride

Pioglitazone depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Metformin hydrochloride

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS, General: Metformin hydrochloride) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics and Drug Metabolism

Absorption and Bioavailability

ACTOPLUS MET

In bioequivalence studies of ACTOPLUS MET 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to ACTOS® 15 mg concomitantly administered with Glucophage® (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects (Table 1).

Table 1: Mean (SD) Pharmacokinetic Parameters for ACTOPLUS MET®

View Enlarged Table

Administration of ACTOPLUS MET 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant.

Pioglitazone hydrochloride

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% -60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration, a 25% lower AUC in plasma concentration versus time curve, and a 35 minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Pioglitazone hydrochloride

The mean apparent volume of distribution (V/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound ( > 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound ( > 98%) to serum albumin.

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 -48 hours and are generally < 1 μg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

Metabolism, Elimination and Excretion

Pioglitazone hydrochloride

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see PRECAUTIONS: DRUG INTERACTIONS, Pioglitazone hydrochloride). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Metformin hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Insufficiency

Pioglitazone hydrochloride

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects.

Metformin hydrochloride

In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see CONTRAINDICATIONS and WARNINGS, Metformin hydrochloride, also see GLUCOPHAGE® prescribing information, CLINICAL PHARMACOLOGY, Pharmacokinetics). Since metformin is contraindicated in patients with renal impairment, ACTOPLUS MET is also contraindicated in these patients.

Hepatic Insufficiency

Pioglitazone hydrochloride

Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

Therapy with ACTOPLUS MET should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, General: Pioglitazone hydrochloride).

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

Elderly

Pioglitazone hydrochloride

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see GLUCOPHAGE® prescribing information, CLINICAL PHARMACOLOGY, Special Populations, Geriatrics).

ACTOPLUS MET treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS, Metformin hydrochloride and DOSAGE AND ADMINISTRATION; also see GLUCOPHAGE® prescribing information).

Pediatrics

Pioglitazone hydrochloride

Pharmacokinetic data in the pediatric population are not available.

Metformin hydrochloride

After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender-and weight-matched healthy adults (20 to 45 years of age), and all with normal renal function.

Gender

Pioglitazone hydrochloride

As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean Cmax and AUC values were increased 20% to 60% in females. In controlled clinical trials, hemoglobin A1C (A1C) decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Ethnicity

Pioglitazone hydrochloride

Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug-Drug Interactions

Co-administration of a single dose of metformin (1000 mg) and pioglitazone after 7 days of pioglitazone (45 mg) did not alter the pharmacokinetics of the single dose of metformin. Specific pharmacokinetic drug interaction studies with ACTOPLUS MET have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

Pioglitazone hydrochloride

The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed below:

Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.

Nifedipine ER: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 -0.95) for Cmax and 0.88 (0.80 -0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

Ketoconazole: Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 -1.23) for Cmax, 1.34 (1.26 -1.41) for AUC and 1.87 (1.71 -2.04) for Cmin.

Atorvastatin Calcium: Co-administration of pioglitazone for 7 days with atorvastatin calcium (LIPITOR®) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57 -0.85) for Cmax, 0.76 (0.65 -0.88) for AUC and 0.96 (0.87 -1.05) for Cmin. For unchanged atorvastatin the ratio of least square mean (90% CI) values were 0.77 (0.66 -0.90) for Cmax, 0.86 (0.78 -0.94) for AUC and 0.92 (0.82 -1.02) for Cmin.

Cytochrome P450: See PRECAUTIONS: DRUG INTERACTIONS, Pioglitazone hydrochloride

Gemfibrozil: Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see PRECAUTIONS: DRUG INTERACTIONS, Pioglitazone hydrochloride).1

Rifampin: Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see PRECAUTIONS: DRUG INTERACTIONS, Pioglitazone hydrochloride).2

In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine HCl or theophylline.

Metformin hydrochloride

See PRECAUTIONS: DRUG INTERACTIONS, Metformin hydrochloride

Pharmacodynamics and Clinical Effects

Pioglitazone hydrochloride

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin levels, and lower A1C values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least one year. In controlled clinical studies, pioglitazone in combination with metformin had an additive effect on glycemic control.

Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16-week and 24-week combination therapy studies of pioglitazone with metformin.

Clinical Studies

There have been no clinical efficacy studies conducted with ACTOPLUS MET. However, the efficacy and safety of the separate components have been previously established and the co­administration of the separate components has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in patients with inadequately controlled type 2 diabetes while on metformin therapy. Bioequivalence of ACTOPLUS MET with co-administered pioglitazone and metformin tablets was demonstrated for both ACTOPLUS MET strengths (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism).

Clinical Trials of Pioglitazone Add-on Therapy in Patients Not Adequately Controlled on Metformin

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 (Table 2), the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose.

Table 2: Glycemic Parameters in 16-Week and 24-Week Pioglitazone Hydrochloride + Metformin Hydrochloride Combination Studies

Parameter Placebo + metformin Pioglitazone 30 mg + metformin
16-Week Study    
A1C (%) N=153 N=161
  Baseline mean 9.77 9.92
  Mean change from Baseline at 16 Weeks 0.19 -0.64* , †
  Difference in change from placebo + metformin   -0.83
Responder rate (%)a 21.6 54.0
FPG (mg/dL) N=157 N=165
  Baseline mean 259.9 254.4
  Mean change from Baseline at 16 Weeks -5.2 -42.8* , †
  Difference in change from placebo +metformin   -37.7
Responder rate (%)b 23.6 59.4
Parameter Pioglitazone 30 mg + metformin Pioglitazone 45 mg + metformin
24-Week Study
A1C (%) N=400 N=398
  Baseline mean 9.88 9.81
  Mean Change from Baseline at 24 Weeks -0.80* -1.01*
Responder rate (%)a 55.8 63.3
FPG (mg/dL) N=398 N=399
  Baseline mean 232.5 232.1
  Mean Change from Baseline at 24 Weeks -38.2* -50.7* , ‡
  Responder rate (%)b  52.3 63.7
* significant change from Baseline p ≤ 0.050.
† significant difference from placebo plus metformin, p ≤ 0.050.
‡ significant difference from 30 mg pioglitazone, p ≤ 0.050.
a patients who achieved an A1C ≤ 6.1% or ≥ 0.6% decrease from Baseline.
b patients who achieved a decrease in FPG by ≥ 30 mg/dL.

REFERENCES

1. Deng, LJ, et al. Effect of gemfibrozil on the pharmacokinetics of pioglitazone. Eur J Clin Pharmacol 2005; 61: 831-836, Table 1.

2. Jaakkola, T, et al. Effect of rifampicin on the pharmacokinetics of pioglitazone. Brit J Clin Pharmacol 2006; 61:1 70-78.


This monograph has been modified to include the generic and brand name in many instances.

Patient Information

MEDICATION GUIDE

ACTOPLUS MET
(ak-TO-plus-met)
(pioglitazone hydrochloride and metformin hydrochloride) tablets

Read this Medication Guide carefully before you start taking ACTOPLUS MET 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, ask your doctor or pharmacist.

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

ACTOPLUS MET can cause serious side effects, including:

  • New or worse heart failure. Pioglitazone, one of the medicines in ACTOPLUS MET, 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.
    • Do not take ACTOPLUS MET if you have severe heart failure
    • If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, ACTOPLUS MET 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
  • Lactic Acidosis. Metformin, one of the medicines in ACTOPLUS MET, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.
  • Call your doctor right away if you have any of the following symptoms which could be signs of lactic acidosis:
    • you feel 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

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 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
  • 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 have not had your kidneys tested

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 for a while if you have any of these things.

ACTOPLUS MET can have other serious side effects. See “What are the possible side effects of ACTOPLUS MET?”

What is ACTOPLUS MET?

ACTOPLUS MET contains 2 prescription diabetes medicines called pioglitazone hydrochloride (ACTOS) and metformin hydrochloride (GLUCOPHAGE). ACTOPLUS MET can be used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

ACTOPLUS MET is not for people with type 1 diabetes

ACTOPLUS MET is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

It is not known if ACTOPLUS MET is safe and effective in children.

Who should not take ACTOPLUS MET?

See “What is the most important information I should know about ACTOPLUS MET?”

Do not take ACTOPLUS MET if you:

  • . have severe heart failure
  • . are allergic to pioglitazone, metformin or any of the ingredients in ACTOPLUS MET. See the end of this Medication Guide for a complete list of ingredients in ACTOPLUS MET
  • . have kidneys which are not working properly
  • . have a condition called metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin

Tell your doctor before taking ACTOPLUS MET if you have any of these conditions.

What should I tell my doctor before taking ACTOPLUS MET?

Before you start taking ACTOPLUS MET, tell your doctor if you:

  • have heart failure
  • have kidney problems
  • are going to have dye injected into a vein for an x-ray, CAT scan, heart study, or other type of scanning
  • will be undergoing a surgical procedure
  • drink a lot of alcohol (all the time or short binge drinking)
  • have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis
  • have a type of diabetic eye disease that causes swelling in the back of the eye (macular edema)
  • have liver problems
  • are pregnant or plan to become pregnant. It is not known if ACTOPLUS MET will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant
  • are a premenopausal woman (before the “change of life”), who does not have periods regularly or at all. ACTOPLUS MET may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking ACTOPLUS MET. Tell your doctor right away if you become pregnant while taking ACTOPLUS MET
  • are breast-feeding or plan to breast-feed. It is not known if ACTOPLUS MET passes into your breast milk. You and your doctor should decide if you will take ACTOPLUS MET or breastfeed. You should not do both. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements.

ACTOPLUS MET and some of your other medicines can affect each other. You may need to have your dose of ACTOPLUS MET or certain other medicines changed.

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 with other medicines.

How should I take ACTOPLUS MET?

  • Take ACTOPLUS MET exactly as your doctor tells you to take it.
  • Your doctor may need to change your dose of ACTOPLUS MET. Do not change your ACTOPLUS MET dose unless your doctor tells you to
  • ACTOPLUS MET may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled
  • Take ACTOPLUS MET with meals to lower your chance of an upset stomach
  • If you miss a dose of ACTOPLUS MET, 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, call your doctor or go to the nearest hospital emergency room right away
  • If your body is under stress such as from a fever, infection, 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
  • Your doctor should do certain blood tests before you start and while you take ACTOPLUS MET
  • Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with ACTOPLUS MET
  • Your doctor should check your eyes regularly while you take ACTOPLUS MET

What are the possible side effects of ACTOPLUS MET?

ACTOPLUS MET may cause serious side effects including:

  • See “What is the most important information I should know about ACTOPLUS MET?”
  • liver problems. Call your doctor right away if you have:
    • nausea or vomiting
    • stomach pain
    • unusual or unexplained tiredness
    • loss of appetite
    • dark urine
    • yellowing of your skin or the whites of your eyes
  • broken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthy
  • bladder cancer. There may be an increased chance of having bladder cancer when you take ACTOPLUS MET. You should not take ACTOPLUS MET if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer:
    • blood or a red color in your urine
    • an increased need to urinate
    • pain while you urinate
  • low blood sugar (hypoglycemia). This can happen if you skip meals, if you also use another medicine that lowers blood sugar, or if you have certain medical problems. Lightheadedness, dizziness, shakiness, or hunger may happen if your blood sugar is too low. Call your doctor if low blood sugar levels are a problem for you
  • diabetic eye disease with swelling in the back of the eye (macular edema). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly
  • release of an egg from an ovary in a woman (ovulation) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take ACTOPLUS MET. This can increase your chance of getting pregnant.
  • low red blood cell count (anemia).

The most common side effects of ACTOPLUS MET include:

  • cold-like symptoms (upper respiratory tract infection)
  • swelling (edema)
  • diarrhea
  • headache
  • increased weight

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. 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.

How should I store ACTOPLUS MET?

  • Store ACTOPLUS MET at 59°F to 86°F (15°C to 30°C). Keep ACTOPLUS MET in the original container and protect from light.
  • Keep the ACTOPLUS MET bottle tightly closed and protect from getting wet (away from moisture and humidity).

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

General information about the safe and effective use of ACTOPLUS MET

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ACTOPLUS MET for a condition for which it was not prescribed. Do not give ACTOPLUS MET 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ACTOPLUS MET that is written for healthcare professionals.

For more information, go to www.actoplusmet.com or call 1-877-825-3327.

What are the ingredients in ACTOPLUS MET?

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

This Medication Guide has been approved by the U.S. Food and Drug Administration.


This monograph has been modified to include the generic and brand name in many instances.

 

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

PIOGLITAZONE/METFORMIN - ORAL

 

(PYE-oh-GLI-ta-zone/met-FOR-min)

 

COMMON BRAND NAME(S): Actoplus Met

 

WARNING: Pioglitazone may infrequently cause or worsen a certain heart problem (congestive heart failure). Tell your doctor right away if you notice any symptoms of heart failure, including swelling of the hands/feet, unusual/sudden weight gain, trouble breathing, or unusual tiredness.

Metformin can rarely cause a serious (sometimes fatal) condition called lactic acidosis. Get medical help right away if you develop any of the following symptoms of lactic acidosis: unusual tiredness, dizziness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, stomach pain with nausea, vomiting, or diarrhea.

Lactic acidosis is more likely to occur in patients who have certain medical conditions, including kidney or liver disease, recent surgery, a serious infection, conditions that may cause a low level of oxygen in the blood or poor circulation (such as congestive heart failure, recent heart attack, recent stroke), heavy alcohol use, a severe loss of body fluids (dehydration), or X-ray or scanning procedures that require an injectable iodinated contrast drug. Tell your doctor immediately if any of these conditions occur or if you notice a big change in your overall health. You may need to stop taking this medication temporarily. The elderly are also at higher risk, especially those older than 80 years who have not had kidney tests. (See also Side Effects and Precautions sections.)

 

USES: This combination medication is used along with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.

Pioglitazone belongs to a class of drugs known as thiazolidinediones or "glitazones". Metformin and pioglitazone work by helping to restore your body's proper response to the insulin you naturally produce. Metformin also decreases the amount of sugar that your liver makes and that your stomach/intestines absorb.

Talk to your doctor about the risks and benefits of using pioglitazone-containing products.

 

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking pioglitazone/metformin and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth as directed by your doctor, usually once or twice daily with meals to decrease stomach upset. Drink plenty of fluids while taking this medication unless otherwise directed by your doctor.

The dosage is based on your medical condition, kidney function, and response to treatment. Your doctor may direct you to take a low dose of this medication at first, gradually increasing your dose to lower the chance of side effects such as upset stomach. Your doctor will adjust your dose based on your blood sugar levels to find the best dose for you. Follow your doctor's directions carefully. The maximum recommended dose is 45 milligrams of pioglitazone or 2250 milligrams of metformin per day.

Take this medication regularly in order to get the most benefit from it. Remember to use it at the same time(s) each day.

If you are already taking another anti-diabetic drug, follow your doctor's directions carefully for stopping/continuing the old drug and starting this medication.

Check your blood sugar regularly as directed by your doctor. Keep track of the results, and share them with your doctor. Tell your doctor if your blood sugar measurements are too high or too low. Your dosage/treatment may need to be changed. It may take up to 2 to 3 months before the full benefit of this drug takes effect.

Consumer Overview Side Effect

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, stomach upset, diarrhea, weakness, sore throat, muscle pain, weight gain, tooth problems or a metallic taste in the mouth may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. If stomach symptoms return later (after taking the same dose for several days or weeks), tell your doctor immediately. Stomach symptoms that occur after the first days of your treatment may be signs of lactic acidosis.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if either of these serious side effects occurs: new/worsening vision problems (such as blurred vision), bone fracture, reddish-colored urine, urgent need to urinate, pain while urinating.

Pioglitazone may rarely cause liver disease. Tell your doctor right away if you develop symptoms of liver disease, including: dark urine, yellowing of eyes/skin, persistent nausea/vomiting, stomach/abdominal pain.

This medication usually does not cause low blood sugar (hypoglycemia). Low blood sugar may occur if this drug is prescribed with other anti-diabetic medications (such as insulin or a sulfonylurea). Low blood sugar is more likely if you drink large amounts of alcohol, do unusually heavy exercise, or do not consume enough calories from food. To help prevent low blood sugar, eat meals on a regular schedule, and do not skip meals. Check with your doctor or pharmacist to find out what you should do if you miss a meal.

Symptoms of low blood sugar include sudden sweating, shaking, fast heartbeat, hunger, blurred vision, dizziness, or tingling hands/feet. It is a good habit to carry glucose tablets or gel to treat low blood sugar. If you don't have these reliable forms of glucose, rapidly raise your blood sugar by eating a quick source of sugar such as table sugar, honey, or candy, or drink fruit juice or non-diet soda. Tell your doctor right away about the reaction and the use of this product.

Symptoms of high blood sugar (hyperglycemia) include thirst, increased urination, confusion, drowsiness, flushing, rapid breathing, or fruity breath odor. If these symptoms occur, tell your doctor right away. Your dosage may need to be increased.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

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

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Actoplus MET, Actoplus MET XR (pioglitazone hcl and metformin hcl) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: See also Warning section.

Before taking this medication, tell your doctor or pharmacist if you are allergic to pioglitazone or metformin; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: severe breathing problems (such as obstructive lung disease, severe asthma), blood problems (such as anemia, vitamin B12 deficiency), kidney disease, liver disease, heart disease (such as congestive heart failure, chest pain), fluid in your lungs, swelling (edema), a certain eye problem (macular edema), bladder cancer.

Before having surgery or any X-ray/scanning procedure using injectable iodinated contrast material, tell your doctor that you are taking this medication. You will need to temporarily stop this medication before the time of your surgery/procedure. Consult your doctor for further instructions.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

You may experience blurred vision, dizziness, or drowsiness due to extremely low or high blood sugar levels. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely.

Limit alcohol while using this medication because it can increase your risk of lactic acidosis and developing low blood sugar.

High fever, "water pills" (diuretics such as hydrochlorothiazide), too much sweating, diarrhea, or vomiting may cause loss of too much body water (dehydration) and increase your risk of lactic acidosis. Stop taking this medication and tell your doctor right away if you have prolonged diarrhea or vomiting. Be sure to drink enough fluids to prevent dehydration unless your doctor directs you otherwise.

It may be harder to control your blood sugar when your body is stressed (such as due to fever, infection, injury, or surgery). Consult your doctor because increased stress may require a change in your treatment plan, medications, or blood sugar testing.

Pioglitazone may increase the risk of bone fracture in women (usually in the upper arm, hand, or foot). See also Notes section.

Older adults may be at greater risk for side effects such as low blood sugar or lactic acidosis.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Your doctor may direct you to use insulin instead of this product during your pregnancy. Follow your doctor's instructions carefully.

This medication can cause changes in the menstrual cycle (promote ovulation) and increase the risk of becoming pregnant. Consult your doctor or pharmacist about the use of reliable birth control while using this medication.

Metformin passes into breast milk in small amounts. It is unknown if pioglitazone passes into breast milk. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Other medications can affect the removal of pioglitazone from your body, which may affect how pioglitazone works. Examples include gemfibrozil, rifamycins including rifampin, among others.

Beta-blocker medications (such as metoprolol, propranolol, glaucoma eye drops such as timolol) may prevent the fast/pounding heartbeat you would usually feel when your blood sugar level falls too low (hypoglycemia). Other symptoms of low blood sugar, such as dizziness, hunger, or sweating, are unaffected by these drugs.

Many drugs can affect your blood sugar levels, making it more difficult to control your blood sugar. Before you start, stop, or change any medication, talk with your doctor or pharmacist about how the medication may affect your blood sugar. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor about the results and of any symptoms of high or low blood sugar. (See also Side Effects section.) Your doctor may need to adjust your anti-diabetic medication, exercise program, or diet.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Overdose can cause lactic acidosis. Symptoms of overdose may include: severe drowsiness, severe nausea/vomiting/diarrhea, rapid breathing, slow/irregular heartbeat.

 

NOTES: Do not share this medication with others.

You should attend a diabetes education program to learn more about diabetes and all the important aspects of its treatment, including meals/diet, exercise, personal hygiene, medications, and getting regular eye/foot/medical exams.

Lifestyle changes that help promote healthy bones include increasing weight-bearing exercise, eating well-balanced meals containing adequate calcium and vitamin D, stopping smoking, and limiting alcohol. Consult your doctor to see if you need to take calcium/vitamin D supplements and discuss lifestyle changes that might benefit you.

Keep all medical appointments. Laboratory and/or medical tests (such as kidney/liver function tests, blood glucose, hemoglobin A1c, complete blood counts, eye exams) should be performed periodically to check for side effects and monitor your response to treatment. Check your blood sugar levels regularly as directed.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

 

Information last revised March 2014. Copyright(c) 2014 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Actoplus Met, Actoplus Met XR

Generic Name: metformin and pioglitazone (Pronunciation: met FOR min and PYE o GLI ta zone)

  • What is metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • What are the possible side effects of metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • What is the most important information I should know about metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • What should I discuss with my healthcare provider before taking metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • How should I take metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • What happens if I miss a dose (Actoplus MET, Actoplus MET XR)?
  • What happens if I overdose (Actoplus MET, Actoplus MET XR)?
  • What should I avoid while taking metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • What other drugs will affect metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?
  • Where can I get more information?

What is metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

Metformin and pioglitazone is a combination of two oral diabetes medicines that help control blood sugar levels.

Metformin and pioglitazone is for people with type 2 diabetes who do not use daily insulin injections. This medication is not for treating type 1 diabetes.

Metformin and pioglitazone may also be used for purposes not listed in this medication guide.

Actoplus Met 15-500 mg

oval, white, imprinted with 4833M, 15/500

What are the possible side effects of metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or irregular heart rate, dizziness, or feeling very weak or tired.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any other serious side effects, such as:

  • stomach pain, blood in your urine, painful urination;
  • feeling short of breath, especially when lying down;
  • swelling or rapid weight gain;
  • pale skin, feeling light-headed, rapid heart rate, trouble concentrating;
  • sudden unusual pain in your hand, arm, or foot; or
  • nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

  • headache;
  • diarrhea, upset stomach; or
  • sneezing, runny nose, cough or other signs of a cold.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Actoplus MET, Actoplus MET XR (pioglitazone hcl and metformin hcl) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

You should not use this medication if you are allergic to metformin (Glucophage) or pioglitazone (Actos), or if you have kidney problems, severe heart failure, active bladder cancer, or metabolic acidosis. Do not use metformin and pioglitazone if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Do not take this medicine for longer than recommended. Taking pioglitazone for longer than 1 year (12 months) may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and pioglitazone.

Before taking metformin and pioglitazone, tell your doctor if you have congestive heart failure or heart disease, a history of bladder cancer, a history of heart attack or stroke, liver disease, eye problems caused by diabetes, or if you are 80 years or older.

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

Side Effects Centers
  • Actoplus MET

Patient Detailed How Take

What should I discuss with my healthcare provider before taking metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

Some people develop a life-threatening condition called lactic acidosis while taking metformin and pioglitazone. You may be more likely to develop lactic acidosis if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your individual risk.

Do not use metformin and pioglitazone if you have kidney disease, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin). You should not use this medication if you are allergic to metformin (Glucophage) or pioglitazone (Actos), or if you have:

  • kidney problems;
  • severe heart failure;
  • active bladder cancer; or
  • metabolic acidosis.

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and pioglitazone. Be sure your caregivers know ahead of time that you are using this medication.

To make sure you can safely take metformin and pioglitazone, tell your doctor if you have any of these other conditions:

  • congestive heart failure or heart disease, or a history of heart attack or stroke;
  • liver disease;
  • a history of bladder cancer;
  • eye problems caused by diabetes; or
  • if you are 80 years or older.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes.

Some women using metformin and pioglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control. Women may also be more likely than men to have bone fractures in the upper arm, hand, or foot while taking this medication. Talk with your doctor if you are concerned about this possibility.

Do not take this medicine for longer than recommended. Taking pioglitazone for longer than 1 year (12 months) may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

FDA pregnancy category C. It is not known whether metformin and pioglitazone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether metformin and pioglitazone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while taking this medication.

Do not give this medication to anyone under 18 years old without medical advice.

How should I take metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take metformin and pioglitazone with meals. Take the extended-release (XR) tablet once daily with your evening meal.

Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office. Visit your doctor regularly. Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, drink alcohol, or skip meals. These things can affect your glucose levels and your dose needs may also change.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating.

Your doctor may want you to stop taking metformin and pioglitazone for a short time if you become ill, have a fever or infection, or if you have surgery or a medical emergency.

Ask your doctor how to adjust your dose if needed. Do not change your medication dose or schedule without your doctor's advice.

If you take extra vitamin B12 while you are taking metformin and pioglitazone, take only the amount of vitamin B12 that your doctor has prescribed.

Store at room temperature away from moisture and heat.

Side Effects Centers
  • Actoplus MET

Patient Detailed Avoid Taking

What happens if I miss a dose (Actoplus MET, Actoplus MET XR)?

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Actoplus MET, Actoplus MET XR)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

Avoid drinking alcohol. It can lower your blood sugar and may increase your risk of lactic acidosis.

What other drugs will affect metformin and pioglitazone (Actoplus MET, Actoplus MET XR)?

Tell your doctor about all other medicines you use, especially:

  • bosentan (Tracleer);
  • delavirdine (Rescriptor);
  • digoxin (Lanoxin);
  • gemfibrozil (Lopid);
  • morphine (MS Contin, Kadian, Oramorph);
  • tolbutamide (Orinase);
  • trimethoprim (Proloprim, Primsol, Bactrim, Cotrim, Septra);
  • vancomycin (Vancocin, Lyphocin);
  • amiloride (Midamor), furosemide (Lasix), or triamterene (Dyrenium);
  • cimetidine (Tagamet) or ranitidine (Zantac);
  • fluconazole (Diflucan) or ketoconazole (Nizoral);
  • nicardipine (Cardene) or nifedipine (Nifedical, Procardia);
  • procainamide (Procan, Pronestyl, Procanbid), quinidine (Quin-G), or quinine (Qualaquin);
  • rifampin (Rifater, Rifadin, Rifamate) or rifapentine (Priftin);
  • a non-steroidal anti-inflammatory drug (NSAID) such as flurbiprofen (Ansaid), ibuprofen (Advil, Motrin), indomethacin (Indocin), mefenamic acid (Ponstel), or piroxicam (Feldene); or
  • seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), phenytoin (Dilantin), phenobarbital (Solfoton), primidone (Mysoline), and others.

You may be more likely to have hyperglycemia (high blood sugar) if you take metformin and pioglitazone with other drugs that can raise blood sugar, such as:

  • isoniazid;
  • diuretics (water pills);
  • steroids (prednisone and others);
  • heart or blood pressure medication (Cartia, Cardizem, Covera, Isoptin, Verelan, and others);
  • niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others);
  • phenothiazines (Compazine and others);
  • thyroid medicine (Synthroid and others);
  • birth control pills and other hormones;
  • seizure medicines (Dilantin and others); and
  • diet pills or medicines to treat asthma, colds or allergies.

These lists are not complete and there are many other medicines that can increase or decrease the effects of metformin and pioglitazone on lowering your blood sugar. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about metformin and pioglitazone.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 8.01. Revision date: 7/6/2012.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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