ACTOPLUS MET (pioglitazone hydrochloride and metformin hydrochloride) tablets ACTOPLUS MET XR (pioglitazone hydrochloride and metformin hydrochloride extended-release) tablets

ACTOPLUS MET tablets are formulated with pioglitazone hydrochloride and immediate-release metformin hydrochloride. ACTOPLUS MET XR tablets are formulated with pioglitazone hydrochloride and extended-release metformin hydrochloride. Both ACTOPLUS METand ACTOPLUS METXR contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: pioglitazone and metformin. ACTOPLUS MET is available in 15 mg pioglitazone/500 mg metformin hydrochloride and 15 mg pioglitazone/850 mg metformin hydrochloride tablets. ACTOPLUS MET XR is available in 15 mg pioglitazone/1000 mg extended-release metformin hydrochloride and 30 mg pioglitazone/1000 mg extended-release metformin hydrochloride tablets.

Pioglitazone 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 is an odorless white crystalline powder that has a molecular formula of CHNOS•HCl and a molecular weight of 392.90. It is soluble in 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 CHN•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

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

ACTOPLUS MET XR is available as a tablet for once-a-day oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 1000 mg metformin hydrochloride (ACTOPLUS MET XR 15 mg/1000 mg) or 30 mg pioglitazone and 1000 mg metformin hydrochloride (ACTOPLUS MET XR 30 mg/1000 mg). ACTOPLUS MET XR is formulated with the following excipients: candelilla wax, cellulose acetate, povidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycols (PEG 400, PEG 8000), sodium lauryl sulfate, titanium dioxide, and triacetin. Tablets are imprinted with ink containing shellac, iron oxide red (15 mg/1000 mg strength only), FD&C Blue No. 2 Lake (30 mg/1000 mg strength only), propylene glycol, and ammonium hydroxide.

ACTOPLUS MET XR consists of an extended-release metformin core coated tablet with an immediate-release pioglitazone layer. The metformin core tablet is an extended-release formulation using the patented single composition osmotic technology (SCOT™) for once-daily (q.d.) oral administration. The tablet is similar in appearance to other film-coated oral administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membrane and coated with a pioglitazone drug layer. Two laser drilled exit ports exist in the membrane, one on either side of the tablet. The core formulation is composed primarily of drug with small concentrations of excipients. The semipermeable membrane is permeable to water but not to higher molecular weight components of biological fluids. Upon ingestion, the pioglitazone layer is dissolved, water is then taken up through the membrane, which in turn dissolves the metformin and excipients in the core formulation. The dissolved metformin and excipients exit through the laser drilled ports in the membrane. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane. This situation exists so long as there is undissolved metformin present in the core tablet. Following the dissolution of the core materials, the rate of drug delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery ceases. The membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces.

ACTOPLUS MET and ACTOPLUS MET XR combine two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone, 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 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 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.

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

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.

In bioequivalence studies of ACTOPLUS MET XR 15 mg/1000 mg and 30 mg/1000 mg, the area under the curve (AUC) and maximum concentration (C) of both the pioglitazone and the extended-release metformin components following a single dose of the combination tablet were bioequivalent to pioglitazone (ACTOS)15 mg and 30 mg concomitantly administered with extended-release metformin hydrochloride (FORTAMET) 1000 mg tablets under fed conditions in healthy subjects (Table 2).

Administration of ACTOPLUS MET XR 30 mg/1000 mg with food resulted in no change in total (AUC) exposure of pioglitazone; however, a decrease in Cby approximately 18% was observed. With the extended-release metformin component there was an increase in C by approximately 98% and AUC exposure by approximately 85% when administered with food. These levels are comparable to exposures obtained with extended release metformin when administered with food. Time to peak serum concentration was prolonged by approximately 3 and 2 hours for pioglitazone and extended-release metformin respectively, under fed conditions.

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.

The absolute bioavailability of a 500 mg immediate-release metformin tablet given under fasting conditions is approximately 50% - 60%. Studies using single oral doses of immediate-release 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 immediate-release 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 immediate-release metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

The appearance of metformin in plasma from an extended-release metformin tablet is slower and more prolonged compared to immediate-release metformin (see FORTAMET prescribing information). In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either extended-release metformin hydrochloride 2000 mg once a day (after dinner) or immediate-release (IR) metformin hydrochloride 1000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (T), and maximum concentration (C) were eva luated. Results are presented in Table 3.

In four single-dose studies and one multiple-dose study, the bioavailability of extended-release metformin 2000 mg given once daily, in the evening, under fed conditions [as measured by the area under the plasma concentration versus time curve (AUC)] was similar to the same total daily dose administered as immediate-release metformin 1000 mg given twice daily. The geometric mean ratios (extended-release metformin/immediate-release metformin) of AUC, AUC, and AUC for these five studies ranged from 0.96 to 1.08.

In a single-dose, four-period replicate crossover design study, comparing two 500 mg extended-release metformin tablets to one 1000 mg extended-release metformin tablet administered in the evening with food to 29 healthy male subjects, two 500 mg extended-release metformin tablets were found to be equivalent to one 1000 mg extended-release metformin tablet.

In a study carried out with extended-release metformin, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1000, 1500, 2000, and 2500 mg.

In three studies with extended-release metformin using different treatment regimens (2000 mg after dinner, 1000 mg after breakfast and after dinner, and 2500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration.

The extent of absorption (as measured by AUC) of extended-release metformin increased by approximately 60% when given with food. When extended-release metformin was administered with food, C was increased by approximately 30% and T was more prolonged compared with the fasting state (6.1 versus 4.0 hours).

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.

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 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 immediate-release metformin, steady-state plasma concentrations of metformin are reached within 24 - 48 hours and are generally <1 µg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

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 ). 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.

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.

Metabolism studies with extended-release metformin tablets have not been conducted.

In healthy nondiabetic adults (N=18) receiving extended-release metformin 2500 mg daily, the percent of the metformin dose excreted in urine over 24 hours was 40.9% and the renal clearance was 542 ± 310 mL/min. After repeated administration of extended-release metformin, there is little or no accumulation of metformin in plasma, with most of the drug being eliminated via renal excretion over a 24-hour dosing interval.

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.

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 and ACTOPLUS MET XR are also contraindicated in these patients.

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 or ACTOPLUS MET XR 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 ).

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

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.

Limited data from controlled pharmacokinetic studies of immediate-release metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cis 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 or ACTOPLUS MET XR 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).

Pharmacokinetic data in the pediatric population are not available. Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data. Risks including fractures and other adverse effects associated with pioglitazone, one of the components of ACTOPLUS MET and ACTOPLUS MET XR, have not been determined in this population (see WARNINGS and PRECAUTIONS ).

After administration of a single oral immediate-release metformin 500 mg tablet with food, geometric mean metformin C 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.

Pharmacokinetic data for extended-release metformin tablets in the pediatric population are not available.

As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean C and AUC values were increased 20% to 60% in females. In controlled clinical trials, decreases from baseline in HbA1c were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

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 immediate-release metformin was comparable in males and females.

Five studies indicated that with extended-release metformin treatment, the pharmacokinetic results for males and females were comparable.

Pharmacokinetic data among various ethnic groups are not available.

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

Co-administration of a single dose of immediate-release 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 or ACTOPLUS MET XR have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

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

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 C respectively. There were no significant changes in norethindrone AUC (0-24h) and C. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

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

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 C 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.

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 C, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for C.

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 C, 0.76 (0.65 - 0.88) for AUC and 0.96 (0.87 - 1.05) for C. For unchanged atorvastatin the ratio of least square mean (90% CI) values were 0.77 (0.66 - 0.90) for C, 0.86 (0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for C.

See PRECAUTIONS, Drug Interactions, Pioglitazone

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 (AUC) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see PRECAUTIONS, Drug Interactions, Pioglitazone ).

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 ).

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

See PRECAUTIONS, Drug Interactions, Metformin 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 HbA1c 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.

There have been no clinical efficacy studies conducted with ACTOPLUS MET or ACTOPLUS MET XR. However, the efficacy and safety of the separate components have been previously established and the co-administration of the separate components has been eva luated 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 immediate-release metformin tablets and ACTOPLUS MET XR with co-administered pioglitazone and extended-release metformin tablets was demonstrated for both tablet strengths of ACTOPLUS MET and ACTOPLUS MET XR, respectively (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism ).

Two treatment-randomized, controlled clinical studies in patients with type 2 diabetes were conducted to eva luate 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 HbA1c by 0.8% and the mean fasting plasma glucose (FPG) by 38 mg/dL at Week 16 compared to that observed with metformin alone. In this 16 week study, patients randomized to either pioglitazone or placebo treatment received a median metformin daily dose of 1500 mg with doses ranging from 500 mg to 3400 mg. In the second study, the mean reductions from Baseline at Week 24 in HbA1c were 0.8% and 1.0% for the 30 mg and 45 mg doses, respectively. Mean reductions from Baseline in FPG were 38 mg/dL and 51 mg/dL, respectively. In this 24 week study, patients randomized to either pioglitazone 30 mg or pioglitazone 45 mg treatment received a median metformin daily dose of 1700 mg with doses ranging from 500 mg to 3000 mg. Based on these reductions in HbA1c and FPG (Table 4), the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose.

ACTOPLUS MET and ACTOPLUS MET XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.

Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. Prior to initiation or escalation of oral antidiabetic therapy in patients with type 2 diabetes mellitus, secondary causes of poor glycemic control, e.g., infection, should be investigated and treated.

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

In addition, ACTOPLUS MET and ACTOPLUS MET XR are contraindicated in patients with:

ACTOPLUS MET or ACTOPLUS MET XR 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).

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) or ACTOPLUS MET XR (pioglitazone hydrochloride and metformin hydrochloride extended-release) 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 l

Manufacturer

Takeda Pharmaceuticals America, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011