Professional Information — Actoplus Met

Indications and Usage

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 and 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 metformin-associated 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.  

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 ).

Adverse Reactions

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

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

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

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

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

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 C_max respectively. There were no significant changes in norethindrone AUC (0-24h) and C_max. 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 C_max 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 C_max 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 C_max, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for C_min.

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

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 (AUC_0-24) 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

Overdosage

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.  

Description

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

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

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.

Clinical Pharmacology

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 (C_max) 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).  

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 6β-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 C_max 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 C_max 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 C_max 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 C_max respectively. There were no significant changes in norethindrone AUC (0-24h) and C_max. 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 C_max 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 C_max 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 C_max, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for C_min.

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

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 (AUC_0-24) 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 co-administration 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.

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 co-administration 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 ).

How Supplied / Storage and Handling

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:

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:

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.

Patient Counseling Information

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