Actosmet

Actosmet

pioglitazone + metformin

Manufacturer:

Celltrion Healthcare

Distributor:

DKSH
Full Prescribing Info
Contents
Pioglitazone HCl, metformin HCl.
Description
Each tablet contains pioglitazone 15 mg and metformin HCl 850 mg.
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 1 asymmetric center and the synthetic compound is a racemate. The 2 enantiomers of pioglitazone interconvert in vivo.
Pioglitazone HCl is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S·HCl and a molecular weight of 392.9. 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 HCl (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white crystalline powder with a molecular formula of C4H11N5·HCl and a molecular weight of 165.62. Metformin HCl 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 HCl is 6.68.
Action
Actosmet contains 2 oral antihyperglycemic drugs used in the management of type 2 diabetes: Pioglitazone HCl and metformin HCl. 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 HCl 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.
Pharmacology: Mechanism of Action: Actosmet combines 2 antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Pioglitazone HCl, a member of the thiazolidinedione class; and metformin HCl, 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 HCl: 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 eg, 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 eg, 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 HCl: Metformin HCl 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 General Precautions: Metformin HCl under Precautions) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.
Pharmacokinetics: Absorption and Bioavailability: In bioequivalence studies of Actosmet 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 or 850 mg respectively) tablets under fasted conditions in healthy subjects (see Table 1).

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Administration of Actosmet 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 hrs for pioglitazone and 0.8 hrs for metformin) under fed conditions. These changes are not likely to be clinically significant.
Pioglitazone HCl: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 min, with peak concentrations observed within 2 hrs. Food slightly delays the time to peak serum concentration to 3-4 hrs, but does not alter the extent of absorption.
Metformin HCl: The absolute bioavailability of a metformin 500 mg given under fasting conditions is approximately 50-60%. Studies using single-oral doses of metformin tablets of 500-1500 mg and 850-2550 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 min prolongation of time to peak plasma concentration following administration of a single metformin 850-mg tablet with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution: Pioglitazone HCl: 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 HCl: 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 hrs and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism, Elimination and Excretion: Pioglitazone HCl: 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 30-50% of the total peak serum concentrations and 20-25% of the total AUC.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P-450 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 P-450 inhibitors and substrates have been performed (see Precautions and Interactions). 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 15-30% 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 3-7 hrs and 16-24 hrs, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5-7 L/hr.
Metformin HCl: IV 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 hrs, with a plasma elimination half-life of approximately 6.2 hrs. In blood, the elimination half-life is approximately 17.6 hrs, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations: Renal Insufficiency: Pioglitazone HCl: The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30-60 mL/min) to severe (creatinine clearance <30 mL/min) renal impairment when compared to normal subjects.
Metformin HCl: 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, see also the prescribing information of Glucophage). Since metformin is contraindicated in patients with renal impairment, Actosmet is also contraindicated in these patients.
Hepatic Insufficiency: Pioglitazone HCl: 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 Actosmet 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 General Precautions: Pioglitazone HCl under Precautions).
Metformin HCl: No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.
Elderly: Pioglitazone HCl: 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 HCl: 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 also the prescribing information of Glucophage).
Actosmet treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Warnings and Dosage & Administration; see also the prescribing information of Glucophage).
Pediatrics: Pioglitazone HCl: Pharmacokinetic data in the pediatric population are not available.
Metformin HCl: After administration of a single oral metformin 500 mg-tablet with food, geometric mean metformin Cmax and AUC differed <5% between pediatric type 2 diabetic patients (12-16 years) and gender- and weight-matched healthy adults (20-45 years) and all with normal renal function.
Gender: Pioglitazone HCl: 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 20-60% 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 HCl: 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 HCl: Pharmacokinetic data among various ethnic groups are not available.
Metformin HCl: 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 Actosmet have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.
Pioglitazone HCl: The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed as follows:
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(0-24 hrs) and Cmax respectively. There were no significant changes in norethindrone AUC(0-24 hrs) 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 nifedipine ER 30 mg 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 (0.8-0.96) 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 P-450: See Precautions and Interactions.
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 and Interactions).
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 and Interactions).
In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine HCl or theophylline.
Metformin HCl: See Precautions and Interactions.
Pharmacodynamics and Clinical Effects: Pioglitazone HCl: 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 1 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- and 24-week combination therapy studies of pioglitazone with metformin.
Clinical Studies: There have been no clinical efficacy studies conducted with Actosmet. 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 2 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 Actosmet with co-administered pioglitazone and metformin tablets was demonstrated for both Actosmet strengths.
Clinical Trials of Pioglitazone Add-on Therapy in Patients Not Adequately Controlled on Metformin: Two (2) 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 1st 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 2nd study, 827 patients received either 30 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 0.8% and 1.01% for the 30- and 45-mg doses, respectively. Mean reductions from baseline in FPG were 38.2 and 50.7 mg/dL, respectively. Based on these reductions in A1C and FPG, the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose. (See Table 2.)

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Toxicology: Animal Toxicology: Pioglitazone HCl: Heart enlargement has been observed in mice (100 mg/kg), rats (≥4 mg/kg) and dogs (3 mg/kg) treated orally with the pioglitazone HCl component of Actosmet (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 (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).
Indications/Uses
As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and metformin or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.
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.
Dosage/Direction for Use
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 Actosmet should be based on the patient's current regimen of pioglitazone and/or metformin. After initiation of Actosmet or with dose increase, patients should be carefully monitored for adverse events related to fluid retention (see Congestive Heart Failure under Warnings). Actosmet should be given in divided daily doses with meals to reduce the gastrointestinal side effects associated with metformin.
Patients Inadequately Controlled on Metformin Monotherapy: Based on the usual starting dose of pioglitazone (15-30 mg daily), Actosmet may be initiated at 15 mg/850 mg tablet strength once or twice daily, and gradually titrated after assessing adequacy of therapeutic response.
Patients Who Initially Responded to Pioglitazone Monotherapy and Require Additional Glycemic Control: Based on the usual starting doses of metformin (850 mg daily), Actosmet may be initiated at 15 mg/850 mg tablet strength once daily, and gradually titrated after assessing adequacy of therapeutic response.
Patients Switching from Combination Therapy of Pioglitazone Plus Metformin as Separate Tablets: Actosmet may be initiated with 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 Actosmet in patients previously treated with other oral hypoglycemic agents and switched to Actosmet. 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 2-3 months. In clinical use, it is recommended that patients be treated with Actosmet 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: Actosmet is not recommended for use in pregnancy or for use in pediatric patients.
The initial and maintenance dosing of Actosmet 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 Actosmet. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see Warnings and General Precautions: Metformin HCl under Precautions).
Therapy with Actosmet should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5 times the upper limit of normal) at start of therapy (see Special Populations under Pharmacokinetics and Pharmacology under Actions, and General Precautions: Pioglitazone HCl under Precautions). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Actosmet and periodically thereafter (see General Precautions: Pioglitazone HCl and Laboratory Tests under Precautions).
Maximum Recommended Dose: Adults: Actosmet tablets are available as a pioglitazone 15 mg plus metformin 850 mg formulation for oral administration. The maximum recommended dose for pioglitazone is 45 mg daily and for metformin is 2550 mg.
Overdosage
Pioglitazone HCl: During controlled clinical trials, 1 case of overdose with pioglitazone was reported. A male patient took 120 mg/day for 4 days, then 180 mg/day for 7 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 HCl: Overdose of metformin HCl has occurred, including ingestion of amounts >50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see Metformin HCl under Warnings). 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 Actosmet in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated (see Congestive Heart Failure under Warnings). In addition, Actosmet is contraindicated in patients with: Known hypersensitivity to pioglitazone, metformin or any other component of Actosmet; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin; renal disease or renal dysfunction [eg, 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 eg, cardiovascular collapse (shock), acute myocardial infarction and septicemia (see Warnings and General Precautions: Metformin HCl under Precautions).
Actosmet 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 General Precautions: Metformin HCl under Precautions).
Patients with active bladder cancer.
Warnings
Congestive Heart Failure: Thiazolidinediones, including pioglitazone cause or exacerbate congestive heart failure in some patients. After initiation of pioglitazone and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, fatigue and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered.
Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone in patients with established NYHA class III or IV heart failure is contraindicated (see Contraindications).
Metformin HCl: Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Actosmet 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 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In >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 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 HCl on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular-radiocontrast study and for any surgical procedure (see General Precautions: Metformin HCl under Precautions).
The onset of lactic acidosis is often subtle, and accompanied only by nonspecific symptoms eg, 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 General Precautions: Metformin HCl under Precautions). 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 <5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms eg, poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling (see General Precautions: Metformin HCl under Precautions).
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 HCl 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 General Precautions: Metformin HCl under Precautions).
Pioglitazone HCl: 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 Congestive Heart Failure as previously-mentioned 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 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 preexisting 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, 2 of the 191 patients receiving pioglitazone 15 mg plus insulin (1.1%) and 2 of the 188 patients receiving pioglitazone 30 mg plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin-therapy alone. All 4 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 <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.
Special Precautions
General Precautions: Pioglitazone HCl: Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Actosmet 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 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 versus 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 Pioglitazone HCl under Warnings). 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 post-marketing 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 post-marketing 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, Actosmet should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see Congestive Heart Failure under Warnings and Information for Patients as follows).
Weight Gain: Dose-related weight gain was observed with pioglitazone alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. (See Table 3.)

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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 Actosmet. 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 2-4% in patients treated with pioglitazone. These changes primarily occurred within the first 4-12 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 Laboratory Abnormalities under Adverse Reactions). Actosmet 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 post-marketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to ≥3 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 post-marketing safety data on pioglitazone, it is recommended that patients treated with Actosmet undergo periodic monitoring of liver enzymes.
Serum alanine aminotransferase (ALT) levels should be evaluated prior to the initiation of therapy with Actosmet in all patients and periodically thereafter, per clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur eg, nausea, vomiting, abdominal pain, fatigue, anorexia or dark urine. The decision whether to continue the patient on therapy with Actosmet should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Therapy with Actosmet 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 1-2.5 times the upper limit of normal) at baseline or any time during therapy with Actosmet should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Actosmet 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 pre-treatment 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, Actosmet 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 1st 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 standard of care.
General Precautions: Metformin HCl: 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 Actosmet. In patients with advanced age, Actosmet 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, renal function should be monitored regularly and generally, Actosmet should not be titrated to the maximum dose of the metformin component (see Dosage & Administration and Metformin HCl under Warnings).
Before initiation of therapy with Actosmet 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 Actosmet 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 eg, cationic drugs that are eliminated by renal tubular secretion (see Precautions and Interactions), should be used with caution.
Radiologic Studies Involving the Use of Intravascular Iodinated Contrast Materials (for example, IV urogram, IV 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, Actosmet should be temporarily discontinued at the time of or prior to the procedure and withheld for 48 hrs 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 Actosmet therapy, the drug should be promptly discontinued.
Surgical Procedures: Use of Actosmet 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 Actosmet.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Actosmet 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 Actosmet and any apparent abnormalities should be appropriately investigated and managed (see General Precautions: Metformin HCl as previously-mentioned 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 2- to 3-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 Actosmet 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, Actosmet must be stopped immediately and other appropriate corrective measures initiated (see Metformin HCl under Warnings).
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 (eg, 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 β-adrenergic blocking drugs.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Actosmet and temporarily administer insulin. Actosmet 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 Actosmet.
Liver enzyme monitoring is recommended prior to initiation of therapy with Actosmet in all patients and periodically thereafter, per the clinical judgment of the health care professional (see General Precautions: Pioglitazone HCl as previously-mentioned and Serum Transaminase Levels under Adverse Reactions).
Initial and periodic monitoring of hematologic parameters (eg, 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 eg, 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 Warnings and General Precautions: Metformin HCl as previously cited, should be explained to patients. Patients should be advised to discontinue Actosmet 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 Actosmet 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 Actosmet.
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 Actosmet 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 Actosmet.
Therapy with a thiazolidinedione, which is the active pioglitazone component of the Actosmet 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 Actosmet. 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 Actosmet, 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 Actosmet as prescribed and instructed that any change in dosing should only be done if directed by their physician.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Actosmet: No animal studies have been conducted with Actosmet. The following data are based on findings in studies performed with pioglitazone or metformin individually.
Pioglitazone HCl: 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 2-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.
During prospective evaluation of urinary cytology involving >1800 patients receiving pioglitazone in clinical trials up to 1 year in duration, no new cases of bladder tumors were identified. In two 3-year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was <1 year at the time of diagnosis of bladder cancer, there were 6 (0.16%) cases on pioglitazone and 2 (0.05%) on placebo.
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 HCl: 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 4 times a human daily dose of 2000 mg of the metformin component of Actosmet 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 3 times the maximum recommended human daily dose of the metformin component of Actosmet based on body surface area comparisons.
Use in pregnancy: Actosmet: 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. Actosmet 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 Actosmet or its individual components. No animal studies have been conducted with the combined products in Actosmet. The following data are based on findings in studies performed with pioglitazone or metformin individually.
Pioglitazone HCl: 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 post-implantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of ≥40 mg/kg/day (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 during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).
Metformin HCl: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 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.
Use in lactation: No studies have been conducted with the combined components of Actosmet. 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, Actosmet should not be administered to a breastfeeding woman. If Actosmet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Use in children: Safety and effectiveness of Actosmet in pediatric patients have not been established.
Use in the elderly: Pioglitazone HCl: Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were ≥65 years. No significant differences in effectiveness and safety were observed between these patients and younger patients.
Metformin HCl: 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, Actosmet should only be used in patients with normal renal function (see Special Populations under Pharmacokinetics under Actions, Contraindications, Metformin HCl under Warnings). Because aging is associated with reduced renal function, Actosmet 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 Actosmet (see Dosage & Administration and Metformin HCl under Warnings).
Use In Pregnancy & Lactation
Use in pregnancy: Actosmet: 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. Actosmet 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 Actosmet or its individual components. No animal studies have been conducted with the combined products in Actosmet. The following data are based on findings in studies performed with pioglitazone or metformin individually.
Pioglitazone HCl: 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 post-implantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of ≥40 mg/kg/day (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 during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).
Metformin HCl: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 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.
Use in lactation: No studies have been conducted with the combined components of Actosmet. 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, Actosmet should not be administered to a breastfeeding woman. If Actosmet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Adverse Reactions
Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This included 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 and >over 4500 patients for ≥1 year. 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%) and headache (1.9% and 6%), 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 2 treatment groups was 7.8% and 7.7%, respectively. (See Table 4.)

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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 General Precautions: Pioglitazone HCl under Precautions).
In monotherapy studies, edema was reported for 4.8% (with doses from 7.5-45 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).
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 received cardiovascular medications (β-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 HbA1c 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 1st occurrence of any event in the cardiovascular composite endpoint. Although there was no statistically significant difference between Actos and placebo for the 3-year incidence of a 1st event within this composite, there was no increase in mortality or in total macrovascular events with Actos. (See Table 5.)

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Post-marketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see General: Pioglitazone HCl under Precautions).
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 2-4% in patients treated with pioglitazone. These changes generally occurred within the first 4-12 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 General Precautions: Pioglitazone HCl under Precautions).
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 General Precautions: Metformin HCl under Precautions).
Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.3%) 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, AP 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 General Precautions: Pioglitazone HCl under Precautions).
Creatine Phosphokinase (CPK) Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in CPK were observed. An isolated elevation to >10 times the upper limit of normal was noted in 9 patients (values of 2150-11400 IU/L). 6 of these patients continued to receive pioglitazone, 2 patients had completed receiving study medication at the time of the elevated value and 1 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.
Drug Interactions
Pioglitazone HCl: 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 (eg, gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (eg, 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 Drug-Drug Interactions under Actions).
Metformin HCl: Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. 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 (eg, 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 Actosmet 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 Actosmet, 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 eg, salicylates, sulfonamides, chloramphenicol and probenecid.
Storage
Store below 25°C.
MIMS Class
ATC Classification
A10BD05 - metformin and pioglitazone ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
Tab (white to off-white, oblong, film-coated tablet with “4833M” on one side, and “15/850” on the other) x 2 x 14's.
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