Duetact Information
Duetact (Pioglitazone) Description
Duetact (Pioglitazone) (pioglitazone hydrochloride and glimepiride) tablets contain two oral antihyperglycemic agents used in the management of type 2 diabetes: pioglitazone hydrochloride and glimepiride. The concomitant use of pioglitazone and a sulfonylurea, the class of drugs that includes glimepiride, has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on a sulfonylurea. Additional efficacy and safety information about pioglitazone and glimepiride monotherapies may be found in the prescribing information for each individual drug.
Pioglitazone hydrochloride is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels.
Pioglitazone (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, biguanides, or the α-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert . The structural formula is as shown:
Pioglitazone hydrochloride is an odorless, white crystalline powder that has a molecular formula of CHNOS•HCl and a molecular weight of 392.90. It is soluble in -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
Glimepiride 1-[[-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl] sulfonyl]-3-(-4-methylcyclohexyl)-urea is an oral blood glucose-lowering drug of the sulfonylurea class and is used in the management of type 2 diabetes. The molecule is the trans-isomer with respect to the cyclohexyl substituents. The chemical structure is as shown:
Glimepiride is a white to yellowish-white crystalline, odorless, to practically odorless powder, that has a molecular formula of CHNOS and a molecular weight of 490.62. It is soluble in dimethylsulfoxide, slightly soluble in acetone, very slightly soluble in acetonitrile and methanol, and practically insoluble in water.
Duetact (Pioglitazone) is available as a tablet for oral administration containing 30 mg pioglitazone hydrochloride (as the base) with 2 mg glimepiride (30 mg/2 mg) or 30 mg pioglitazone hydrochloride (as the base) with 4 mg glimepiride (30 mg/4 mg) formulated with the following excipients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, hydroxypropyl cellulose NF, polysorbate 80 NF, and microcrystalline cellulose NF.
Duetact (Pioglitazone) Clinical Pharmacology
Duetact (Pioglitazone)
Duetact (Pioglitazone) 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 glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretogogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells.
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. 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.
Glimepiride
The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.
Pioglitazone hydrochloride
The mean apparent volume of distribution (Vd/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.
Glimepiride
After intravenous (IV) dosing in normal subjects, Vd/F was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
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.
Glimepiride
Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). CYP2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.
Pioglitazone hydrochloride
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.
Glimepiride
When C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.
Co-administration of pioglitazone (45 mg) and a sulfonylurea (5 mg glipizide) administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Glimepiride and glipizide have similar metabolic pathways and are mediated by CYP2C9; therefore, drug-drug interaction between pioglitazone and glimepiride is considered unlikely. Specific pharmacokinetic drug interaction studies with Duetact (Pioglitazone) have not been performed, although such studies have been conducted with the individual pioglitazone and glimepiride 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
Midazolam
max
Nifedipine ER
max
Ketoconazole
Atorvastatin Calcium
®
0-24
1
2
In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.
Glimepiride
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for hypoglycemia when these drugs are co-administered. Conversely, when these drugs are withdrawn, the patient should be observed closely for loss of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for loss of glycemic control when these drugs are co-administered. Conversely, when these drugs are withdrawn, the patient should be observed closely for hypoglycemia.
Aspirin
max
Cimetidine/Ranitidine
Propranolol
Warfarin
Ramipril
Miconazole
Although no specific interaction studies were performed with glimepiride, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of calcium-channel blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone.
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 a sulfonylurea 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 a sulfonylurea.
Glimepiride
A mild glucose-lowering effect first appeared following single oral doses as low as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [T]) was about 2 to 3 hours. In patients with type 2 diabetes, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.
In larger dose-ranging studies, blood glucose and A1C were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of glimepiride. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of glimepiride up to 8 mg once daily. No difference in response was found when glimepiride was administered once or twice daily.
In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in A1C for patients treated with 8 mg of glimepiride once daily was 2.0% in absolute units compared with placebo-treated patients. In a long-term, randomized, placebo-controlled study of patients with type 2 diabetes unresponsive to dietary management, glimepiride therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and A1C. Efficacy results were not affected by age, gender, weight, or race. In long-term extension trials with previously-treated patients, no meaningful deterioration in mean fasting plasma glucose (FPG) or A1C levels was seen after 2 1/2 years of glimepiride therapy.
Glimepiride therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for type 2 diabetes.
Duetact (Pioglitazone) Indications And Usage
Duetact (Pioglitazone) is a thiazolidinedione and sulfonylurea 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 a sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone.
Duetact (Pioglitazone) Contraindications
Initiation of Duetact (Pioglitazone) in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see ).
In addition, Duetact (Pioglitazone) is contraindicated in patients with:
Duetact (Pioglitazone) Precautions
Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Duetact (Pioglitazone) should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycemia
In postmarketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.
A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS , compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure, a duration of ACTOS therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without ACTOS] to approximately 10 in 10,000 [with ACTOS]).
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, Duetact (Pioglitazone) should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Duetact (Pioglitazone) should be considered in patients with a prior history of bladder cancer.
Ovulation
Hepatic Effects
During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with pioglitazone and 2 of 793 (0.25%) placebo-treated patients had ALT values ≥ 3 times the upper limit of normal. The ALT elevations in patients treated with pioglitazone were reversible and were not clearly related to therapy with pioglitazone.
In postmarketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.
Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data on pioglitazone, it is recommended that patients treated with Duetact (Pioglitazone) undergo periodic monitoring of liver enzymes.
Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with Duetact (Pioglitazone) in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with Duetact (Pioglitazone) should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Therapy with Duetact (Pioglitazone) should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with Duetact (Pioglitazone) should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Duetact (Pioglitazone) in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, Duetact (Pioglitazone) therapy should be discontinued.
Fractures
Macrovascular Outcomes
Loss of control of blood glucose
Hemolytic Anemia
FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to Duetact (Pioglitazone) .
Liver enzyme monitoring is recommended prior to initiation of therapy with Duetact (Pioglitazone) in all patients and periodically thereafter per the clinical judgment of the health care professional (see and ).
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. Patients should also be informed of the potential risks and advantages of Duetact (Pioglitazone) and of alternative modes of therapy.
Prior to initiation of Duetact (Pioglitazone) therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members (see and ). Combination therapy of Duetact (Pioglitazone) with other antihyperglycemic agents may also cause hypoglycemia.
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 Duetact (Pioglitazone) 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.
Therapy with a thiazolidinedione, including the active pioglitazone component of the Duetact (Pioglitazone) 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 Duetact (Pioglitazone) . This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Thus, adequate contraception in premenopausal women should be recommended. Patients who become pregnant while on Duetact (Pioglitazone) or are planning a pregnancy should be advised to discuss with their physician a regimen appropriate for maintaining adequate glycemic control (see ).
Patients should be told to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
Patients should be told to take a single dose of Duetact (Pioglitazone) once daily with the first main meal and instructed that any change in dosing should be made only if directed by their physician (see ).
Pioglitazone hydrochloride
In vivo
An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response (see ).
Glimepiride
(See )
Duetact (Pioglitazone)
No animal studies have been conducted with Duetact (Pioglitazone) . The following data are based on findings in studies performed with pioglitazone or glimepiride individually.
Pioglitazone hydrochloride
A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m). 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/m). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m). No drug-induced tumors were observed in any organ.
Pioglitazone hydrochloride 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 cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an micronucleus assay.
No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m).
Glimepiride
Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.
Glimepiride was non-mutagenic in a battery of and mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).
There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
Pioglitazone hydrochloride
Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m). 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/m). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m), 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/m).
Glimepiride
Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to 320 mg glimepiride/kg/day for 12 months (approximately 1,000 times the recommended human dose based on surface area). No evidence of tumor formation was observed in any organ. One female and one male dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that glimepiride was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of glimepiride in several diabetic and cataract rat models was negative and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture.
Pioglitazone hydrochloride
Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.
Glimepiride
In U.S. clinical studies of glimepiride, 608 of 1986 patients were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42) was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups (see ).
Glimepiride is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal and hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents (see ; and ).
Duetact (Pioglitazone) Adverse Reactions
The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea-treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%) and combined edema/peripheral edema (2.1% and 7.2%), 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 a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6.0% and 9.7%, respectively.
In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus a sulfonylurea (see ).
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.
Most clinical adverse events were similar between groups treated with pioglitazone in combination with a sulfonylurea and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical studies 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 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 ).
Duetact (Pioglitazone) Array Prospective Pioglitazone Clinical Trial In Macrovascular Events (proactive)
In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.
Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see ).
Adverse events that occurred in controlled clinical trials with placebo and glimepiride monotherapy, other than hypoglycemia, headache and nausea, also included dizziness (0.3% and 1.7%) and asthenia (1.0% and 1.6%), respectively.
Duetact (Pioglitazone) Overdosage
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.
Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.
Duetact (Pioglitazone) Dosage And Administration
Based on the usual starting dose of pioglitazone (15 mg or 30 mg daily), Duetact (Pioglitazone) may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.
For patients with type 2 diabetes and systolic dysfunction, see
Based on the usual starting doses of glimepiride (1 mg or 2 mg once daily), and pioglitazone 15 mg or 30 mg, Duetact (Pioglitazone) may be initiated at 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.
For patients who are not currently on glimepiride and may be more sensitive to hypoglycemia, see
No exact dosage relationship exists between glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg glimepiride, Duetact (Pioglitazone) should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.
Any change in diabetic therapy should be undertaken with care and appropriate monitoring as changes in glycemic control can occur. Patients should be observed carefully for hypoglycemia (1-2 weeks) when being transferred to Duetact (Pioglitazone) , especially from longer half-life sulfonylureas (e.g. chlorpropamide) due to potential overlapping of drug effect.
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 Duetact (Pioglitazone) for a period of time adequate to evaluate change in A1C (8-12 weeks) unless glycemic control as measured by FPG deteriorates.
Duetact (Pioglitazone) is not recommended for use in pregnancy, nursing mothers or for use in pediatric patients.
In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage of Duetact (Pioglitazone) should be conservative to avoid hypoglycemic reactions. These patients should be started at 1 mg of glimepiride prior to prescribing Duetact (Pioglitazone) . During initiation of Duetact (Pioglitazone) therapy and any subsequent dose adjustment, patients should be observed carefully for hypoglycemia (see ).
Therapy with Duetact (Pioglitazone) should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see and ). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Duetact (Pioglitazone) and periodically thereafter (see and ).
The lowest approved dose of Duetact (Pioglitazone) therapy should be prescribed to patients with type 2 diabetes and systolic dysfunction only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated. If subsequent dose adjustment is necessary, patients should be carefully monitored for weight gain, edema, or signs and symptoms of CHF exacerbation (see ).
Duetact (Pioglitazone) tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride formulation for oral administration. The maximum recommended daily dose for pioglitazone is 45 mg and the maximum recommended daily dose for glimepiride is 8 mg.
Duetact (Pioglitazone) should therefore not be given more than once daily at any of the tablet strengths.
Duetact (Pioglitazone) How Supplied
Duetact (Pioglitazone) is available in 30 mg pioglitazone plus 2 mg glimepiride or 30 mg pioglitazone plus 4 mg glimepiride tablets as follows:
30 mg/2 mg tablet: white to off-white, round, convex, uncoated tablet, debossed with 30/2 on one side and 4833G on the other, available in:NDC 64764-302-30 Bottles of 30NDC 64764-302-90 Bottles of 90
30 mg/4 mg tablet: white to off-white, round, convex, uncoated tablet, debossed with 30/4 on one side and 4833G on the other, available in:NDC 64764-304-30 Bottles of 30NDC 64764-304-90 Bottles of 90
Duetact (Pioglitazone) Human Ophthalmology Data
Ophthalmic examinations were carried out in over 500 subjects during long-term studies using the methodology of Taylor and West and Laties et al. No significant differences were seen between glimepiride and glyburide in the number of subjects with clinically important changes in visual acuity, intraocular tension, or in any of the five lens-related variables examined.
Ophthalmic examinations were carried out during long-term studies using the method of Chylack et al. No significant or clinically meaningful differences were seen between glimepiride and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination.
Duetact (Pioglitazone)
Duetact (Pioglitazone) Medication Guide
Read this Medication Guide carefully before you start taking Duetact (Pioglitazone) and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Duetact (Pioglitazone) , ask your doctor or pharmacist.
Duetact (Pioglitazone) can cause serious side effects, including
Call your doctor right away if you have any of the following:
Duetact (Pioglitazone) can have other serious side effects. See "What are the possible side effects of Duetact (Pioglitazone) ?"
Duetact (Pioglitazone) is a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.
Duetact (Pioglitazone) contains 2 prescription diabetes medicines called, pioglitazone hydrochloride (ACTOS) and glimepiride, a sulfonylurea.
Your doctor will decide if you should take Duetact (Pioglitazone) .
It is important to eat the right foods, lose weight if needed, and exercise regularly in order to manage your type 2 diabetes. Diet, weight loss, and exercise are the main treatments for type 2 diabetes and they also help your diabetes medicines work better for you.
Duetact (Pioglitazone) has not been studied in children and is not recommended for children under the age of 18. The risks of giving Duetact (Pioglitazone) to a child are not known. See "What are some other possible side effects of Duetact (Pioglitazone) ?"
Do not take Duetact (Pioglitazone) if you:
People with severe heart failure should not start taking Duetact (Pioglitazone) . See "What is the most important information I should know about Duetact (Pioglitazone) ?"
Before starting Duetact (Pioglitazone) , ask your doctor about what the choices are for diabetes medicines and what the expected benefits and possible risks are for you in particular.
Tell your doctor about all of your medical conditions, especially if you:
Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Duetact (Pioglitazone) and some of your other medicines can affect each other. You may need to have your dose of Duetact (Pioglitazone) or certain other medicines adjusted. Certain other medicines can affect your blood sugar (glucose) control.
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is okay to take Duetact (Pioglitazone) with other medicines.
Other common side effects of Duetact (Pioglitazone) are:
Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of Duetact (Pioglitazone) . For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Keep Duetact (Pioglitazone) and all medicines out of the reach of children.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Duetact (Pioglitazone) for a condition for which it is not prescribed. Do not give Duetact (Pioglitazone) to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about Duetact (Pioglitazone) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Duetact (Pioglitazone) that is written for healthcare professionals. For more information, go to www.Duetact (Pioglitazone) .com or call 1-877-825-3327.
Active Ingredients: pioglitazone hydrochloride and glimepiride
Inactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, hydroxypropyl cellulose, polysorbate 80, and microcrystalline cellulose.
Always check to make sure that the medicine you are taking is the correct one. Duetact (Pioglitazone) tablets look like this:
Duetact (Pioglitazone) ® is a registered trademark of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc.
All other trademarks are the property of their respective owners.
Distributed by: Deerfield, IL 60015
© 2009, 2011 Takeda Pharmaceuticals America, Inc.
July 2011
DTA007 R9
Duetact (Pioglitazone) Principal Display Panel - / Mg Tablet Bottle Label
NDC 64764-302-30
Each tablet contains pioglitazonehydrochloride equivalent to 30 mgpioglitazone and 2 mg glimepiride.
Duetact (Pioglitazone) Principal Display Panel - / Mg Tablet Bottle Label
NDC 64764-304-30
Each tablet contains pioglitazonehydrochloride equivalent to 30 mgpioglitazone and 4 mg glimepiride.
