"The cumulative odds ratio (OR) and incidence rate ratio (IRR) were significantly higher in antipsychotic-exposed youth compared with healthy control persons (OR, 2.58; 95% confidence interval [CI], 1.56-4.24; IRR, 3.02; 95% CI, 1.71 - 5.35; for b"...
Congestive Heart Failure
Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when DUETACT is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of DUETACT must be considered [see BOXED WARNING, CONTRAINDICATIONS and ADVERSE REACTIONS].
All sulfonylureas, including glimepiride, a component of DUETACT, can cause severe hypoglycemia [see ADVERSE REACTIONS]. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing DUETACT doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other antidiabetic medications). Debilitated or malnourished patients and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking betaadrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, a component of DUETACT, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue DUETACT, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride tablets and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone-controlled clinical trial database to date [see ADVERSE REACTIONS].
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating DUETACT therapy. In patients with abnormal liver tests, DUETACT should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), DUETACT treatment should be interrupted and investigation done to establish the probable cause. DUETACT should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on DUETACT. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with DUETACT can be used with caution.
Urinary Bladder Tumors
Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology]. In two 3-year trials 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 less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo.
A five-year interim report of an ongoing 10-year observational cohort study found a nonsignificant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.9 -1.5]). Compared to never exposure, a duration of pioglitazone 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 pioglitazone 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 three cases in 10,000 (from approximately seven in 10,000 [without pioglitazone] to approximately 10 in 10,000 [with pioglitazone]).
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, DUETACT should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with DUETACT should be considered in patients with a prior history of bladder cancer.
In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose-related [see ADVERSE REACTIONS]. In postmarketing experience, reports of new onset or worsening edema have been received.
DUETACT should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, DUETACT should be used with caution in patients at risk for congestive heart failure. Patients treated with DUETACT should be monitored for signs and symptoms of congestive heart failure [see BOXED WARNING, and PATIENT INFORMATION].
In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted 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 the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with DUETACT and attention should be given to assessing and maintaining bone health according to current standards of care.
Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because DUETACT contains glimepiride, which belongs to the class of sulfonylurea agents, use caution in patients with G6PD deficiency and consider the use of a nonsulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency [see ADVERSE REACTIONS].
Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see ADVERSE REACTIONS].
Therapy with pioglitazone, like other thiazolidinediones, 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 [see Use in Specific Populations]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with DUETACT is recommended.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with DUETACT or any other antidiabetic drug.
Patient Counseling Information
See FDA-Approved Patient Labeling (Medication Guide).
- Inform patients that DUETACT is not recommended for patients with symptoms of heart failure.
- Inform patients that patients with severe heart failure (NYHA Class III or IV) cannot start DUETACT as the risks exceed the benefits in such patients.
- It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. 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 and of alternative modes of therapy.
- Tell patients 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.
- Prior to initiation of DUETACT 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 WARNINGS AND PRECAUTIONS]. Combination therapy of DUETACT 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 should immediately report these symptoms to a physician.
- Tell patients to promptly stop taking DUETACT and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
- Inform patients that therapy with a thiazolidinedione, including the active pioglitazone component of the DUETACT 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. Therefore, adequate contraception should be recommended for all premenopausal women who are prescribed DUETACT [see Use In Specific Populations].
- Patients should be told to take a single dose of DUETACT once daily with the first main meal and instructed that any change in dosing should be made only if directed by their physician [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with DUETACT. The following data are based on findings in studies performed with pioglitazone or glimepiride individually.
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 of male rats. 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). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.
The relevance to humans of the bladder findings in the male rat cannot be excluded.
A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ.
Pioglitazone 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 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 hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m²).
Studies in rats at doses of up to 5000 parts per million (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 that was dose-related and was thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was observed at a dose of 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 in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis and 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).
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of DUETACT in pregnant women. Animal studies show increased rates of postimplantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. DUETACT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.
In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m²); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m² basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m² basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m² basis).
Glimepiride - Teratogenic Effects
In animal studies there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has beensimilarly noted with other sulfonylureas. DUETACT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.
No studies have been conducted with the combined components of DUETACT. In studies performed with the individual components, pioglitazone was secreted in the milk of lactating rats and significant concentrations of glimepiride were observed in the serum and breast milk of the dams and serum of the pups. It is not known whether pioglitazone or glimepiride are secreted in human milk. However, other sulfonylureas are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for DUETACT to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue DUETACT, taking into account the importance of DUETACT to the mother.
Safety and effectiveness of DUETACT in pediatric patients have not been established. DUETACT is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see WARNINGS AND PRECAUTIONS].
The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.
The pharmacokinetics of a 1 mg single dose of glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (±SD) AUC (0-last) (339±203 ng•hr/mL), Cmax (102±48 ng/mL) and t1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC (0-last) 315±96 ng•hr/mL, Cmax 103±34 ng/mL and t1/2 5.3±4.1 hours).
The safety and efficacy of glimepiride in pediatric patients was evaluated in a singleblind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (n=135) or metformin (n=137). Both treatment-na´ve patients (those treated with only diet and exercise for at least two weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least three months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) through Week 12, targeting a self monitored fasting fingerstick blood glucose < 126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).
After 24 weeks, the overall mean treatment difference in HbA1c between glimepiride and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%).
Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c with glimepiride compared to metformin.
The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.
Hypoglycemic events documented by blood glucose values < 36 mg/dL were observed in 4% of pediatric patients treated with glimepiride and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).
To minimize the risk of hypoglycemia, the initial dosing, dose increments, and maintenance dosage of DUETACT should be conservative. During initiation of DUETACT therapy and any subsequent dose adjustments, geriatric patients should be observed carefully for hypoglycemia.
A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26- week double-blind, placebo-controlled, monotherapy trials were ≥ 65 years old and two patients (0.3%) were ≥ 75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥ 65 years old and 19 (1.8%) were ≥ 75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥ 65 years old and 19 (1.9%) were ≥ 75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥ 65 years old and 22 (2.1%) were ≥ 75 years old.
In PROactive, 1068 patients (41.0%) treated with pioglitazone were ≥ 65 years old and 42 (1.6%) were ≥ 75 years old.
In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see CLINICAL PHARMACOLOGY].
Although clinical experiences have not identified differences in effectiveness and safety between the elderly ( ≥ 65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥ 75 years old.
In clinical trials of glimepiride, 1053 of 3491 patients (30%) were ≥ 65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤ 65 years (n=49) and those > 65 years (n=42) [see CLINICAL PHARMACOLOGY].
Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Use caution when initiating DUETACT and increasing the dose of DUETACT in this patient population.
To minimize the risk of hypoglycemia, the initial dosing, dose increments and maintenance dosage of DUETACT should be conservative. During initiation of DUETACT therapy and any subsequent dose adjustments, these patients should be observed carefully for hypoglycemia.
A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal impairment using doses ranging from 1 mg to 8 mg daily for three months. Baseline creatinine clearance ranged from 10 to 60 mL/min. The pharmacokinetics of glimepiride were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of glimepiride increased when kidney function was impaired. Both studies also demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 11/25/2013
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