Pioglitazone and Glimepiride Tablets

Recommendations for All Patients

Pioglitazone and Glimepiride Tablets should be taken once daily with the first main meal.

Pioglitazone and Glimepiride Tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride tablet. If therapy with a combination tablet containing pioglitazone and glimepiride is considered appropriate the recommended starting dose is:

• 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
• for patients inadequately controlled on glimepiride monotherapy: 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
• for patients inadequately controlled on pioglitazone monotherapy: 30 mg/2 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
• for patients who are changing from combination therapy of pioglitazone plus glimepiride as separate tablets: Pioglitazone and Glimepiride Tablets should be taken at doses that are as close as possible to the dose of pioglitazone and glimepiride already being taken,
• for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide): 30 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response. Observe for hypoglycemia for one to two weeks due to the potential overlapping drug effect.
• for patients with systolic dysfunction, the lowest approved dose of Pioglitazone and Glimepiride Tablets should be prescribed only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated.

After initiation of Pioglitazone and Glimepiride Tablets or with dose increase, monitor patients carefully for hypoglycemia and adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.7)].

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Pioglitazone and Glimepiride Tablets. Routine periodic monitoring of liver tests during treatment with Pioglitazone and Glimepiride Tablets is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Pioglitazone and Glimepiride Tablets or who are found to have abnormal liver tests while taking Pioglitazone and Glimepiride Tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient coadministered Pioglitazone and Glimepiride Tablets and an insulin secretagogue, the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered Pioglitazone and Glimepiride Tablets and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3 fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors. If gemfibrozil or other CYP2C8 inhibitors need to co-administered, patients should switch to individual components of Pioglitazone and Glimepiride Tablets because the minimum dose of pioglitazone in Pioglitazone and Glimepiride Tablets exceeds 15 mg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Concomitant Use with Colesevelam

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, Pioglitazone and Glimepiride Tablets should be administered at least four hours prior to colesevelam [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].

Congestive Heart Failure

Pioglitazone

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 Pioglitazone and Glimepiride Tablets are 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 Pioglitazone and Glimepiride Tablets must be considered [see Boxed Warning, Contraindications (4) and Adverse Reactions (6.1)].

Hypoglycemia

Glimepiride

All sulfonylureas, including glimepiride, a component of Pioglitazone and Glimepiride Tablets, can cause severe hypoglycemia [see Adverse Reactions (6.1)]. 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 pioglitazone and glimepiride tablet 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 beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.

Hypersensitivity Reactions

Glimepiride

There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, a component of Pioglitazone and Glimepiride Tablets, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Pioglitazone and Glimepiride Tablets, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas

Glimepiride

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.

Hepatic Effects

Pioglitazone

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 (6.1)].

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 pioglitazone and glimepiride tablet therapy. In patients with abnormal liver tests, Pioglitazone and Glimepiride Tablets 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), pioglitazone and glimepiride tablet treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone and Glimepiride Tablets 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 Pioglitazone and Glimepiride Tablets. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Pioglitazone and Glimepiride Tablets can be used with caution.

Urinary Bladder Tumors

Pioglitazone

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer . After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–1.72]).

Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did.

A large prospective 10 year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89-1.26]).

A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22–2.19]).

Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10 year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data.

Pioglitazone may be associated with an increase in the risk of urinary bladder tumors.There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.

Consequently, Pioglitazone and Glimepiride Tablets should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Pioglitazone and Glimepiride Tablets should be considered in patients with a prior history of bladder cancer.

Edema

Pioglitazone

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 (6.1)]. In postmarketing experience, reports of new onset or worsening edema have been received.

Pioglitazone and Glimepiride Tablets 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, Pioglitazone and Glimepiride Tablets should be used with caution in patients at risk for congestive heart failure. Patients treated with Pioglitazone and Glimepiride Tablets should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)].

Fractures

Pioglitazone

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 Pioglitazone and Glimepiride Tablets and attention should be given to assessing and maintaining bone health according to current standards of care.

Hemolytic Anemia

Glimepiride

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because Pioglitazone and Glimepiride Tablets contain 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 (6.2)].

Macular Edema

Pioglitazone

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 (6.1)].

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Pioglitazone and Glimepiride Tablets or any other antidiabetic drug.

Pregnancy

Risk Summary

Limited data with Pioglitazone and Glimepiride Tablets or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are clinical considerations related to fetal and neonatal adverse reactions and drug discontinuation if glimepiride is used during pregnancy. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

No adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on the body surface area. Administration of glimepiride to pregnant rats and rabbits during organogenesis induced maternal hypoglycemia and also increased fetal mortality at doses 50 (rats) and 0.1 times (rabbits) the 8 mg clinical dose, respectively, based on body surface area [see Data].

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Fetal/Neonatal Adverse Reaction

Neonates of women with gestational diabetes, who are treated with sulfonylureas during pregnancy, may be at increased risk for neonatal intensive care unit admission, and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.

Dose adjustments during pregnancy and the postpartum period

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, pioglitazone and glimepiride should be discontinued at least two weeks before expected delivery [see Fetal/Neonatal Adverse Reaction].

Data

Animal Data

Pioglitazone and Glimepiride

Animal reproduction studies were not conducted with the combined products in Pioglitazone and Glimepiride Tablets. The following data are based on studies conducted with the individual components of Pioglitazone and Glimepiride Tablets.

Pioglitazone

Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5 times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9 times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35 times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69 times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area.

Glimepiride

Fetal deaths occurred in rats and rabbits administered glimepiride during the period of organogenesis at doses 50 times (rats) and 0.1 times (rabbits) the 8 mg clinical 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 been similarly noted with other sulfonylureas.

Lactation

Risk Summary

There is no information regarding the presence of pioglitazone or glimepiride in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and glimepiride are present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Pioglitazone and Glimepiride Tablets and any potential adverse effects on the breastfed infant from pioglitazone and glimepiride or from the underlying maternal condition.

Data

During pre- and postnatal studies in rats, glimepiride was present in lactational milk and in serum of nursing rat pups. Offspring exposed to high levels of glimepiride during lactation developed skeletal abnormalities (shortening, thickening and bending of the humerus) during the postnatal period.

Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

Pediatric Use

Safety and effectiveness of Pioglitazone and Glimepiride Tablets in pediatric patients have not been established.

Pioglitazone and Glimepiride Tablets are 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 (5.1, 5.6, 5.7, 5.8)].

Glimepiride

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 single-blind, 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-naïve 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).

Geriatric Use

To minimize the risk of hypoglycemia, the initial dosing, dose increments, and maintenance dosage of Pioglitazone and Glimepiride Tablets should be conservative. During initiation of pioglitazone and glimepiride tablet therapy and any subsequent dose adjustments, geriatric patients should be observed carefully for hypoglycemia.

Pioglitazone

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 (12.3)].

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.

Glimepiride

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 (12.3)].

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 (2.1) and Warnings and Precautions (5.2)]. Use caution when initiating Pioglitazone and Glimepiride Tablets and increasing the dose of Pioglitazone and Glimepiride Tablets in this patient population.

Renal Impairment

To minimize the risk of hypoglycemia, the initial dosing, dose increments and maintenance dosage of Pioglitazone and Glimepiride Tablets should be conservative. During initiation of pioglitazone and glimepiride tablet 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 (12.3)].

Read this Medication Guide carefully before you start taking Pioglitazone and Glimepiride Tablets 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 Pioglitazone and Glimepiride Tablets, ask your doctor or pharmacist.

What is the most important information I should know about Pioglitazone and Glimepiride Tablets?

Pioglitazone and Glimepiride Tablets can cause serious side effects, including new or worse heart failure.

• Pioglitazone, one of the medicines in Pioglitazone and Glimepiride Tablets, can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough
• Do not take Pioglitazone and Glimepiride Tablets if you have severe heart failure
• If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, Pioglitazone and Glimepiride Tablets may not be right for you

Call your doctor right away if you have any of the following:

• swelling or fluid retention, especially in the ankles or legs
• shortness of breath or trouble breathing, especially when you lie down
• an unusually fast increase in weight
• unusual tiredness

Pioglitazone and Glimepiride Tablets can have other serious side effects. See "What are the possible side effects of Pioglitazone and Glimepiride Tablets?"

What are Pioglitazone and Glimepiride Tablets?

Pioglitazone and Glimepiride Tablets are a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

Pioglitazone and Glimepiride Tablets contain 2 prescription diabetes medicines called pioglitazone (ACTOS) and glimepiride, a sulfonylurea.

Pioglitazone and Glimepiride Tablets are not for people with type 1 diabetes.

Pioglitazone and Glimepiride Tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

It is not known if Pioglitazone and Glimepiride Tablets are safe and effective in children under the age of 18. Pioglitazone and Glimepiride Tablets are not recommended for use in children.

Who should not take Pioglitazone and Glimepiride Tablets?

See "What is the most important information I should know about Pioglitazone and Glimepiride Tablets?"

Do not take Pioglitazone and Glimepiride Tablets if you:

• have severe heart failure
• are allergic to any of the ingredients in Pioglitazone and Glimepiride Tablets. See the end of this Medication Guide for a complete list of ingredients in Pioglitazone and Glimepiride Tablets
• have a condition called diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin

Talk to your doctor before taking Pioglitazone and Glimepiride Tablets if you have any of these conditions.

What should I tell my doctor before taking Pioglitazone and Glimepiride Tablets?

Before you take Pioglitazone and Glimepiride Tablets, tell your doctor if you:

• have heart failure
• have kidney problems
• have type 1 ("juvenile") diabetes or had diabetic ketoacidosis
• have a type of diabetic eye disease that causes swelling in the back of the eye (macular edema)
• have liver problems
• have or have had cancer of the bladder
• are pregnant or plan to become pregnant. It is not known if Pioglitazone and Glimepiride Tablets can harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant
• are a premenopausal woman (before the "change of life"), who does not have periods regularly or at all. Pioglitazone and Glimepiride Tablets may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking Pioglitazone and Glimepiride Tablets. Tell your doctor right away if you become pregnant while taking Pioglitazone and Glimepiride Tablets
• are breastfeeding or plan to breastfeed. It is not known if Pioglitazone and Glimepiride Tablets pass into your milk and if it can harm your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding
• have G6PD deficiency (an inherited condition where you don't produce enough of the enzyme [G6PD]). Taking glimepiride, one of the medicines in Pioglitazone and Glimepiride Tablets, with this condition may cause your red blood cells to be destroyed too quickly (hemolytic anemia)

Tell your doctor about all the medicines you take including prescription and over the counter medicines, vitamins, and herbal supplements.

Pioglitazone and Glimepiride Tablets and some of your other medicines can affect each other. You may need to have your dose of Pioglitazone and Glimepiride Tablets or certain other medicines changed.

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 Pioglitazone and Glimepiride Tablets with other medicines.

How should I take Pioglitazone and Glimepiride Tablets?

• Take Pioglitazone and Glimepiride Tablets exactly as your doctor tells you to take them
• Your doctor may change your dose of Pioglitazone and Glimepiride Tablets. Do not change your dose unless your doctor tells you to
• Pioglitazone and Glimepiride Tablets may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled
• Take Pioglitazone and Glimepiride Tablets one time each day with the first main meal
• If you take colesevelam, a medicine used to lower your cholesterol, take your Pioglitazone and Glimepiride Tablets at least 4 hours before you take your colesevelam.
• If you miss a dose of Pioglitazone and Glimepiride Tablets, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day
• If you take too many Pioglitazone and Glimepiride Tablets, call your doctor or go to the nearest hospital emergency room right away
• If your body is under stress such as from a fever, infection, accident, or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away
• Stay on your diet and exercise programs and test your blood sugar regularly while taking Pioglitazone and Glimepiride Tablets
• Your doctor should do certain blood tests before you start and while you take Pioglitazone and Glimepiride Tablets
• Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with Pioglitazone and Glimepiride Tablets
• Your doctor should check your eyes regularly while you take Pioglitazone and Glimepiride Tablets

What are the possible side effects of Pioglitazone and Glimepiride Tablets?

Pioglitazone and Glimepiride Tablets may cause serious side effects including:

• See "What is the most important information I should know about Pioglitazone and Glimepiride Tablets?"
• low blood sugar (hypoglycemia). This can happen if you skip meals, if you also use another medicine that lowers blood sugar, or if you have certain medical problems. Lightheadedness, dizziness, shakiness, or hunger may happen if your blood sugar is too low. Severe low blood sugar can cause unconsciousness (passing out), seizures, and death. Call your doctor if low blood sugar levels are a problem for you
• liver problems. Call your doctor right away if you have:
  • nausea or vomiting
  • stomach pain
  • unusual or unexplained tiredness
  • loss of appetite
  • dark urine
  • yellowing of your skin or the whites of your eyes
• bladder cancer. There may be an increased chance of having bladder cancer when you take Pioglitazone and Glimepiride Tablets. You should not take Pioglitazone and Glimepiride Tablets if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer:
  • blood or a red color in your urine
  • an increased need to urinate
  • pain while you urinate
• broken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthy.
• diabetic eye disease with swelling in the back of the eye (macular edema). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly
• release of an egg from an ovary in a woman (ovulation) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take Pioglitazone and Glimepiride Tablets. This can increase your chance of getting pregnant

The most common side effects of Pioglitazone and Glimepiride Tablets include:

• cold-like symptoms (upper respiratory tract infection)
• headache
• sinus infection
• diarrhea
• nausea
• muscle pain
• sore throat

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 Pioglitazone and Glimepiride Tablets. 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.

How should I store Pioglitazone and Glimepiride Tablets?

• Store Pioglitazone and Glimepiride Tablets at 68°F to 77°F (20°C to 25°C). Keep Pioglitazone and Glimepiride Tablets in the original container to protect from light
• Keep the Pioglitazone and Glimepiride Tablets bottle tightly closed and keep tablets dry
• Keep Pioglitazone and Glimepiride Tablets and all medicines out of the reach of children

General information about the safe and effective use of Pioglitazone and Glimepiride Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Pioglitazone and Glimepiride Tablets for a condition for which it was not prescribed. Do not give Pioglitazone and Glimepiride Tablets 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 Pioglitazone and Glimepiride Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Pioglitazone and Glimepiride Tablets that is written for healthcare professionals. For more information, call 1-877-825-3327.

What are the ingredients in Pioglitazone and Glimepiride Tablets?

Active ingredients: pioglitazone and glimepiride

Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, hydroxypropyl cellulose, polysorbate 80, and microcrystalline cellulose

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:
Prasco Laboratories
Mason, OH 45040 USA

Revised: December 2016

ACTOS is a registered trademark of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc.

PGL329 R2

PRINCIPAL DISPLAY PANEL – 30/2 mg Tablet Bottle Label

NDC 66993-821-30
30 Tablets

Rx Only

Prasco logo

Pioglitazone 30mg and
Glimepiride 2mg Tablets

Each tablet contains pioglitazone
hydrochloride equivalent to 30 mg
pioglitazone and 2 mg glimepiride.

Dispense with Medication Guide
available in package insert.

PRINCIPAL DISPLAY PANEL – 30/4 mg Tablet Bottle Label

NDC66993-822-30
30 Tablets

Rx Only

Prasco logo

Pioglitazone 30mg and
Glimepiride 4mg Tablets

Each tablet contains pioglitazone
hydrochloride equivalent to 30 mg
pioglitazone and 4 mg glimepiride.

Dispense with Medication Guide
available in package insert.