Monotherapy and Combination Therapy

Pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14)] .

Important Limitations of Use

Pioglitazone tablet exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

Use caution in patients with liver disease [see Warnings and Precautions (5.3)] .

2.1 Recommendations for All Patients

Pioglitazone tablets should be taken once daily and can be taken without regard to meals.

The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.

The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.

The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.

After initiation of pioglitazone tablets or with dose increase, monitor patients carefully for 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 (5.5)] .

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating pioglitazone tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone tablets are not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone tablets or who are found to have abnormal liver tests while taking pioglitazone tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)] .

2.2 Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient co-administered pioglitazone tablets and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered pioglitazone 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.

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone tablets and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone tablet is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.1 Congestive Heart Failure

Pioglitazone hydrochloride, 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 hydrochloride 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 pioglitazone hydrochloride must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions (6.1)] .

5.2 Hypoglycemia

Patients receiving pioglitazone hydrochloride in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration (2.2)] .

5.3 Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone hydrochloride, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone hydrochloride 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 hydrochloride therapy. In patients with abnormal liver tests, pioglitazone hydrochloride 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 hydrochloride treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone hydrochloride 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 hydrochloride. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone hydrochloride can be used with caution.

5.4 Urinary Bladder Tumors

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 hydrochloride 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 hydrochloride 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 hydrochloride. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone hydrochloride or placebo (HR =1.00; [95% CI: 0.59 to 1.72]).

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

A large prospective10-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 hydrochloride, compared to those never exposed to pioglitazone hydrochloride (HR =1.06 [95% CI 0.89 to 1.26]).

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

Associations between cumulative dose or cumulative duration of exposure to pioglitazone hydrochloride 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 hydrochloride 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 hydrochloride should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone hydrochloride should be considered in patients with a prior history of bladder cancer.

5.5 Edema

In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone hydrochloride 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 hydrochloride should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone hydrochloride, can cause fluid retention, which can exacerbate or lead to congestive heart failure, pioglitazone hydrochloride should be used with caution in patients at risk for congestive heart failure. Patients treated with pioglitazone hydrochloride should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1) and Patient Counseling Information (17)].

5.6 Fractures

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 hydrochloride (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 hydrochloride 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 hydrochloride (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone hydrochloride and attention should be given to assessing and maintaining bone health according to current standards of care.

5.7 Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone hydrochloride 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)] .

5.8 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone hydrochloride.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Over 8500 patients with type 2 diabetes have been treated with pioglitazone hydrochloride in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone hydrochloride in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone hydrochloride for six months or longer, over 4500 patients have been treated with pioglitazone hydrochloride for one year or longer, and over 3000 patients have been treated with pioglitazone hydrochloride for at least two years.

In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone hydrochloride and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone hydrochloride than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone hydrochloride and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone hydrochloride and 0.6% of patients treated with placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pioglitazone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)] .
• Fatal and nonfatal hepatic failure [see Warnings and Precautions (5.3)] .

Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone hydrochloride, both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)] .

7.1 Strong CYP2C8 Inhibitors

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t 1/2) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone hydrochloride is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

7.2 CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone hydrochloride, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone hydrochloride [see Clinical Pharmacology (12.3)] .

7.3 Topiramate

A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3)] . The clinical relevance of this decrease is unknown; however, when pioglitazone and topiramate are used concomitantly, monitor patients for adequate glycemic control.

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information regarding the presence of pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pioglitazone hydrochloride and any potential adverse effects on the breastfed infant from pioglitazone hydrochloride or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

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

8.4 Pediatric Use

Safety and effectiveness of pioglitazone hydrochloride in pediatric patients have not been established.

Pioglitazone hydrochloride 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 ( 5.1, 5.4, 5.5 and 5.6)].

8.5 Geriatric Use

A total of 92 patients (15.2%) treated with pioglitazone hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride were ≥65 years old and 22 (2.1%) were ≥75 years old.

In PROactive, 1068 patients (41.0%) treated with pioglitazone hydrochloride 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.

12.1 Mechanism of Action

Pioglitazone hydrochloride is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone hydrochloride decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an 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.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

12.2 Pharmacodynamics

Clinical studies demonstrate that pioglitazone hydrochloride improves insulin sensitivity in insulin-resistant patients. Pioglitazone hydrochloride enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone hydrochloride results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone hydrochloride had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14.2)].

Patients with lipid abnormalities were included in clinical trials with pioglitazone hydrochloride. Overall, patients treated with pioglitazone hydrochloride had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone hydrochloride or any other antidiabetic medication [see Warnings and Precautions (5.8) and Adverse Reactions (6.1)] .

In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg pioglitazone hydrochloride dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone hydrochloride than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone hydrochloride compared to placebo ( see Table 14) .

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks ) or insulin (16 weeks and 24 weeks), the results were generally consistent with the data above.

12.3 Pharmacokinetics

Following once-daily administration of pioglitazone hydrochloride, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.

C max, AUC, and trough serum concentrations (C min) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 2). 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/m 2). 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/m 2). 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/m 2).

13.2 Animal Toxicology and/or Pharmacology

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 2). 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 2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the maximum recommended human oral dose based on mg/m 2), 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 2).

14.1 Monotherapy

Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of pioglitazone hydrochloride as monotherapy in patients with type 2 diabetes. These trials examined pioglitazone hydrochloride at doses up to 45 mg or placebo once daily in a total of 865 patients.

In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of pioglitazone hydrochloride, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued eight weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of pioglitazone hydrochloride produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 17).

Figure 1 shows the time course for changes in HbA1c in this 26-week study.

In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration pioglitazone hydrochloride treatment groups or a mock-titration placebo group. Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. In one pioglitazone hydrochloride treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks). In the second pioglitazone hydrochloride treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with pioglitazone hydrochloride, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo ( see Table 18 )

In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of pioglitazone hydrochloride or placebo once daily. Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. Treatment with 30 mg of pioglitazone hydrochloride produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo ( see Table 19).

14.2 Combination Therapy

Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of pioglitazone hydrochloride (15 mg and/or 30 mg) on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin, or insulin. In addition, three 24-week randomized, double-blind clinical trials were conducted to evaluate the effects of pioglitazone hydrochloride 30 mg vs. pioglitazone hydrochloride 45 mg on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.

• 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 who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on pioglitazone tablets should immediately report these symptoms to a physician.
• Tell patients to promptly stop taking pioglitazone tablets 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.
• 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.
• Tell patients to take pioglitazone tablets once daily. Pioglitazone tablets can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day.
• When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
• Inform female patients that treatment with pioglitazone tablets, like other thiazolidinediones, may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].