Pioglitazone Tablets

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 [seeBoxed 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 is 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)].

Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient coadministered Pioglitazone Tablets and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered 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.

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 Tablets 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)].

Initiation in patients with established NYHA Class III or IV heart failure [seeBoxed Warning].

Use in patients with known hypersensitivity to Pioglitazone Tablets or any other component of pioglitazone.

Pregnancy

Risk Summary

Limited data with pioglitazone in pregnant women are not sufficient to determine a drug- associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal reproduction studies, 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 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

Data

Animal Data

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.

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 and any potential adverse effects on the breastfed infant from pioglitazone or from the underlying maternal condition.

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 in pediatric patients have not been established.

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

Geriatric Use

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, 1,068 patients (41%) 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.

Pioglitazone Tablets, USP are a thiazolidinedione and an agonist for peroxisome proliferatoractivated receptor (PPAR) gamma that contains an oral antidiabetic medication: pioglitazone.

Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:

Pioglitazone is an odorless, white to off white, crystalline powder that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Pioglitazone Tablets, USP contain 15 mg, 30 mg, and 45 mg of pioglitazone (as the base). In addition, each tablet contains the following inactive ingredients: carboxymethyl cellulose calcium, hydroxypropyl cellulose, lactose monohydrate, and magnesium stearate.

NDC 0781-5420-31

Pioglitazone
Tablets, USP
15 mg

Rx Only

PHARMACIST: Dispense the Medication

Guide provided separately to each patient.

30 Tablets

Sandoz