pioglitazone (as pioglitazone hydrochloride) 30 MG Oral Tablet
Generic Name: PIOGLITAZONE
Brand Name: pioglitazone
- Substance Name(s):
- PIOGLITAZONE HYDROCHLORIDE
DRUG INTERACTIONS
7 Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations.
Limit pioglitazone dose to 15 mg daily.
(2.3, 7.1) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations.
(7.2) 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 (t½) of pioglitazone.
Therefore, the maximum recommended dose of pioglitazone 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, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical Pharmacology (12.3)].
OVERDOSAGE
10 During controlled clinical trials, one case of overdose with pioglitazone hydrochloride was reported.
A male patient took 120 mg per day for four days, then 180 mg per day for seven days.
The patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.
DESCRIPTION
11 Pioglitazone tablets, USP are thiazolidinedione and an agonist for peroxisome proliferator-activated 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 hydrochloride, USP is a white to creamish yellow 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, acetonitrile and practically insoluble in water and in ether.
Each pioglitazone tablet, USP intended for oral administration contains pioglitazone hydrochloride, USP equivalent to 15 mg or 30 mg or 45 mg of pioglitazone.
In addition each tablet contains the following inactive ingredients: carboxy methyl cellulose calcium, hydroxypropyl cellulose, lactose monohydrate and magnesium stearate.
Structural formula
CLINICAL STUDIES
14 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 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, 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 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.
Figure 1 Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study (Observed Values) Table 17 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Monotherapy Trial * Adjusted for baseline, pooled center, and pooled center by treatment interaction †p ≤ 0.05 vs.
placebo Placebo Pioglitazone 15 mg Once Daily Pioglitazone 30 mg Once Daily Pioglitazone 45 mg Once Daily Total Population HbA1c (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) 95% Confidence Interval -1† (-1.6, -0.4) -1† (-1.6, -0.4) -1.6† (-2.2, -1) Fasting Plasma Glucose (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) 95% Confidence Interval -39† (-63, -16) -41† (-64, -18) -65† (-89, -42) In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration pioglitazone 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 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 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, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 18).
Table 18 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy Trial * Final dose in forced titration †Adjusted for baseline, pooled center, and pooled center by treatment interaction ‡ p ≤ 0.05 vs.
placebo Placebo Pioglitazone 30 mg* Once Daily Pioglitazone 45 mg* Once Daily Total Population HbA1c (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10.8 Change from baseline (adjusted mean†) 0.9 -0.6 -0.6 Difference from placebo (adjusted mean†) 95% Confidence Interval -1.5‡ (-2, -1) -1.5‡ (-2, -1) Fasting Plasma Glucose (mg/dL) N=78 N=82 N=85 Baseline (mean) 279 268 281 Change from baseline (adjusted mean†) 18 -44 -50 Difference from placebo (adjusted mean†) 95% Confidence Interval -62‡ (-82, -0.41) -68‡ (-88, -0.48) In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of pioglitazone 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 produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 19).
Table 19 Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial *Adjusted for baseline, pooled center, and pooled center by treatment interaction †p ≤ 0.05 vs.
placebo Placebo Pioglitazone 30 mg Once Daily Total Population HbA1c (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0.8 -0.6 Difference from placebo (adjusted mean*) 95% Confidence Interval -1.4† (-1.8, -0.9) Fasting Plasma Glucose (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean*) 8 -50 Difference from placebo (adjusted mean*) 95% Confidence Interval -58† (-77, -38) 14.2 Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of pioglitazone (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 30 mg vs.
pioglitazone 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.
Add-on to Sulfonylurea Trials Two clinical trials were conducted with pioglitazone hydrochloride in combination with a sulfonylurea.
Both studies included patients with type 2 diabetes on any dose of a sulfonylurea, either alone or in combination with another antidiabetic agent.
All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment.
In the first study, 560 patients were randomized to receive 15 mg or 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen.
Treatment with pioglitazone hydrochloride as add-on to sulfonylurea produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to sulfonylurea (see Table 20).
Table 20 Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Sulfonylurea Trial *Adjusted for baseline, pooled center, and pooled center by treatment interaction †p ≤ 0.05 vs.
placebo + sulfonylurea Placebo + Sulfonylurea Pioglitazone 15 mg + Sulfonylurea Pioglitazone 30 mg + Sulfonylurea Total Population HbA1c (%) N=181 N=176 N=182 Baseline (mean) 9.9 10 9.9 Change from baseline (adjusted mean*) 0.1 -0.8 -1.2 Difference from placebo + sulfonylurea (adjusted mean*) 95% Confidence Interval -0.9† (-1.2, -0.6) -1.3† (-1.6, -1) Fasting Plasma Glucose (mg/dL) N=182 N=179 N=186 Baseline (mean) 236 247 239 Change from baseline (adjusted mean*) 6 -34 -52 Difference from placebo + sulfonylurea (adjusted mean*) 95% Confidence Interval -39† (-52, -27) -58† (-70, -46) In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current sulfonylurea regimen.
The mean reduction from baseline at Week 24 in HbA1c was 1.6% for the 30 mg dose and 1.7% for the 45 mg dose (see Table 21).
The mean reduction from baseline at Week 24 in FPG was 52 mg/dL for the 30 mg dose and 56 mg/dL for the 45 mg dose.
The therapeutic effect of pioglitazone hydrochloride in combination with sulfonylurea was observed in patients regardless of the sulfonylurea dose.
Table 21 Glycemic Parameters in a 24-Week Add-on to Sulfonylurea Trial 95% CI = 95% confidence interval *Adjusted for baseline, pooled center, and pooled center by treatment interaction Pioglitazone 30 mg + Sulfonylurea Pioglitazone 45 mg + Sulfonylurea Total Population HbA1c (%) N=340 N=332 Baseline (mean) 9.8 9.9 Change from baseline (adjusted mean*) -1.6 -1.7 Difference from 30 mg daily pioglitazone + sulfonylurea (adjusted mean*) (95% CI) -0.1 (-0.4, 0.1) Fasting Plasma Glucose (mg/dL) N=338 N=329 Baseline (mean) 214 217 Change from baseline (adjusted mean*) -52 -56 Difference from 30 mg daily pioglitazone + sulfonylurea (adjusted mean*) (95% CI) -5 (-12, 3) Add-on to Metformin Trials Two clinical trials were conducted with pioglitazone hydrochloride in combination with metformin.
Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent.
All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment.
In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current metformin regimen.
Treatment with pioglitazone hydrochloride as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22).
Table 22 Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Metformin Trial *Adjusted for baseline, pooled center, and pooled center by treatment interaction †p ≤ 0.05 vs.
placebo + metformin Placebo + Metformin Pioglitazone 30 mg + Metformin Total Population HbA1c (%) N=153 N=161 Baseline (mean) 9.8 9.9 Change from baseline (adjusted mean*) 0.2 -0.6 Difference from placebo + metformin (adjusted mean*) 95% Confidence Interval -0.8† (-1.2, -0.5) Fasting Plasma Glucose (mg/dL) N=157 N=165 Baseline (mean) 260 254 Change from baseline (adjusted mean*) -5 -43 Difference from placebo + metformin (adjusted mean*) 95% Confidence Interval -38† (-49, -26) In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current metformin regimen.
The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1% for the 45 mg dose (see Table 23).
The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
Table 23 Glycemic Parameters in a 24-Week Add-on to Metformin Study 95% CI = 95% confidence interval *Adjusted for baseline, pooled center, and pooled center by treatment interaction † p ≤ 0.05 vs.
30 mg daily pioglitazone + metformin Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin Total Population HbA1c (%) N=400 N=398 Baseline (mean) 9.9 9.8 Change from baseline (adjusted mean*) -0.8 -1 Difference from 30 mg daily pioglitazone + Metformin (adjusted mean*) (95% CI) -0.2 (-0.5, 0.1) Fasting Plasma Glucose (mg/dL) N=398 N=399 Baseline (mean) 233 232 Change from baseline (adjusted mean*) -38 -51 Difference from 30 mg daily pioglitazone + Metformin (adjusted mean*) (95% CI) -12† (-21, -4) The therapeutic effect of pioglitazone hydrochloride in combination with metformin was observed in patients regardless of the metformin dose.
Add-on to Insulin Trials Two clinical trials were conducted with pioglitazone hydrochloride in combination with insulin.
Both trials included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent.
All other antidiabetic agents were withdrawn prior to starting study treatment.
In the first trial, 566 patients were randomized to receive either 15 mg or 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their insulin regimen.
Treatment with pioglitazone hydrochloride as add-on to insulin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin (see Table 24).
The mean daily insulin dose at baseline in each treatment group was approximately 70 units.
The majority of patients (75% overall, 86% treated with placebo, 77% treated with pioglitazone 15 mg, and 61% treated with pioglitazone 30 mg) had no change in their daily insulin dose from baseline to the final study visit.
The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -3 units in the patients treated with pioglitazone 15 mg, -8 units in the patients treated with pioglitazone 30 mg, and -1 unit in patients treated with placebo.
Table 24 Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Insulin Trial *Adjusted for baseline, pooled center, and pooled center by treatment interaction †p ≤ 0.05 vs.
placebo + insulin Placebo + Insulin Pioglitazone 15 mg + Insulin Pioglitazone 30 mg + Insulin Total Population HbA1c (%) N=177 N=177 N=185 Baseline (mean) 9.8 9.8 9.8 Change from baseline (adjusted mean*) -0.3 -1 -1.3 Difference from placebo + Insulin (adjusted mean*) 95% Confidence Interval -0.7† (-1, -0.5) -1† (-1.3, -0.7) Fasting Plasma Glucose (mg/dL) N=179 N=183 N=184 Baseline (mean) 221 222 229 Change from baseline (adjusted mean*) 1 -35 -48 Difference from placebo + Insulin (adjusted mean*) 95% Confidence Interval -35† (-51, -19) -49† (-65, -33) In the second trial, 690 patients receiving a median of 60 units per day of insulin were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current insulin regimen.
The mean reduction from baseline at Week 24 in HbA1c was 1.2% for the 30 mg dose and 1.5% for the 45 mg dose.
The mean reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and 46 mg/dL for the 45 mg dose (see Table 25).
The mean daily insulin dose at baseline in both treatment groups was approximately 70 units.
The majority of patients (55% overall, 58% treated with pioglitazone 30 mg, and 52% treated with pioglitazone 45 mg) had no change in their daily insulin dose from baseline to the final study visit.
The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -5 units in the patients treated with pioglitazone 30 mg and -8 units in the patients treated with pioglitazone 45 mg.
The therapeutic effect of pioglitazone hydrochloride in combination with insulin was observed in patients regardless of the insulin dose.
Table 25 Glycemic Parameters in a 24 Week Add-on to Insulin Trial 95% CI = 95% confidence interval *Adjusted for baseline, pooled center, and pooled center by treatment interaction † p ≤ 0.05 vs.
30 mg daily pioglitazone + insulin Pioglitazone 30 mg + Insulin Pioglitazone 45 mg + Insulin Total Population HbA1c (%) N=328 N=328 Baseline (mean) 9.9 9.7 Change from baseline (adjusted mean*) -1.2 -1.5 Difference from 30 mg daily pioglitazone + Insulin (adjusted mean*) (95% CI) -0.3† (-0.5, -0.1) Fasting Plasma Glucose (mg/dL) N=325 N=327 Baseline (mean) 202 199 Change from baseline (adjusted mean*) -32 -46 Difference from 30 mg daily pioglitazone + Insulin (adjusted mean*) (95% CI) -14† (-25, -3) Pioglitazone Tablets, USP
HOW SUPPLIED
16 /STORAGE AND HANDLING Pioglitazone Tablets, USP equivalent to 15 mg of pioglitazone are off-white to cream white, round flat faced beveled edge uncoated tablet debossed with “306” on one side and plain on other side and are supplied as follows: NDC 70771-1021-3 in bottle of 30 tablets NDC 70771-1021-9 in bottle of 90 tablets NDC 70771-1021-1 in bottle of 100 tablets NDC 70771-1021-5 in bottle of 500 tablets NDC 70771-1021-0 in bottle of 1000 tablets NDC 70771-1021-4 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Pioglitazone Tablets, USP equivalent to 30 mg of pioglitazone are off-white to cream white, round flat faced beveled edge uncoated tablet debossed with “307” on one side and plain on other side and are supplied as follows: NDC 70771-1022-3 in bottle of 30 tablets NDC 70771-1022-9 in bottle of 90 tablets NDC 70771-1022-1 in bottle of 100 tablets NDC 70771-1022-5 in bottle of 500 tablets NDC 70771-1022-0 in bottle of 1000 tablets NDC 70771-1022-4 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Pioglitazone Tablets, USP equivalent to 45 mg of pioglitazone are off-white to cream white, round flat faced beveled edge uncoated tablet debossed with “308” on one side and plain on other side and are supplied as follows: NDC 70771-1023-3 in bottle of 30 tablets NDC 70771-1023-9 in bottle of 90 tablets NDC 70771-1023-1 in bottle of 100 tablets NDC 70771-1023-5 in bottle of 500 tablets NDC 70771-1023-0 in bottle of 1000 tablets NDC 70771-1023-4 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets STORAGE Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Keep container tightly closed, and protect from light, moisture and humidity.
RECENT MAJOR CHANGES
Warnings and Precautions Urinary bladder tumors (5.4) 12/2016
GERIATRIC USE
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%) 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.
DOSAGE FORMS AND STRENGTHS
3 Tablets: 15 mg, 30 mg, and 45 mg (3) 15 mg are off-white to cream white, round flat faced beveled edge uncoated tablet debossed with “306” on one side and plain on other side.
30 mg are off-white to cream white, round flat faced beveled edge uncoated tablet debossed with “307” on one side and plain on other side.
45 mg are off-white to cream white, round flat faced beveled edge uncoated tablet debossed with “308” on one side and plain on other side.
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 Monotherapy and Combination Therapy Pioglitazone tablets, USP 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 hydrochloride exerts its antihyperglycemic effect only in the presence of endogenous insulin.
Pioglitazone hydrochloride 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)].
Pioglitazone tablets, USP are a thiazolidinedione and an agonist for peroxisome proliferator- activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
(1, 14) Important Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis.
(1)
PEDIATRIC USE
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)].
PREGNANCY
8.1 Pregnancy Risk Summary Limited data with pioglitazone hydrochloride 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 % to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 % to 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 % to 4% and 15 % to 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.
NUSRING MOTHERS
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.
BOXED WARNING
WARNING: CONGESTIVE HEART FAILURE WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning.
Thiazolidinediones, including pioglitazone hydrochloride, cause or exacerbate congestive heart failure in some patients.
(5.1) After initiation of pioglitazone hydrochloride, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema).
If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone hydrochloride must be considered.
(5.1) Pioglitazone hydrochloride is not recommended in patients with symptomatic heart failure.(5.2) Initiation of pioglitazone hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
(4, 5.1) Thiazolidinediones, including pioglitazone hydrochloride, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
After initiation of pioglitazone hydrochloride, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema).
If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone hydrochloride must be considered.
Pioglitazone hydrochloride is not recommended in patients with symptomatic heart failure.
Initiation of pioglitazone hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure.
Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk.
Monitor patients for signs and symptoms.
(5.1) Hypoglycemia: When used with insulin or an insulin secretagogue, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia.
(5.2) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal.
Causality cannot be excluded.
If liver injury is detected, promptly interrupt pioglitazone hydrochloride and assess patient for probable cause, then treat cause if possible, to resolution or stabilization.
Do not restart pioglitazone hydrochloride if liver injury is confirmed and no alternate etiology can be found.
(5.3) Bladder cancer: May increase the risk of bladder cancer.
Do not use in patients with active bladder cancer.
Use caution when using in patients with a prior history of bladder cancer.
(5.4) Edema: Dose-related edema may occur.
(5.5) Fractures: Increased incidence in female patients.
Apply current standards of care for assessing and maintaining bone health.
(5.6) Macular edema: Postmarketing reports.
Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes.
(5.7) Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone hydrochloride or any other anti-diabetic drug.
(5.8) 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 or any other anti-diabetic drug.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Medication Guide) 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 hydrochloride should immediately report these symptoms to a physician.
Tell patients to promptly stop taking pioglitazone hydrochloride 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 hydrochloride once daily.
Pioglitazone hydrochloride 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 hydrochloride, 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)] .
DOSAGE AND ADMINISTRATION
2 Initiate pioglitazone tablets at 15 mg or 30 mg once daily.
Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure.
(2.1) If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily.
(2.1) Obtain liver tests before starting pioglitazone hydrochloride.
If abnormal, use caution when treating with pioglitazone hydrochloride, investigate the probable cause, treat (if possible) and follow appropriately.
Monitoring liver tests while on pioglitazone hydrochloride is not recommended in patients without liver disease.
(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 hydrochloride 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 hydrochloride.
Routine periodic monitoring of liver tests during treatment with pioglitazone hydrochloride is not recommended in patients without liver disease.
Patients who have liver test abnormalities prior to initiation of pioglitazone hydrochloride or who are found to have abnormal liver tests while taking pioglitazone hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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)].