PIOGLITAZONE HYDROCHLORIDE- pioglitazone hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PIOGLITAZONE HYDROCHLORIDE (UNII: JQT35NPK6C) (PIOGLITAZONE - UNII:X4OV71U42S)
Available from:
NuCare Pharmaceuticals, Inc.
INN (International Name):
PIOGLITAZONE HYDROCHLORIDE
Composition:
PIOGLITAZONE 15 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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)] . 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)]. Do not initiate in patients with NYHA Class III or IV heart failure [see Boxed Warning] . Do not use in patients with a history of a serious hypersensitivity reaction to pioglitazone tablets or any of its ingredients. Pregnancy Category C. There are no adequate and well-controlled studies of pioglitazone hydrochloride in pregnant women. Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maxim
Product summary:
Pioglitazone tablets USP are available in 15 mg, tablets as follows: 15 mg tablet: White to off-white, round, biconvex, uncoated tablets debossed with ‘P’ on one side and ‘15’ on other side, available in: NDC 68071-2170-3 Bottles of 30 Storage: Store at 20º to 25ºC (68º to 77 ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-2170-3

NuCare Pharmaceuticals, Inc.

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MEDICATION GUIDE

Pioglitazone Tablets USP

Read this Medication Guide carefully before you start taking pioglitazone 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 tablets, ask

your doctor or pharmacist.

What is the most important information I should know about pioglitazone tablets?

Pioglitazone tablets can cause serious side effects, including new or worse heart failure.

Pioglitazone 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 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 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 tablets can have other serious side effects. See " What are the possible side effects of

pioglitazone tablets?"

What are pioglitazone tablets?

Pioglitazone tablet is a prescription medicine used with diet and exercise to improve blood sugar

(glucose) control in adults with type 2 diabetes. Pioglitazone tablet is a diabetes medicine called

pioglitazone hydrochloride that may be taken alone or with other diabetes medicines.

It is not known if pioglitazone tablet is safe and effective in children.

Who should not take pioglitazone tablets?

See " What is the most important information I should know about pioglitazone tablets?"

Do not take pioglitazone tablets if you:

have severe heart failure

are allergic to any of the ingredients in pioglitazone tablets . See the end of this Medication Guide

for a complete list of ingredients in pioglitazone tablets

Talk to your doctor before taking pioglitazone tablets if you have either of these conditions.

What should I tell my doctor before taking pioglitazone tablets?

Before you start taking pioglitazone tablets, tell your doctor if you:

have heart failure

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

are pregnant or plan to become pregnant. It is not known if pioglitazone tablets will 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 tablets may increase your chance of becoming pregnant. Talk to your doctor

about birth control choices while taking pioglitazone tablets. Tell your doctor right away if you

become pregnant while taking pioglitazone tablets

are breast-feeding or plan to breast-feed. It is not known if pioglitazone tablets passes into your

milk and if it can harm your baby. You should not take pioglitazone tablets if you breastfeed your

baby. Talk to your doctor about the best way to control your blood glucose levels while

breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines,

vitamins, and herbal supplements.

Pioglitazone tablets and some of your other medicines can affect each other. You may need to have your

dose of pioglitazone 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 tablets with other

medicines.

How should I take pioglitazone tablets?

Take pioglitazone tablets exactly as your doctor tells you to take it

Your doctor may change your dose of pioglitazone tablets. Do not change your pioglitazone

tablets dose unless your doctor tells you to

Pioglitazone tablets may be prescribed alone or with other diabetes medicines. This will depend on

how well your blood sugar is controlled

Take pioglitazone tablets 1 time each day, with or without food

If you miss a dose of pioglitazone 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 much pioglitazone 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 tablets

Your doctor should do certain blood tests before you start and while you take pioglitazone tablets

Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is

controlled with pioglitazone tablets

Your doctor should check your eyes regularly while you take pioglitazone tablets

It may take 2 to 3 months to see the full effect of pioglitazone tablets on your blood sugar level.

What are the possible side effects of pioglitazone tablets?

Pioglitazone tablets may cause serious side effects including:

See " What is the most important information about pioglitazone tablets."

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

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.

bladder cancer. There may be an increased chance of having bladder cancer when you take

pioglitazone tablets. You should not take pioglitazone 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

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. Call your doctor if low

blood sugar levels are a problem for you

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

tablets. This can increase your chance of getting pregnant

The most common side effects of pioglitazone tablets include:

cold-like symptoms (respiratory tract infection)

headache

sinus infection

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 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 tablets?

Store pioglitazone tablets at 59°F to 86°F (15°C to 30°C). Keep pioglitazone tablets in the original

container and protect from light

Keep the pioglitazone tablets bottle tightly closed and protect from getting wet (away from

moisture and humidity)

Keep pioglitazone tablets and all medicines out of the reach of children

General information about the safe and effective use of pioglitazone tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use pioglitazone tablets for a condition for which it was not prescribed. Do not give pioglitazone 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 tablets. If you

would like more information, talk with your doctor. You can ask your doctor or pharmacist for

information about pioglitazone tablets that is written for healthcare professionals.

What are the ingredients in pioglitazone tablets?

Active Ingredient: pioglitazone hydrochloride

Inactive Ingredients: lactose monohydrate, hydroxypropylcellulose, carboxymethylcellulose calcium, and

magnesium stearate.

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

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. : 457, 458,

Village – Matoda,

Bavla Road, Ta.- Sanand,

Dist.- Ahmedabad – 382 210,

INDIA.

10 1383 2 662575

Issued August 2015

Revised: 3/2019

Document Id: 8348be95-d9e9-3f84-e053-2a91aa0a78e7

34391-3

Set id: 46f1f990-7dc2-027b-e054-00144ff8d46c

Version: 2

Effective Time: 20190304

NuCare Pharmaceuticals, Inc.

PIOGLITAZONE HYDROCHLORIDE- pioglitazone hydrochloride tablet

NuCare Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PIOGLITAZONE TABLETS, USP safely and

effectively. See full prescribing information for PIOGLITAZONE TABLETS, USP.

PIOGLITAZONE tablets, for oral use

Initial U.S. Approval: 1999

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 tablets, 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 tablets must be considered. ( 5.1)

Pioglitazone tablets are not recommended in patients with symptomatic heart failure.

Initiation of pioglitazone tablets in patients with established New York Heart Association (NYHA)

Class III or IV heart failure is contraindicated. ( 4, 5.1)

RECENT MAJOR CHANGES

Indications and Usage

Important Limitations of Use ( 1.2)

01/2011

Dosage and Administration

Recommendations for All Patients ( 2.1)

01/2011

Coadministration with Strong CYP2C8 Inhibitors ( 2.3)

01/2011

Warnings and Precautions

Hepatic Effects ( 5.3)

01/2011

Urinary Bladder Tumors ( 5.5)

07/2011

INDICATIONS AND USAGE

Pioglitazone tablet is 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. ( 1.1, 14)

Important Limitation of Use:

Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1.2)

DOSAGE AND ADMINISTRATION

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 tablets. If abnormal, use caution when treating with pioglitazone tablets,

investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on pioglitazone

tablet is not recommended in patients without liver disease. ( 5.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 15 mg, 30 mg, and 45 mg ( 3)

CONTRAINDICATIONS

Do not initiate pioglitazone tablets in patients with established NYHA Class III or IV heart failure. ( 4)

Do not use in patients with a history of a serious hypersensitivity reaction to pioglitazone tablets or its ingredients. ( 4)

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)

Edema: Dose-related edema may occur. ( 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)

Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone

health. ( 5.4)

Bladder cancer: Preclinical and clinical trial data, and results from an observational study suggest an increased risk of

bladder cancer in pioglitazone users. The observational data further suggest that the risk increases with duration of use.

Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder

cancer ( 5.5)

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. ( 5.6)

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. ( 5.9)

ADVERSE REACTIONS

Most common adverse reactions (≥ 5% and at a rate higher than with placebo) include upper respiratory tract infection,

headache, sinusitis, myalgia, and pharyngitis. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone tablets dose to 15

mg daily. ( 2.3, 7.1)

CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. ( 7.2)

USE IN SPECIFIC POPULATIONS

Pregnancy Category C: Based on animal data, may cause fetal harm ( 8.1)

Nursing mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother ( 8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 3/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CONGESTIVE HEART FAILURE

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

1.2 Important Limitation of Use

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for all patients

2.2 Concomitant use with an insulin secretagogue or insulin

2.3 Coadministration with strong CYP2C8 inhibitors

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure

5.2 Edema

5.3 Hepatic Effects

5.4 Fractures

5.5 Urinary Bladder Tumors

5.6 Hypoglycemia

5.7 Macular Edema

5.8 Ovulation

5.9 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Laboratory Abnormalities

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Strong CYP2C8 Inhibitors

7.2 CYP2C8 Inducers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

13.3 Reproductive and Developmental Toxicology

14 CLINICAL STUDIES

14.1 Monotherapy

14.2 Combination Therapy

16 HOW SUPPLIED/ STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Instructions

17.2 FDA-Approved Medication Guide

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: CONGESTIVE HEART FAILURE

Thiazolidinediones, including pioglitazone hydrochloride, cause or exacerbate

congestive heart failure in some patients [see Warnings and Precautions (5.1)] .

After initiation of pioglitazone tablets, 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 tablets are 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)] .

1 INDICATIONS AND USAGE

1.1 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)] .

1.2 Important Limitation 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 DOSAGE AND ADMINISTRATION

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 (5.2)] . 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 Coadministration 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)].

3 DOSAGE FORMS AND STRENGTHS

Round tablet contains pioglitazone as follows:

15 mg: White to off-white, debossed with "P" on one side and "15" on the other

30 mg: White to off-white, debossed with "PIO" on one side and "30" on the other

45 mg: White to off-white, debossed with "PIO" on one side and "45" on the other

4 CONTRAINDICATIONS

Do not initiate in patients with NYHA Class III or IV heart failure [see Boxed Warning] .

Do not use in patients with a history of a serious hypersensitivity reaction to pioglitazone tablets or any

of its ingredients.

5 WARNINGS AND PRECAUTIONS

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 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 (17.1)] .

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 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.

5.5 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 two 3-year trials in which pioglitazone hydrochloride was compared

to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking

pioglitazone hydrochloride compared to 5/3679 (0.14%) in patients not taking pioglitazone

hydrochloride. After excluding patients in whom exposure to study drug was less than one year at the

time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone hydrochloride and

two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a non-significant

increase in the risk for bladder cancer in subjects ever exposed to pioglitazone hydrochloride,

compared to subjects never exposed to pioglitazone hydrochloride (HR 1.2 [95% CI 0.9 to 1.5]).

Compared to never exposure, a duration of pioglitazone hydrochloride therapy longer than 12 months

was associated with an increase in risk (HR 1.4 [95% CI 0.9 to 2.1]), which reached statistical

significance after more than 24 months of pioglitazone hydrochloride use (HR 1.4 [95% CI 1.03 to

2.0]). Interim results from this study suggested that taking pioglitazone hydrochloride longer than 12

months increased the relative risk of developing bladder cancer in any given year by 40% which

equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without

pioglitazone hydrochloride] to approximately 10 in 10,000 [with pioglitazone hydrochloride]).

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.

5.6 Hypoglycemia

Patients receiving pioglitazone hydrochloride in combination with insulin or other anti-diabetic

medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia.

A reduction in the dose of the concomitant anti-diabetic medication may be necessary to reduce the risk

of hypoglycemia [see Dosage and Administration (2.2)].

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 Ovulation

Therapy with pioglitazone hydrochloride, like other thiazolidinediones, may result in ovulation in some

premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy

while taking pioglitazone hydrochloride [see Use in Specific Populations (8.1)] . This effect has not been

investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception

in all premenopausal women treated with pioglitazone hydrochloride is recommended.

5.9 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction

with pioglitazone hydrochloride or any other anti-diabetic drug.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]

Edema [see Warnings and Precautions (5.2)]

Fractures [see Warnings and Precautions (5.4)]

6.1 Clinical Studies 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 6 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 2 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.

Common Adverse Events: 16 to 26-Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16 to 26-week

placebo-controlled monotherapy trials of pioglitazone hydrochloride is provided in Table 1. Terms that

are reported represent those that occurred at an incidence of >5% and more commonly in patients treated

with pioglitazone hydrochloride than in patients who received placebo. None of these adverse events

were related to pioglitazone hydrochloride dose.

Table 1: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of

Pioglitazone Hydrochloride Monotherapy: Adverse Events Reported at an

Incidence > 5% and More Commonly in Patients Treated with Pioglitazone

Hydrochloride than in Patients Treated with Placebo

% of Patients

Placebo

N=259

Pioglitazone

Hydrochloride

N=606

Upper Respiratory Tract

Infection

13.2

Headache

Sinusitis

Myalgia

Pharyngitis

Common Adverse Events: 16 to 24-Week Add-on Combination Therapy Trials

A summary of the overall incidence and types of common adverse events reported in trials of

pioglitazone hydrochloride add-on to sulfonylurea is provided in Table 2. Terms that are reported

represent those that occurred at an incidence of >5% and more commonly with the highest tested dose

of pioglitazone hydrochloride.

Table 2: 16 to 24 Week Clinical Trials of Pioglitazone Hydrochloride Add-on to Sulfonylurea

16-Week Placebo-Controlled Trial Adverse Events Reported in >

5% of Patients and More Commonly in Patients Treated with

Pioglitazone Hydrochloride 30 mg + Sulfonylurea than in Patients

Treated with Placebo + Sulfonylurea

% of Patients

Placebo +

Sulfonylurea

Pioglitazone

Hydrochloride

15 mg

Pioglitazone Hydrochloride

30 mg

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention

were combined to form the aggregate term of “edema.”

Sulfonylurea

N=187

15 mg

+ Sulfonylurea

N=184

+ Sulfonylurea

N=189

Edema

12.7

Headache

Flatulence

Weight Increased

24-Week Non-Controlled Double-Blind Trial Adverse Events

Reported in > 5% of Patients and More Commonly in Patients

Treated with pioglitazone hydrochloride 45 mg + Sulfonylurea than

in Patients Treated with pioglitazone hydrochloride 30 mg +

Sulfonylurea

% of Patients

Pioglitazone Hydrochloride

30 mg

+ Sulfonylurea

N=351

Pioglitazone Hydrochloride

45 mg

+ Sulfonylurea

N=351

Hypoglycemia

13.4

15.7

Edema

10.5

23.1

Upper Respiratory Tract

Infection

12.3

14.8

Weight Increased

13.4

Urinary Tract Infection

A summary of the overall incidence and types of common adverse events reported in trials of

pioglitazone hydrochloride add-on to metformin is provided in Table 3. Terms that are reported

represent those that occurred at an incidence of >5% and more commonly with the highest tested dose

of pioglitazone hydrochloride.

Table 3: 16 to 24 Week Clinical Trials of pioglitazone hydrochloride Add-on to Metformin

16-Week Placebo-Controlled Trial

Adverse Events Reported in > 5% of Patients and More

Commonly in Patients Treated with pioglitazone

hydrochloride + Metformin than in Patients Treated with

Placebo + Metformin

% of Patients

Placebo

+ Metformin

N=160

Pioglitazone Hydrochloride

30 mg + Metformin

N=168

Edema

Headache

24-Week Non-Controlled Double-Blind Trial

Adverse Events Reported in > 5% of Patients and More

Commonly in Patients Treated with Pioglitazone

Hydrochloride 45 mg + Metformin than in Patients

Treated with Pioglitazone Hydrochloride 30 mg +

Metformin

% of Patients

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention

were combined to form the aggregate term of "edema."

Pioglitazone Hydrochloride

30 mg + Metformin

N=411

Pioglitazone Hydrochloride

45 mg + Metformin

N=416

Upper Respiratory Tract Infection

12.4

13.5

Edema

13.9

Headache

Weight Increased

Table 4 summarizes the incidence and types of common adverse events reported in trials of pioglitazone

hydrochloride add-on to insulin. Terms that are reported represent those that occurred at an incidence

of > 5% and more commonly with the highest tested dose of pioglitazone hydrochloride.

Table 4: 16 to 24 Week Clinical Trials of Pioglitazone Hydrochloride Add-on to Insulin

16-Week Placebo-Controlled Trial

Adverse Events Reported in >5% of Patients and More

Commonly in Patients Treated with Pioglitazone Hydrochloride

30 mg + Insulin than in Patients Treated with Placebo + Insulin

% of Patients

Placebo

+Insulin

N=187

Pioglitazone

Hydrochloride

15 mg + Insulin

N=191

Pioglitazone

Hydrochloride

30 mg + Insulin

N=188

Hypoglycemia

15.4

Edema

12.6

17.6

Upper Respiratory Tract

Infection

14.9

Headache

Weight Increased

Back Pain

Dizziness

Flatulence

24-Week Non-Controlled Double-Blind Trial Adverse Events

Reported in > 5% of Patients and More Commonly in Patients

Treated with Pioglitazone Hydrochloride 45 mg + Insulin than in

Patients Treated with Pioglitazone Hydrochloride 30 mg +

Ins ulin

% of Patients

Pioglitazone Hydrochloride

30 mg + Insulin

N=345

Pioglitazone

Hydrochloride

45 mg + Insulin

N=345

Hypoglycemia

43.5

47.8

Edema

22.0

26.1

Weight Increased

13.9

Urinary Tract Infection

Diarrhea

Back Pain

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention

were combined to form the aggregate term of "edema."

Blood Creatine Phosphokinase

Sinusitis

Hypertension

A summary of the overall incidence and types of common adverse events reported in the PROactive trial

is provided in Table 5. Terms that are reported represent those that occurred at an incidence of >5% and

more commonly in patients treated with pioglitazone hydrochloride than in patients who received

placebo.

Table 5: PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients

Treated with Pioglitazone Hydrochloride and More Commonly than Placebo

% of Patients

Placebo

N=2633

Pioglitazone Hydrochloride

N=2605

Mean duration of patient follow-up was 34.5 months.

Hypoglycemia

18.8

27.3

Edema

15.3

26.7

Cardiac Failure

Pain in Extremity

Back Pain

Chest Pain

Congestive Heart Failure: A summary of the incidence of adverse events related to congestive heart

failure is provided in Table 6 for the 16 to 24-week add-on to sulfonylurea trials, for the 16 to 24-week

add-on to insulin trials, and for the 16 to 24-week add-on to metformin trials. None of the events were

fatal.

Table 6: Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients Treated with Pioglitazone Hydrochloride or Placebo Added on to a Sulfonylurea

Number (%) of Patients

Placebo-Controlled Trial

(16 weeks)

Non-Controlled

Double Blind Trial

(24 weeks)

Placebo +

Sulfonylurea

N=187

Pioglitazone

Hydrochloride

15 mg

+ Sulfonylurea

N=184

Pioglitazone

Hydrochloride

30 mg

+ Sulfonylurea

N=189

Pioglitazone

Hydrochloride

30 mg

+ Sulfonylurea

N=351

Pioglitazone

Hydrochloride

45 mg

+ Sulfonylurea

N=351

At least one congestive

heart failure event

2 (1.1%)

1 (0.3%)

6 (1.7%)

Hospitalized

2 (1.1%)

2 (0.6%)

Patients Treated with Pioglitazone Hydrochloride or Placebo Added on to Insulin

Number (%) of Patients

Placebo-Controlled Trial

(16 weeks)

Non-Controlled

Double-Blind Trial

(24 weeks)

Placebo +

Insulin

N=187

Pioglitazone

Hydrochloride

15 mg

+ Insulin

N=191

Pioglitazone

Hydrochloride

30 mg

+ Insulin

N=188

Pioglitazone

Hydrochloride

30 mg

+ Insulin

N=345

Pioglitazone

Hydrochloride

45 mg

+ Insulin

N=345

At least one congestive

heart failure event

2 (1.0%)

2 (1.1%)

3 (0.9%)

5 (1.4%)

Hospitalized

2 (1.0%)

1 (0.5%)

1 (0.3%)

3 (0.9%)

Patients Treated with Pioglitazone Hydrochloride or Placebo Added on to Metformin

Number (%) of Patients

Placebo-Controlled Trial

(16 weeks)

Non-Controlled Double-Blind

Trial

(24 weeks)

Placebo

+ Metformin

N=160

Pioglitazone

Hydrochloride

30 mg + Metformin

N=168

Pioglitazone

Hydrochloride

30 mg +

Metformin

N=411

Pioglitazone

Hydrochloride

45 mg +

Metformin

N=416

At least one congestive

heart failure event

1 (0.6%)

1 (0.2%)

Hospitalized

1 (0.6%)

1 (0.2%)

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were

randomized to receive 24 weeks of double-blind treatment with either pioglitazone hydrochloride at

daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A

summary of the incidence of adverse events related to congestive heart failure reported in this study is

provided in Table 7.

Table 7: Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients

with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone Hydrochloride or

Glyburide

Number (%) of Subjects

Pioglitazone

Hydrochloride

N=262

Glyburide

N=256

Death due to cardiovascular causes (adjudicated)

5 (1.9%)

6 (2.3%)

Overnight hospitalization for worsening CHF

(adjudicated)

26 (9.9%)

12 (4.7%)

Emergency room visit for CHF (adjudicated)

4 (1.5%)

3 (1.2%)

Patients experiencing CHF progression during

study

35 (13.4%)

21 (8.2%)

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are

summarized in Table 8.

Table 8: Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive

T rial

Number (%) of Patients

Placebo

Pioglitazone

Placebo

N=2633

Hydrochloride

N=2605

At least one hospitalized congestive heart failure

event

108 (4.1%)

149 (5.7%)

Fatal

22 (0.8%)

25 (1.0%)

Hospitalized, non-fatal

86 (3.3%)

124 (4.7%)

Cardiovascular Safety: In the PROactive trial, 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. Almost all patients (95%) were

receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers,

calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a

mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration

of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of pioglitazone hydrochloride on mortality

and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for

macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in

a cardiovascular composite endpoint that included all-cause mortality, non-fatal myocardial infarction

(MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary

artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass

surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone

hydrochloride and 572 (21.7%) placebo-treated patients experienced at least one event from the primary

composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between pioglitazone hydrochloride and

placebo for the 3-year incidence of a first event within this composite, there was no increase in

mortality or in total macrovascular events with pioglitazone hydrochloride. The number of first

occurrences and total individual events contributing to the primary composite endpoint is shown in

Table 9.

Table 9: PROactive: Number of First and Total Events for Each Component within the

Cardiovascular Composite Endpoint

Cardiovascular Events

Placebo

N=2633

Pioglitazone Hydrochloride

N=2605

First Events

n (%)

Total Events

n

First Events

n (%)

Total Events

n

CABG = coronary artery bypass grafting; PCI = percutaneous intervention

Any event

572 (21.7)

514 (19.7)

All-cause mortality

122 (4.6)

110 (4.2)

Non-fatal myocardial infarction (MI)

118 (4.5)

105 (4.0)

Stroke

96 (3.6)

76 (2.9)

Acute coronary syndrome

63 (2.4)

42 (1.6)

Cardiac intervention (CABG/PCI)

101 (3.8)

101 (3.9)

Major leg amputation

15 (0.6)

9 (0.3)

Leg revascularization

57 (2.2)

71 (2.7)

Weight Gain: Dose-related weight gain occurs when pioglitazone hydrochloride is used alone or in

combination with other anti-diabetic medications. The mechanism of weight gain is unclear but probably

involves a combination of fluid retention and fat accumulation.

Table 10 and Table 11 summarize the changes in body weight with pioglitazone hydrochloride and

placebo in the 16 to 26-week randomized, double-blind monotherapy and 16 to 24-week combination

add-on therapy trials and in the PROactive trial.

Table 10: Weight Changes (kg) from Baseline during Randomized, Double-Blind Clinical Trials

Control Group

(Placebo)

Pioglitazone

Hydrochloride

15 mg

Pioglitazone

Hydrochloride

30 mg

Pioglitazone

Hydrochloride

45 mg

Median

(25

/75

percentile)

Median

(25

/75

percentile)

Median

(25

/75

percentile)

Median

(25

/75

percentile)

Monotherapy

(16 to 26 weeks)

-1.4 (-2.7/0.0)

N=256

0.9 (-0.5/3.4)

N=79

1.0 (-0.9/3.4)

N=188

2.6 (0.2/5.4)

N=79

Combination

Therapy

(16 to 24 weeks)

Sulfonylurea

-0.5 (-1.8/0.7)

N=187

2.0 (0.2/3.2)

N=183

3.1 (1.1/5.4)

N=528

4.1 (1.8/7.3)

N=333

Metformin

-1.4 (-3.2/0.3)

N=160

0.9 (-1.3/3.2)

N=567

1.8 (-0.9/5.0)

N=407

Insulin

0.2 (-1.4/1.4)

N=182

2.3 (0.5/4.3)

N=190

3.3 (0.9/6.3)

N=522

4.1 (1.4/6.8)

N=338

Table 11: Median Change in Body Weight in Patients Treated with Pioglitazone Hydrochloride

Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the

PROactive Trial

Placebo

Pioglitazone

Hydrochloride

Median

(25

/75

percentile)

Median

(25

/75

percentile)

Note: median exposure for both pioglitazone hydrochloride and Placebo was 2.7 years.

Change from Baseline to Final Visit (kg)

-0.5 (-3.3, 2.0)

N=2581

+3.6 (0.0, 7.5)

N=2560

Edema: Edema induced from taking pioglitazone hydrochloride is reversible when pioglitazone

hydrochloride is discontinued. The edema usually does not require hospitalization unless there is

coexisting congestive heart failure. A summary of the frequency and types of edema adverse events

occurring in clinical investigations of pioglitazone hydrochloride is provided in Table 12.

Table 12: Adverse Events of Edema in Patients Treated with Pioglitazone Hydrochloride

Number (%) of Patients

Placebo

Pioglitazone

Hydrochloride

15 mg

Pioglitazone

Hydrochloride

30 mg

Pioglitazone

Hydrochloride

45 mg

Monotherapy (16 to 26 weeks)

3 (1.2%)

N=259

2 (2.5%)

N= 81

13 (4.7%)

N= 275

11 (6.5%)

N=169

Combined Therapy

(16 to 24 weeks)

Sulfonylurea

4 (2.1%)

N=187

3 (1.6%)

N=184

61 (11.3%)

N=540

81 (23.1%)

N=351

Metformin

4 (2.5%)

N=160

34 (5.9%)

N=579

58 (13.9%)

N=416

Insulin

13 (7.0%)

N=187

24 (12.6%)

N=191

109 (20.5%)

N=533

90 (26.1%)

N=345

th

th

th

th

th

th

th

th

th

th

th

th

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention

were combined to form the aggregate term of "edema."

Table 13: Adverse Events of Edema in Patients in the PROactive Trial

Number (%) of Patients

Placebo

N=2633

Pioglitazone Hydrochloride

N=2605

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention

were combined to form the aggregate term of "edema."

419 (15.9%)

712 (27.3%)

Hepatic Effects: There has been no evidence of pioglitazone hydrochloride-induced hepatotoxicity in

the pioglitazone hydrochloride controlled clinical trial database to date. One randomized, double-blind,

3-year trial comparing pioglitazone hydrochloride to glyburide as add-on to metformin and insulin

therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than 3

times the upper limit of the reference range, measured every 8 weeks for the first 48 weeks of the trial

then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone

hydrochloride and 9/1046 (0.9%) patients treated with glyburide developed ALT values >3 times the

upper limit of the reference range. None of the patients treated with pioglitazone hydrochloride in the

pioglitazone hydrochloride clinical trial database to date have had a serum ALT > 3 times the upper

limit of the reference range and a corresponding total bilirubin >2 times the upper limit of the reference

range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia: In the pioglitazone hydrochloride clinical trials, adverse events of hypoglycemia were

reported based on clinical judgment of the investigators and did not require confirmation with

fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with

pioglitazone hydrochloride 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the

incidence of reported hypoglycemia was 7.9% with pioglitazone hydrochloride 15 mg, 15.4% with

pioglitazone hydrochloride 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone hydrochloride 45 mg compared

to pioglitazone hydrochloride 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%)

and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were

receiving pioglitazone hydrochloride 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional

14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's

usual activities) that did not require hospitalization. These patients were receiving pioglitazone

hydrochloride 45 mg in combination with sulfonylurea (n=2) or pioglitazone hydrochloride 30 mg or 45

mg in combination with insulin (n=12).

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 two 3-year trials in which pioglitazone

hydrochloride was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder

cancer in patients taking pioglitazone hydrochloride compared to 5/3679 (0.14%) in patients not taking

pioglitazone hydrochloride. After excluding patients in whom exposure to study drug was less than one

year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone

hydrochloride and two (0.05%) cases on placebo. There are too few events of bladder cancer to

establish causality.

6.2 Laboratory Abnormalities

Hematologic Effects: Pioglitazone hydrochloride may cause decreases in hemoglobin and hematocrit. In

placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients

treated with pioglitazone hydrochloride compared with a mean change in hemoglobin of -1% to +1% in

placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and

remained relatively constant thereafter. These changes may be related to increased plasma volume

associated with pioglitazone hydrochloride therapy and are not likely to be associated with any

clinically significant hematologic effects.

Creatine Phosphokinase: During protocol-specified measurement of serum creatine phosphokinase

(CPK) in pioglitazone hydrochloride clinical trials, an isolated elevation in CPK to greater than 10 times

the upper limit of the reference range was noted in 9 (0.2%) patients treated with pioglitazone

hydrochloride (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine

patients continued to receive pioglitazone hydrochloride, two patients were noted to have the CPK

elevation on the last day of dosing and one patient discontinued pioglitazone hydrochloride due to the

elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these

events to pioglitazone hydrochloride therapy is unknown.

6.3 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 (5.2)] .

Fatal and non-fatal 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 DRUG INTERACTIONS

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 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)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies of pioglitazone

hydrochloride in pregnant women. Animal studies show increased rates of post-implantation loss,

delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the

maximum recommended human dose. Pioglitazone hydrochloride should be used during pregnancy only

if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations: Abnormal blood glucose concentrations during pregnancy are associated with a

higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most

experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as

close to normal as possible for patients with diabetes.

Animal Data: In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up

to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD)

based on body surface area (mg/m

); no teratogenicity was observed [see Nonclinical Toxicology (13.3)]

. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal

weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more

times the MRHD (mg/m

basis). No functional or behavioral toxicity was observed in rat offspring.

When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal

development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses

approximately 2 or more times the MRHD (mg/m

basis). In rabbits, embryotoxicity occurred at oral

doses approximately 40 times the MRHD (mg/m

basis).

8.3 Nursing Mothers

It is not known whether pioglitazone hydrochloride is secreted in human milk. Pioglitazone is secreted

in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential

for pioglitazone hydrochloride to cause serious adverse reactions in nursing infants, a decision should

be made to discontinue nursing or discontinue pioglitazone hydrochloride, taking into account the

importance of pioglitazone hydrochloride to the mother.

8.4 Pediatric Use

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

Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term

safety data. Risks including fractures and other adverse effects associated with pioglitazone

hydrochloride have not been determined in this population [see Warnings and Precautions (5.4)].

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 2 patients (0.3%)

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. These clinical experiences have not

identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients

although small sample sizes for patients ≥75 years old limit conclusions [see Clinical Pharmacology

(12.3)] .

10 OVERDOSAGE

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.

11 DESCRIPTION

Pioglitazone hydrochloride is an oral antidiabetic medication.

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 is an odorless white crystalline powder that has a molecular formula of C

SHCl 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 are available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg

of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate,

hydroxypropylcellulose, carboxymethylcellulose calcium, and magnesium stearate.

12 CLINICAL PHARMACOLOGY

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 (5.9) 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 Table 14.

Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study

Placebo

Pioglitazone

Hydrochloride

15 mg

Once Daily

Pioglitazone

Hydrochloride

30 mg

Once Daily

Pioglitazone

Hydrochloride

45 mg

Once Daily

Triglycerides (mg/dL)

N=79

N=79

N=84

N=77

Baseline (mean)

Percent change from baseline

(adjusted mean

4.8%

-9.0%

-9.6%

-9.3%

HDL Cholesterol (mg/dL)

N=79

N=79

N=83

N=77

Baseline (mean)

Percent change from baseline

(adjusted mean

8.1%

14.1%

12.2%

19.1%

LDL Cholesterol (mg/dL)

N=65

N=63

N=74

N=62

Baseline (mean)

Percent change from baseline

(adjusted mean

4.8%

7.2%

5.2%

6.0%

Total Cholesterol (mg/dL)

N=79

N=79

N=84

N=77

Baseline (mean)

Percent change from baseline

(adjusted mean

4.4%

4.6%

3.3%

6.4%

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 7 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

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p <0.05 versus placebo

the total AUC.

Maximum serum concentration (C

), AUC, and trough serum concentrations (C

) for pioglitazone

and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

Absorption: Following oral administration of pioglitazone hydrochloride, peak concentrations of

pioglitazone were observed within 2 hours. Food slightly delays the time to peak serum concentration

) to 3 to 4 hours, but does not alter the extent of absorption (AUC).

Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose

administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein

bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum

proteins, but with lower affinity. M-III and M-IV are also extensively bound (> 98%) to serum albumin.

Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites

also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major

circulating active metabolites in humans.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The

cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional

contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study

of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor showed that pioglitazone is

a CYP2C8 substrate [see Dosage and Administration (2.3) and Drug Interactions (7)]. Urinary 6ß-

hydroxycortisol/ cortisol ratios measured in patients treated with pioglitazone hydrochloride showed

that pioglitazone is not a strong CYP3A4 enzyme inducer.

Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone

dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted

primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into

the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3 to 7 hours

and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7

L/hr.

Renal Impairment: The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged

in patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance < 30

mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose

adjustment in patients with renal impairment is required.

Hepatic Impairment: Compared with healthy controls, subjects with impaired hepatic function (Child-

Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone

(pioglitazone, M-III and M-IV) mean peak concentrations but no change in the mean AUC values.

Therefore, no dose adjustment in patients with hepatic impairment is required.

There are postmarketing reports of liver failure with pioglitazone hydrochloride and clinical trials have

generally excluded patients with serum ALT >2.5× the upper limit of the reference range. Use caution

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

Geriatric Patients: In healthy elderly subjects, peak serum concentrations of pioglitazone are not

significantly different, but AUC values are approximately 21% higher than those achieved in younger

subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about

10 hours) as compared to younger subjects (about 7 hours). These changes were not of a magnitude that

would be considered clinically relevant.

Pediatric Patients: Safety and efficacy of pioglitazone in pediatric patients have not been established.

Pioglitazone hydrochloride is not recommended for use in pediatric patients [see Use in Specific

Populations (8.4)] .

Gender: The mean C

and AUC values of pioglitazone were increased 20% to 60% in women

compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater

for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be

individualized for each patient to achieve glycemic control, no dose adjustment is recommended based

on gender alone.

Ethnicity: Pharmacokinetic data among various ethnic groups are not available.

Drug-Drug Interactions

Table 15: Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs

Co-administered Drug

Pioglitazone

Dosage Regimen

(mg)

Name and Dose Regimens

Change in AUC

Change in C

45 mg

(N = 12)

Warfarin

Daily loading then maintenance

doses based PT and INR

values

Quick's Value = 35 ± 5%

R-Warfarin

↓3%

R-Warfarin

↓2%

S-Warfarin

↓1%

S-Warfarin

↑1%

45 mg

(N = 12)

Digoxin

0.200 mg twice daily (loading

dose) then 0.250 mg daily

(maintenance dose, 7 days)

↑15%

↑17%

45 mg daily

for 21 days

(N = 35)

Oral Contraceptive

[Ethinyl Estradiol (EE) 0.035

mg plus Norethindrone (NE) 1

mg] for 21 days

↓11%

↓13%

↑3%

↓7%

45 mg

(N = 23)

Fexofenadine

60 mg twice daily for 7 days

↑30%

↑37%

45 mg

(N = 14)

Glipizide

5 mg daily for 7 days

↓3%

↓8%

45 mg daily

for 8 days

(N = 16)

Metformin

1000 mg single dose on Day 8

↓3%

↓5%

45 mg

(N = 21)

Midazolam

7.5 mg single dose on day 15

↓26%

↓26%

45 mg

(N = 24)

Ranitidine

150 mg twice daily for 7 days

↑1%

↓1%

45 mg daily

for 4 days

(N = 24)

Nifedipine ER

30 mg daily for 4 days

↓13%

↓17%

45 mg

(N = 25)

Atorvastatin Ca

80 mg daily for 7 days

↓14%

↓23%

45 mg

(N = 22)

Theophylline

400 mg twice daily for 7 days

↑2%

↑5%

*

max

Daily for 7 days unless otherwise noted

% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure

increase and decrease, respectively.

Pioglitazone had no clinically significant effect on prothrombin time

Table 16: Effect of Coadministered Drugs on Pioglitazone Systemic Exposure

Coadministered Drug and Dosage

Regimen

Pioglitazone

Dose Regimen

(mg)

Change in AUC

Change in C

Gemfibrozil 600 mg twice daily for 2

days

(N = 12)

30 mg single dose

↑3.4-fold

↑6%

Ketoconazole 200 mg

twice daily for 7 days

(N = 28)

45 mg

↑34%

↑14%

Rifampin 600 mg daily for 5 days

(N = 10)

30 mg single dose

↓54%

↓5%

Fexofenadine 60 mg

twice daily for 7 days

(N = 23)

45 mg

↑1%

Ranitidine 150 mg

twice daily for 4 days

(N = 23)

45 mg

↓13%

↓16%

Nifedipine ER 30 mg

daily for 7 days

(N = 23)

45 mg

↑5%

↑4%

Atorvastatin Ca 80 mg

daily for 7 days

(N = 24)

45 mg

↓24%

↓31%

Theophylline 400 mg

twice daily for 7 days

(N = 22)

45 mg

↓4%

↓2%

13 NONCLINICAL TOXICOLOGY

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

). Drug-

induced tumors were not observed in any organ except for the urinary bladder. 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

). A two-year carcinogenicity study was

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

). 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

*

max

Daily for 7 days unless otherwise noted

Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered

drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.

The half-life of pioglitazone increased from 6.5 h to 15.1 h in the presence of gemfibrozil [ see Dosage and

Administration (2.3) and Drug Interactions (7)]]

pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times

the maximum recommended human oral dose based on mg/m

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

). 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

). Heart

enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above

(approximately 4 times the maximum recommended human oral dose based on mg/m

), 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

13.3 Reproductive and Developmental Toxicology

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg

during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose

based on mg/m

, respectively). Delayed parturition and embryotoxicity (as evidenced by increased

postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral

doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose

based on mg/m

). No functional or behavioral toxicity was observed in offspring of rats. In rabbits,

embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum

recommended human oral dose based on mg/m

). Delayed postnatal development, attributed to

decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during

late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose

based on mg/m

14 CLINICAL STUDIES

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 8 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.

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

T rial

Placebo

Pioglitazone

Hydrochloride

15 mg

Once Daily

Pioglitazone

Hydrochloride

30 mg

Once Daily

Pioglitazone

Hydrochloride

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

-0.3

-0.3

-0.9

Difference from placebo (adjusted

mean

95% Confidence Interval

-1.0

(-1.6, -0.4)

-1.0

(-1.6, -0.4)

-1.6

(-2.2, -1.0)

Fasting Plasma Glucose (mg/dL)

N=79

N=79

N=84

N=77

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted

mean

95% Confidence Interval

(-63, -16)

(-64, -18)

(-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 hydrochloride treatment groups or a mock-titration placebo

group. Therapy with any previous antidiabetic agent was discontinued 6 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

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. placebo

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 Table 18.

Table 18: Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy

T rial

Placebo

Pioglitazone

Hydrochloride

30 mg

Once Daily

Pioglitazone

Hydrochloride

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

-0.6

-0.6

Difference from placebo (adjusted mean

95% Confidence Interval

-1.5

(-2.0, -1.0)

-1.5

(-2.0, -1.0)

Fasting Plasma Glucose (mg/dL)

N=78

N=82

N=85

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

95% Confidence Interval

(-82, -0.41)

(-88, -0.48)

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 6 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 Table 19.

Table 19: Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial

Placebo

Pioglitazone

Hydrochloride

30 mg

Once Daily

Total Population

HbA1c (%)

N=93

N=100

Baseline (mean)

10.3

10.5

Change from baseline (adjusted mean

-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)

Change from baseline (adjusted mean

Difference from placebo (adjusted mean

*

*

Final dose in forced titration

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. placebo

95% Confidence Interval

(-77, -38)

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.

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 3 weeks prior to starting study treatment.

In the first study, 560 patients were randomized to receive 15 mg or 30 mg of pioglitazone

hydrochloride 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 Table 20.

Table 20: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Sulfonylurea Trial

Placebo +

Sulfonylurea

Pioglitazone

Hydrochloride

15 mg +

Sulfonylurea

Pioglitazone

Hydrochloride

30 mg +

Sulfonylurea

Total Population

HbA1c (%)

N=181

N=176

N=182

Baseline (mean)

10.0

Change from baseline (adjusted mean

-0.8

-1.2

Difference from placebo + sulfonylurea

(adjusted mean

95% Confidence Interval

-0.9

(-1.2, -0.6)

-1.3

(-1.6, -1.0)

Fasting Plasma Glucose (mg/dL)

N=182

N=179

N=186

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo + sulfonylurea

(adjusted mean

95% Confidence Interval

(-52, -27)

(-70, -46)

In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of pioglitazone

hydrochloride once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean

reduction from baseline at Week 24 in HbA1 c 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.

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.050 vs. placebo

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. placebo + sulfonylurea

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

Pioglitazone

Hydrochloride 30 mg +

Sulfonylurea

Pioglitazone

Hydrochloride 45 mg +

Sulfonylurea

95% CI = 95% confidence interval

Total Population

HbA1c (%)

N=340

N=332

Baseline (mean)

Change from baseline (adjusted mean

-1.6

-1.7

Difference from 30 mg daily pioglitazone

hydrochloride + sulfonylurea (adjusted mean

(95% CI)

-0.1

(-0.4, 0.1)

Fasting Plasma Glucose (mg/dL)

N=338

N=329

Baseline (mean)

Change from baseline (adjusted mean

Difference from 30 mg daily pioglitazone

hydrochloride + sulfonylurea (adjusted mean

(95% CI)

(-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 3 weeks prior to starting study treatment.

In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone hydrochloride 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

Placebo + Metformin

Pioglitazone

Hydrochloride

30 mg

+ Metformin

Total Population

HbA1c (%)

N=153

N=161

Baseline (mean)

Change from baseline (adjusted mean

-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)

Change from baseline (adjusted mean

Difference from placebo + metformin (adjusted

Adjusted for baseline, pooled center, and pooled center by treatment interaction

mean

95% Confidence Interval

(-49, -26)

In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone

hydrochloride once daily for 24 weeks in addition to their current metformin regimen. The mean

reduction from baseline at Week 24 in HbA1 c was 0.8% for the 30 mg dose and 1.0% 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

Pioglitazone

Hydrochloride 30 mg

+ Metformin

Pioglitazone

Hydrochloride 45 mg

+ Metformin

95% CI = 95% confidence interval

Total Population

HbA1C (%)

N=400

N=398

Baseline (mean)

Change from baseline (adjusted mean

-0.8

-1.0

Difference from 30 mg daily pioglitazone

hydrochloride + Metformin (adjusted mean

) (95%

-0.2

(-0.5, 0.1)

Fasting Plasma Glucose (mg/dL)

N=398

N=399

Baseline (mean)

Change from baseline (adjusted mean

Difference from 30 mg daily pioglitazone

hydrochloride + Metformin (adjusted mean

) (95%

(-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 hydrochloride 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 hydrochloride 15 mg,

and 61% treated with pioglitazone hydrochloride 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

hydrochloride 15 mg, -8 units in the patients treated with pioglitazone hydrochloride 30 mg, and -1 unit

in patients treated with placebo.

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. placebo + metformin

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. 30 mg daily pioglitazone hydrochloride + metformin

Table 24: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Insulin Trial

Placebo

+ Insulin

Pioglitazone

Hydrochloride 15

mg

+ Insulin

Pioglitazone

Hydrochloride 30

mg

+ Insulin

Total Population

HbA1C (%)

N=177

N=177

N=185

Baseline (mean)

Change from baseline (adjusted mean

-0.3

-1.0

-1.3

Difference from placebo + Insulin

(adjusted mean

95% Confidence Interval

-0.7

(-1.0, -0.5)

-1.0

(-1.3, -0.7)

Fasting Plasma Glucose (mg/dL)

N=179

N=183

N=184

Baseline (mean)

Change from baseline (adjusted mean

Difference from placebo + Insulin

(adjusted mean

95% Confidence Interval

(-51, -19)

(-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 hydrochloride 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 hydrochloride 30 mg, and 52% treated with pioglitazone hydrochloride

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 hydrochloride 30 mg and -8 units in the patients treated

with pioglitazone hydrochloride 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

Pioglitazone Hydrochloride

30 mg + Insulin

Pioglitazone Hydrochloride

45 mg + Insulin

Total Population

HbA1c (%)

N=328

N=328

Baseline (mean)

Change from baseline (adjusted mean

-1.2

-1.5

Difference from 30 mg daily

pioglitazone hydrochloride + Insulin

(adjusted mean

) (95% CI)

-0.3

(-0.5, -0.1)

Fasting Plasma Glucose (mg/dL)

N=325

N=327

Baseline (mean)

Change from baseline (adjusted mean

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. placebo + insulin

95% CI = 95% confidence interval

Difference from 30 mg daily

pioglitazone hydrochloride + Insulin

(adjusted mean

) (95% CI)

(-25, -3)

16 HOW SUPPLIED/ STORAGE AND HANDLING

Pioglitazone tablets USP are available in 15 mg, tablets as follows:

15 mg tablet: White to off-white, round, biconvex, uncoated tablets debossed with ‘P’ on one side and

‘15’ on other side, available in:

NDC 68071-2170-3 Bottles of 30

Storage: Store at 20º to 25ºC (68º to 77 ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP

Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide (17.2).

17.1 Instructions

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.

Therapy with pioglitazone tablets, like other thiazolidinediones, may result in ovulation in some

premenopausal anovulatory women. As a result, these patients may be at an increased risk for

pregnancy while taking pioglitazone tablets. Therefore, adequate contraception should be

recommended for all pre-menopausal women who are prescribed pioglitazone tablets.

17.2 FDA-Approved Medication Guide

See attached leaflet.

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Adjusted for baseline, pooled center, and pooled center by treatment interaction

p ≤ 0.05 vs. 30 mg daily pioglitazone hydrochloride + insulin

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. : 457, 458,

Village – Matoda,

Bavla Road, Ta.- Sanand,

Dist.- Ahmedabad – 382 210,

INDIA.

10 1383 2 662575

Issued August 2015

“Licensed-United States Patent Nos. 5,965,584, 6,150,383, 6,150,384, 6,166,042, 6,166,043,

6,172,090, 6,211,205, 6,271,243, 6,329,404, and 6,303,640.”

MEDICATION GUIDE

Pioglitazone Tablets USP

Read this Medication Guide carefully before you start taking pioglitazone 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

tablets, ask your doctor or pharmacist.

What is the most important information I should know about pioglitazone tablets?

Pioglitazone tablets can cause serious side effects, including new or worse heart failure.

Pioglitazone 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 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 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 tablets can have other serious side effects. See " What are the possible side effects of

pioglitazone tablets?"

What are pioglitazone tablets?

Pioglitazone tablet is a prescription medicine used with diet and exercise to improve blood sugar

(glucose) control in adults with type 2 diabetes. Pioglitazone tablet is a diabetes medicine called

pioglitazone hydrochloride that may be taken alone or with other diabetes medicines.

It is not known if pioglitazone tablet is safe and effective in children.

Who should not take pioglitazone tablets?

See " What is the most important information I should know about pioglitazone tablets?"

Do not take pioglitazone tablets if you:

have severe heart failure

are allergic to any of the ingredients in pioglitazone tablets . See the end of this Medication Guide

for a complete list of ingredients in pioglitazone tablets

Talk to your doctor before taking pioglitazone tablets if you have either of these conditions.

What should I tell my doctor before taking pioglitazone tablets?

Before you start taking pioglitazone tablets, tell your doctor if you:

have heart failure

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

are pregnant or plan to become pregnant. It is not known if pioglitazone tablets will 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 tablets may increase your chance of becoming pregnant. Talk to

your doctor about birth control choices while taking pioglitazone tablets. Tell your doctor right

away if you become pregnant while taking pioglitazone tablets

are breast-feeding or plan to breast-feed. It is not known if pioglitazone tablets passes into your

milk and if it can harm your baby. You should not take pioglitazone tablets if you breastfeed your

baby. Talk to your doctor about the best way to control your blood glucose levels while

breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription

medicines, vitamins, and herbal supplements.

Pioglitazone tablets and some of your other medicines can affect each other. You may need to have your

dose of pioglitazone 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 tablets with other

medicines.

How should I take pioglitazone tablets?

Take pioglitazone tablets exactly as your doctor tells you to take it

Your doctor may change your dose of pioglitazone tablets. Do not change your pioglitazone tablets

dose unless your doctor tells you to

Pioglitazone tablets may be prescribed alone or with other diabetes medicines. This will depend on

how well your blood sugar is controlled

Take pioglitazone tablets 1 time each day, with or without food

If you miss a dose of pioglitazone 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 much pioglitazone 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 tablets

Your doctor should do certain blood tests before you start and while you take pioglitazone tablets

Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is

controlled with pioglitazone tablets

Your doctor should check your eyes regularly while you take pioglitazone tablets

It may take 2 to 3 months to see the full effect of pioglitazone tablets on your blood sugar level.

What are the possible side effects of pioglitazone tablets?

Pioglitazone tablets may cause serious side effects including:

See " What is the most important information about pioglitazone tablets."

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

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.

bladder cancer. There may be an increased chance of having bladder cancer when you take

pioglitazone tablets. You should not take pioglitazone 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

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. Call your doctor if low

blood sugar levels are a problem for you

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

tablets. This can increase your chance of getting pregnant

The most common side effects of pioglitazone tablets include:

cold-like symptoms (respiratory tract infection)

headache

sinus infection

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 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 tablets?

Store pioglitazone tablets at 59°F to 86°F (15°C to 30°C). Keep pioglitazone tablets in the original

container and protect from light

Keep the pioglitazone tablets bottle tightly closed and protect from getting wet (away from moisture

and humidity)

Keep pioglitazone tablets and all medicines out of the reach of children

General information about the safe and effective use of pioglitazone tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use pioglitazone tablets for a condition for which it was not prescribed. Do not give pioglitazone

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 tablets. If you

would like more information, talk with your doctor. You can ask your doctor or pharmacist for

information about pioglitazone tablets that is written for healthcare professionals.

What are the ingredients in pioglitazone tablets?

Active Ingredient: pioglitazone hydrochloride

Inactive Ingredients: lactose monohydrate, hydroxypropylcellulose, carboxymethylcellulose calcium,

and magnesium stearate.

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

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. : 457, 458,

Village – Matoda,

Bavla Road, Ta.- Sanand,

Dist.- Ahmedabad – 382 210,

INDIA.

10 1383 2 662575

Issued August 2015

PIOGLITAZONE HYDROCHLORIDE

pioglitazone hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 71-2170 (NDC:16 729 -0 20 )

Route of Administration

ORAL

NuCare Pharmaceuticals, Inc.

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength Strength

PIO GLITAZO NE HYDRO CHLO RIDE (UNII: JQT35NPK6 C) (PIOGLITAZONE -

UNII:X4OV71U42S)

PIOGLITAZONE

15 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

CARBO XYMETHYLCELLULO SE CALCIUM (UNII: UTY7PDF9 3L)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

white (white to o ff-white)

S core

no sco re

S hap e

ROUND (ro und, bico nvex)

S iz e

Flavor

Imprint Code

P;15

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 71-2170 -3

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/25/20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 0 0 44

0 2/13/20 13

Labeler -

NuCare Pharmaceuticals, Inc. (010632300)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

NuCare Pharmaceuticals, Inc.

0 10 6 3230 0

re pa c k(6 8 0 71-2170 )

Revised: 3/2019

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