Actos

Name: Actos

What should I avoid while taking pioglitazone?

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

Actos Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Chest pain
  • decreased urine output
  • dilated neck veins
  • extreme fatigue
  • irregular breathing
  • irregular heartbeat
  • problems with teeth
  • swelling of the face, fingers, feet, or lower legs
  • tightness in the chest
  • trouble breathing
  • weight gain
Less common
  • Pain or swelling in the arms or legs without an injury
  • pale skin
  • swelling
  • trouble with breathing when active
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Incidence not known
  • Dark urine
  • loss of appetite
  • nausea or vomiting
  • stomach pain
  • unexplained, rapid weight gain
  • yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Blurred vision or other changes in vision
  • cough
  • dry mouth
  • flushed, dry skin
  • fruit-like breath odor
  • headache
  • increased hunger
  • increased thirst
  • increased urination
  • loss of consciousness
  • muscle pain or soreness
  • problems with your teeth
  • runny or stuffy nose
  • sore throat
  • stomachache
  • sweating
  • unexplained weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Uses of Actos

  • It is used to lower blood sugar in patients with high blood sugar (diabetes).

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Indications and Usage for Actos

Monotherapy and Combination Therapy

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

Important Limitations of Use

Actos exerts its antihyperglycemic effect only in the presence of endogenous insulin. Actos 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)].

Dosage Forms and Strengths

Round tablet contains pioglitazone as follows:

• 15 mg: White to off-white, debossed with "Actos" on one side and "15" on the other • 30 mg: White to off-white, debossed with "Actos" on one side and "30" on the other • 45 mg: White to off-white, debossed with "Actos" on one side and "45" on the other

Warnings and Precautions

Congestive Heart Failure

Actos, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when Actos 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 Actos must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions (6.1)].

Hypoglycemia

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

Hepatic Effects

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

Urinary Bladder Tumors

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

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

A large prospective10-year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to Actos, compared to those never exposed to Actos (HR =1.06 [95% CI 0.89−1.26]).

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

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

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

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

Edema

In controlled clinical trials, edema was reported more frequently in patients treated with Actos 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.

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

Fractures

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

Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking Actos or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see Adverse Reactions (6.1)].

Macrovascular Outcomes

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

Use in specific populations

Pregnancy

Risk Summary

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

In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area [see Data].

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

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

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

Data

Animal Data

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

Lactation

Risk Summary

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

Females and Males of Reproductive Potential

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

Pediatric Use

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

Actos is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions (5.1, 5.4, 5.5 and 5.6)].

Geriatric Use

A total of 92 patients (15.2%) treated with Actos in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with Actos were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with Actos were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with Actos were ≥65 years old and 22 (2.1%) were ≥75 years old.

In PROactive, 1068 patients (41.0%) treated with Actos were ≥65 years old and 42 (1.6%) were ≥75 years old.

In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology (12.3)].

Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.

Actos - Clinical Pharmacology

Mechanism of Action

Actos is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Actos 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.

Pharmacodynamics

Clinical studies demonstrate that Actos improves insulin sensitivity in insulin-resistant patients. Actos 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 Actos results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, Actos 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 Actos. Overall, patients treated with Actos 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 Actos or any other antidiabetic medication [see Warnings and Precautions (5.8) and Adverse Reactions (6.1)].

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

Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study
Placebo Actos
15 mg
Once Daily
Actos
30 mg
Once Daily
Actos
45 mg
Once Daily
* Adjusted for baseline, pooled center, and pooled center by treatment interaction † p <0.05 versus placebo

Triglycerides (mg/dL)

N=79

N=79

N=84

N=77

Baseline (mean)

263

284

261

260

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)

42

40

41

41

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)

139

132

136

127

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)

225

220

223

214

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.

Pharmacokinetics

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

Cmax, AUC, and trough serum concentrations (Cmin) 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, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four 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, which include 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 Actos 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 (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.

Renal Impairment

The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min) and severe (CLcr <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 Cmax 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 Actos and clinical trials have generally excluded patients with serum ALT >2.5 times 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, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven 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. Actos is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].

Gender

The mean Cmax 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
Coadministered Drug
Pioglitazone Dosage
Regimen (mg)*
Name and Dose Regimens Change in AUC† Change in Cmax†
* 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

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

EE

↓11%

EE

↓13%

NE

↑3%

NE

↓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%

Table 16. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure
Coadministered Drug and Dosage Regimen Pioglitazone
Dose Regimen
(mg)*
Change
in AUC†
Change
in Cmax†
* 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 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7)]

Gemfibrozil 600 mg
twice daily for 2 days
(N = 12)

15 mg
single dose

↑3.2-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%

0%

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%

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide).

• It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. • Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Actos should immediately report these symptoms to a physician. • Tell patients to promptly stop taking Actos 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 Actos once daily. Actos can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. • When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. • Inform female patients that treatment with Actos, like other thiazolidinediones, may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].

Distributed by:
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015

Actos is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

©1999 - 2016 Takeda Pharmaceuticals America, Inc.

ACT003 R21

MEDICATION GUIDE

Actos (ak-TŌS)
(pioglitazone) tablets

Read this Medication Guide carefully before you start taking Actos 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 Actos, ask your doctor or pharmacist.

What is the most important information I should know about Actos?

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

• Actos 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 Actos 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, Actos 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

Actos can have other serious side effects. See "What are the possible side effects of Actos?"

What is Actos?

Actos is a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes. Actos is a diabetes medicine called pioglitazone that may be taken alone or with other diabetes medicines.

It is not known if Actos is safe and effective in children under the age of 18.

Actos is not recommended for use in children.

Actos is not for people with type 1 diabetes.

Actos is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

Who should not take Actos?

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

Do not take Actos if you:

• have severe heart failure • are allergic to any of the ingredients in Actos. See the end of this Medication Guide for a complete list of ingredients in Actos

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

What should I tell my doctor before taking Actos?

Before you take Actos, 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 • have or have had cancer of the bladder • are pregnant or plan to become pregnant. It is not known if Actos can harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant • are a premenopausal woman (before the "change of life") who does not have periods regularly or at all. Actos may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking Actos. Tell your doctor right away if you become pregnant while taking Actos • are breastfeeding or plan to breastfeed. It is not known if Actos passes into your milk and if it can harm your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding

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

Actos and some of your other medicines can affect each other. You may need to have your dose of Actos 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 Actos with other medicines.

How should I take Actos?

• Take Actos exactly as your doctor tells you to take it • Your doctor may change your dose of Actos. Do not change your Actos dose unless your doctor tells you to • Actos may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled • Take Actos one time each day, with or without food • If you miss a dose of Actos, 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 Actos, 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 Actos • Your doctor should do certain blood tests before you start and while you take Actos • Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with Actos • Your doctor should check your eyes regularly while you take Actos

What are the possible side effects of Actos?

Actos may cause serious side effects including:

• See "What is the most important information I should know about Actos?" • 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 • liver problems. Call your doctor right away if you have: o nausea or vomiting o stomach pain o unusual or unexplained tiredness o loss of appetite o dark urine o yellowing of your skin or the whites of your eyes • bladder cancer. There may be an increased chance of having bladder cancer when you take Actos. You should not take Actos if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer: o blood or a red color in your urine o an increased need to urinate o pain while you urinate • broken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthy. • diabetic eye disease with swelling in the back of the eye (macular edema). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly • release of an egg from an ovary in a woman (ovulation) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take Actos. This can increase your chance of getting pregnant

The most common side effects of Actos include:

o cold-like symptoms (upper respiratory tract infection) o headache o sinus infection o muscle pain o 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 Actos. 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 Actos?

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

General information about the safe and effective use of Actos

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

What are the ingredients in Actos?

Active Ingredient: pioglitazone

Inactive Ingredients: lActose monohydrate, hydroxypropylcellulose, carboxymethylcellulose calcium, and magnesium stearate

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

Distributed by:
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015

Revised: December 2016

Actos is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

© 2009-2016 Takeda Pharmaceuticals America, Inc.

ACT003 R21

PRINCIPAL DISPLAY PANEL - 15 mg Bottle Label

NDC 64764-151-06
500 Tablets

Actos
(pioglitazone)
Tablets

15 mg

Each tablet contains pioglitazone
hydrochloride equivalent to 15 mg
pioglitazone.

Dispense with Medication Guide
available in package insert or at
www.Actos.com

Takeda logo

Rx Only

PRINCIPAL DISPLAY PANEL - 30 mg Bottle Label

NDC 64764-301-16
500 Tablets

Actos
(pioglitazone)
Tablets

30 mg

Each tablet contains pioglitazone
hydrochloride equivalent to 30 mg
pioglitazone.

Dispense with Medication Guide
available in package insert or at
www.Actos.com

Takeda logo

Rx Only

PRINCIPAL DISPLAY PANEL - 45 mg Bottle Label

NDC 64764-451-26
500 Tablets

Actos

(pioglitazone)
Tablets

45 mg

Each tablet contains pioglitazone
hydrochloride equivalent to 45 mg
pioglitazone.

Dispense with Medication Guide
available in package insert or at
www.Actos.com

Takeda logo

Rx Only

Actos 
pioglitazone tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:64764-151
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIOGLITAZONE HYDROCHLORIDE (pioglitazone) pioglitazone 15 mg
Inactive Ingredients
Ingredient Name Strength
carboxymethylcellulose calcium  
HYDROXYPROPYL CELLULOSE (1200000 MW)  
lActose monohydrate  
magnesium stearate  
Product Characteristics
Color WHITE (white to off-white) Score no score
Shape ROUND (round, convex) Size 7mm
Flavor Imprint Code Actos;15
Contains     
Packaging
# Item Code Package Description
1 NDC:64764-151-04 30 TABLET in 1 BOTTLE
2 NDC:64764-151-05 90 TABLET in 1 BOTTLE
3 NDC:64764-151-06 500 TABLET in 1 BOTTLE
4 NDC:64764-151-02 6 CARTON in 1 TRAY
4 1 BLISTER PACK in 1 CARTON
4 7 TABLET in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021073 07/15/1999
Actos 
pioglitazone tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:64764-301
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIOGLITAZONE HYDROCHLORIDE (pioglitazone) pioglitazone 30 mg
Inactive Ingredients
Ingredient Name Strength
carboxymethylcellulose calcium  
HYDROXYPROPYL CELLULOSE (1200000 MW)  
lActose monohydrate  
magnesium stearate  
Product Characteristics
Color WHITE (white to off-white) Score no score
Shape ROUND (round, flat) Size 7mm
Flavor Imprint Code Actos;30
Contains     
Packaging
# Item Code Package Description
1 NDC:64764-301-14 30 TABLET in 1 BOTTLE
2 NDC:64764-301-15 90 TABLET in 1 BOTTLE
3 NDC:64764-301-16 500 TABLET in 1 BOTTLE
4 NDC:64764-301-02 6 CARTON in 1 TRAY
4 1 BLISTER PACK in 1 CARTON
4 7 TABLET in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021073 07/15/1999
Actos 
pioglitazone tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:64764-451
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIOGLITAZONE HYDROCHLORIDE (pioglitazone) pioglitazone 45 mg
Inactive Ingredients
Ingredient Name Strength
carboxymethylcellulose calcium  
HYDROXYPROPYL CELLULOSE (1200000 MW)  
lActose monohydrate  
magnesium stearate  
Product Characteristics
Color WHITE (white to off-white) Score no score
Shape ROUND (round, flat) Size 8mm
Flavor Imprint Code Actos;45
Contains     
Packaging
# Item Code Package Description
1 NDC:64764-451-24 30 TABLET in 1 BOTTLE
2 NDC:64764-451-25 90 TABLET in 1 BOTTLE
3 NDC:64764-451-26 500 TABLET in 1 BOTTLE
4 NDC:64764-451-02 6 CARTON in 1 TRAY
4 1 BLISTER PACK in 1 CARTON
4 7 TABLET in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021073 07/15/1999
Labeler - Takeda Pharmaceuticals America, Inc. (830134016)
Establishment
Name Address ID/FEI Operations
Takeda Pharmaceutical Company Limited, Osaka Plant 695132274 ANALYSIS(64764-151, 64764-301, 64764-451), MANUFACTURE(64764-151, 64764-301, 64764-451)
Revised: 12/2016   Takeda Pharmaceuticals America, Inc.

Actos and Pregnancy

Tell your doctor if you:

  • are pregnant or plan to become pregnant. It is not known if Actos 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. Actos may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking Actos. Tell your doctor right away if you become pregnant while taking Actos.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Actos FDA Warning

WARNING: CONGESTIVE HEART FAILURE

  • Thiazolidinediones, including Actos tablets, cause or exacerbate congestive heart failure in some patients.
  • After initiation of Actos 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 Actos tablets must be considered.
  • Actos tablets are not recommended in patients with symptomatic heart failure.
  • Initiation of Actos tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

Warnings

Black Box Warnings

Thiazolidinediones, including pioglitazone and rosiglitazone, cause or exacerbate congestive heart failure in some patients

After initiation of these drugs, as well as after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema); if these signs or symptoms develop, the heart failure should be managed according to the current standards of care; furthermore, discontinuation or dose reduction of these drugs must be considered.

These drugs are not recommended for patients with symptomatic heart failure; initiation of these drugs in patients with established NYHA class III or IV heart failure is contraindicated

Contraindications

Hypersensitivity to pioglitazone

Diabetic ketoacidosis

Moderate-severe hepatic impairment (ALT >2.5x ULN)

CHF (NYHA class III, IV)

Cautions

Do initiate treatment in patients with active liver disease who have ALT levels >2.5 times the upper limit of normal (ULN); if ALT >3 times the ULN, stop treatment; if ALT is 1.5-3 times the ULN, retest qWeek until normal or until it reaches 3 times the ULN and treatment must be discontinued

Not recommended for patients with symptomatic heart failure; may cause or exacerbate congestive heart failure in some patients; monitor patients carefully after initiating therapy; observe for signs and symptoms of heart failure; if signs and symptoms develop, manage heart failure according to current standards of care; consider discontinuing therapy or reducing the dose

New onset or exacerbation of existing edema and dyspnea reported

Macular edema reported; patients should be seen by an ophthalmologist if any visual symptoms arise during therapy; all diabetic patients should have regular eye exams

Delayed related weight gain reported with use; likely associated with fluid retention and fat accumulation

Thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin

Risk of hypoglycemia, in combination with insulin or other oral agents

May result in ovulation in some premenopausal, anovulatory women; ensure adequate contraception

May decrease hemoglobin/hematocrit

Increased fracture risk in females

Use with caution in premenopausal/anovulatory females (patient may resume ovulation and increase the risk of pregnancy)

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

Increased risk of CHF; not recommended in symptomatic heart failure

Cancer risk

  • Bladder cancer
    • Pioglitazone may be linked to an increased risk of bladder cancer
    • Do not prescribe for patients with active bladder cancer
    • Consider benefit:risk ratio before prescribing in patients with a history of bladder cancer
    • Instruct patients to contact their physician if signs of bladder cancer observed after initiating therapy (eg, blood or red colored urine, new or worsening urinary urgency, pain on urination)
  • Prostate cancer
    • 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for prostate cancer (453.3 vs. 449.3 per 100,000 person-years) [JAMA 2015 July 21;314(3):265-277]
  • Pancreatic cancer
    • 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for pancreatic cancer (81.1 vs. 48.4 per 100,000 person-years)

Patient Handout

Print without Office InfoPrint with Office Info

What is pioglitazone (actos)?

Pioglitazone is an oral diabetes medicine that helps control blood sugar levels.

Pioglitazone is for people with type 2 diabetes. Pioglitazone is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes.

Pioglitazone may also be used for purposes not listed in this medication guide.

Important information

You should not use Actos if you have severe or uncontrolled heart failure, active bladder cancer, or diabetic ketoacidosis (call your doctor for treatment with insulin). This medicine is not for treating type 1 diabetes.

Actos can cause or worsen congestive heart failure. Stop using this medicine and call your doctor at once if you have shortness of breath (even with mild exertion), swelling, or rapid weight gain.

Pioglitazone Identification

Substance Name

Pioglitazone

CAS Registry Number

111025-46-8

Drug Class

Hypoglycemic Agents

Thiazolidinediones

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