Actos

ACTOS- pioglitazone hydrochloride tablet
Takeda Pharmaceuticals America, Inc.

WARNING: CONGESTIVE HEART FAILURE

Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
After initiation of ACTOS, 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 must be considered.
ACTOS is not recommended in patients with symptomatic heart failure.
Initiation of ACTOS 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

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)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients

ACTOS 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 ACTOS or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.5)].

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOS. Routine periodic monitoring of liver tests during treatment with ACTOS is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of ACTOS or who are found to have abnormal liver tests while taking ACTOS 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 ACTOS and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered ACTOS and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of ACTOS and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of ACTOS 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 “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

4 CONTRAINDICATIONS

Initiation in patients with established NYHA Class III or IV heart failure [see Boxed Warning].
Use in patients with known hypersensitivity to pioglitazone or any other component of ACTOS.

5 WARNINGS AND PRECAUTIONS

5.1 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)].

5.2 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)].

5.3 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.

5.4 Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to 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.

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