Takeda Responds to the FDA Advisory Committee Recommendation

Takeda Responds to the FDA Advisory Committee Recommendation: With all the publicity about TZD’s and the cardiovascular ischemic/thrombotic risks the Drug Safety and Risk Management Advisory Committees to the U.S. Food and Drug Administration (FDA) made some blanket statements about all drugs in the class. Takeda makers of Actos, responded to these blanket claims with data from studies showing not all TZD’s are the same. Click to read more.

Takeda Responds to the FDA Advisory Committee Recommendation

Dear Colleagues:
As you may be aware, the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees to the U.S. Food and Drug Administration (FDA) recently met jointly to review the cardiovascular ischemic/thrombotic risks of the thiazolidinediones (TZDs), with focus on rosiglitazone. The discussions of the Advisory Committees further reinforce the scientific evidence supporting the proven cardiovascular safety profile of ACTOS® (pioglitazone HCl) which supports Takeda’s position that, although drugs may be in the same class, they also can have different clinical effects due to differences in molecular structure.

ACTOS is the only TZD with safety data from a cardiovascular outcomes trial in its label. The PROactive study (PROspective PioglitAzone Clinical Trial In MacroVascular Events) was a prospective, randomized, double-blind, placebo-controlled outcomes trial investigating the effects of ACTOS on total mortality and macrovascular morbidity in 5,238 high-risk patients with type 2 diabetes. Patients were randomized to ACTOS or placebo in addition to diabetes and cardiovascular standard of care, and followed for up to 3.5 years. This landmark study is the first and only macrovascular outcomes trial with any TZD. The totality of ACTOS data has included more than 16,000 patients from short and long term studies, both prospective and observational, and show no evidence that ACTOS is associated with an increased incidence of heart attack or stroke.

In the U.S., the FDA reviewed the data and approved the addition of some reassuring safety information from the PROactive trial that confirmed ACTOS was not associated with an increase in mortality or in total macrovascular events, including myocardial infarction and stroke. In PROactive, while the incidence of serious heart failure was higher for ACTOS-treated vs. placebo-treated patients (5.7% v. 4.1%), there was no increase in the incidence of death subsequent to a report of serious heart failure (1.5% vs. 1.4%, respectively).

While a separate issue, we recognize that use of the TZD class of medications has been associated with an increased risk of congestive heart failure (CHF) and have provided warning about this issue since 1999 with periodic updates to the label. We are currently in discussions with the FDA for label changes that will heighten patient and physician awareness of this already known but serious side effect. Our goal is to optimize treatment benefit and minimize risk for the patient.
Takeda is committed to providing important clinical information to enable you to have open discussions with your patients concerning diabetes treatments. As you evaluate the needs of your patients in the coming weeks, please feel free to call 1- 877-TAKEDA-7 if you have any questions regarding ACTOS.
Sincerely,

Robert Spanheimer, MD
Senior Medical Director, Diabetes and Metabolism

ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. ACTOS is approved for use as monotherapy and in combination with sulfonylureas, metformin, or insulin when diet and exercise plus a single agent do not result in glycemic control.

Important Safety Information about ACTOS® (pioglitazone HCl)
Like other thiazolidinediones (TZDs), pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop congestive heart failure (CHF) when treated with pioglitazone in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease. Patients with NYHA Class III and IV cardiac status were not studied in pioglitazone clinical trials; therefore, ACTOS is not indicated in these patients. Patients with systolic heart failure (NYHA Class II) naÏve to pioglitazone therapy should be initiated at the lowest approved dose. Patients should be monitored for signs and symptoms of CHF exacerbation.
Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOS.

ACTOS may also be associated with hypoglycemia, edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women. Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams, and be instructed to immediately report any visual changes to their healthcare provider.
In US placebo-controlled ACTOS monotherapy clinical trials, the most common adverse events (≥5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.
ACTOS should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.
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