Drug safety and availability > fda drug safety communication: update to ongoing safety review of actos (pioglitazone) and incre
Drug Safety and Availability > FDA Drug Safety Communication: Update .
http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm
FDA Drug Safety Communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer Safety Announcement Additional Information for Patients Additional Information for Healthcare Professionals Data Summary References
Safety Announcement [6-15-2011] The U.S. Food and Drug Administration (FDA) is informing the public that use of the diabetes medication
Actos (pioglitazone) for more than one year may be associated with an increased risk of bladder cancer. Information
about this risk will be added to the Warnings and Precautions section of the label for pioglitazone-containing medicines
The patient Medication Guide for these medicines will also be revised to include information on the risk of bladder
This safety information is based on FDA's review of data
Facts about pioglitazone
from a planned five-year interim analysis of an ongoing,
Sold as a single-ingredient product under the
ten-year epidemiological study1, described in FDA's
brand-name Actos. Also sold in combination with
September 2010 ongoing safety review 1 and in the Data
metformin (Actoplus Met, Actoplus Met XR) and
Summary below. The five-year results showed that
although there was no overall increased risk of bladder
Used along with diet and exercise to improve control of
cancer with pioglitazone use, an increased risk of bladder
blood sugar in adults with type 2 diabetes mellitus.
cancer was noted among patients with the longest
exposure to pioglitazone, and in those exposed to the
highest cumulative dose of pioglitazone.
approximately 2.3 million patients filled a prescription
for a pioglitazone-containing product from outpatient
FDA is also aware of a recent epidemiological study
conducted in France 2 which suggests an increased risk of
bladder cancer with pioglitazone. Based on the results of this study, France has suspended the use of pioglitazone and
Germany has recommended not to start pioglitazone in new patients. FDA recommends that healthcare professionals should:
Not use pioglitazone in patients with active bladder cancer. Use pioglitazone with caution in patients with a prior history of bladder cancer. The benefits of blood sugar
control with pioglitazone should be weighed against the unknown risks for cancer recurrence.
FDA will continue to evaluate data from the ongoing ten-year epidemiological study. The Agency will also conduct a
comprehensive review of the results from the French study. FDA will update the public when more information
becomes available. Additional Information for Patients
There may be an increased chance of having bladder cancer when you take pioglitazone. You should not take pioglitazone if you are receiving treatment for bladder cancer.
Drug Safety and Availability > FDA Drug Safety Communication: Update .
http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm
Tell your doctor right away if you have any of the following symptoms of bladder cancer: blood or red color in
urine; urgent need to urinate or pain while urinating; pain in back or lower abdomen. Read the Medication Guide you get along with your pioglitazone medicine. It explains the risks associated with
the use of pioglitazone. Talk to your healthcare professional if you have questions or concerns about pioglitazone medicines. Report side effects from the use of pioglitazone medicines to the FDA MedWatch program, using the information
in the "Contact Us" box at the bottom of the page.
Additional Information for Healthcare Professionals
Do not use pioglitazone in patients with active bladder cancer. Use pioglitazone with caution in patients with a prior history of bladder cancer. The benefits of glycemic control
versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history
of bladder cancer. Counsel patients to report any signs or symptoms of blood in the urine, urinary urgency, pain on urination, or
back or abdominal pain, as these may be due to bladder cancer. Encourage patients to read the Medication Guide they get with their pioglitazone medicine. Report adverse events involving pioglitazone medicines to the FDA MedWatch program using the information in
the "Contact Us" box at the bottom of this page.
Data Summary To address the long-term risk of bladder cancer associated with pioglitazone use, the drug manufacturer (Takeda) is
conducting a ten-year, observational cohort study as well as a nested case-control study in patients with diabetes whoare members of Kaiser Permanente Northern California (KPNC) health plan.1 Patients selected in this study had
diabetes mellitus and were ≥40 years of age at study entry. Patients with bladder cancer prior to study entry or within
six months of joining KPNC were excluded from this study. The cohort included 193,099 patients with diabetes. The primary outcome of the cohort study is an incident (new) diagnosis of bladder cancer identified from the KPNC
cancer registry. The primary exposure of interest is treatment with pioglitazone. Data on drug dose, duration of
exposure and potential confounding factors are also obtained in the study. A planned five-year interim analysis was performed with data collected from January 1, 1997 through April 30, 2008.
The median duration of therapy among pioglitazone-treated patients was 2 years (range 0.2-8.5 years). The results
showed that after adjusting for age, sex, use of tobacco products, use of other categories of diabetes medications, and
other risk factors, there was no significant increase in the risk for bladder cancer in patients ever exposed to
pioglitazone compared to patients never exposed to pioglitazone (Hazard Ratio [HR] 1.2, 95% Confidence Interval [CI
0.9 to 1.5). However, the risk of bladder cancer increased with increasing dose and duration of pioglitazone use.
Compared to never being exposed to pioglitazone, a duration of pioglitazone therapy longer than 12 months was
associated with a 40% increase in risk (HR 1.4; 95% CI 0.9 to 2.1). The hazard ratio after more than 24 months of
pioglitazone use was 1.4 (95% CI 1.03 to 2.0) and was of nominal statistical significance. Based on these data, FDA
calculated that duration of therapy longer than 12 months was associated with 27.5 excess cases of bladder cancer per
100,000 person-years follow-up, compared to never use of pioglitazone. FDA is also aware of a retrospective cohort study using data from the French National Health Insurance Plan. The study
cohort included approximately 1.5 million patients with diabetes, followed for up to 4 years (2006-2009). The results
showed that after adjusting for age, sex, and use of other anti-diabetic medications, there was a statistically significan
increase in the risk for bladder cancer in patients exposed to pioglitazone compared to patients exposed to other
anti-diabetic agents (HR 1.22; 95% CI 1.03 to 1.43). The results also showed a dose effect related to cumulative dose
>28,000 mg (HR 1.75; 95% CI 1.22 to 2.5) and for exposures longer than 1 year (HR 1.34; 95% CI 1.02 to 1.75). A
significant increase in risk was observed in males (HR 1.28; 95% CI 1.09 to 1.51), but not females, who experiencedonly a few cases. Further information is available in the European Medicines Agency (EMA) press release 3 and theAgence Française de SécuritéSanitaire des Produits de Santé (AFSSAPS) press release 4 (in French). FDA will continue to evaluate data received from the ongoing KPNC study. The Agency will also conduct a
comprehensive review of the results from the French epidemiological study. FDA will update the public when additiona
information becomes available. References
1. Lewis JD, Ferrara A, PengHedderson M, Bilker WB, QuesenberryJr, et al. Diabetes Care. 2011;34:916-22.
2. SDI, Vector One®: Total Patient Tracker (TPT). January 2010-October 2010. Data extracted 12-15-10.
Drug Safety and Availability > FDA Drug Safety Communication: Update .
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Related Information
Agence Francaise de Securite Sanitaire des Produits de Sante (Afssaps) 5 6Update on ongoing European review of pioglitazone–containing medicines 7 8FDA Drug Safety Communication: Ongoing Safety Review of Actos (pioglitazone) and Potential Increased Risk ofBladder Cancer After Two Years Exposure 9
Pioglitazone HCl (marketed as Actos, Actoplus Met, and Duetact) Information 10
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