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FDA places more restrictions on GSK's Avandia,
Pioglitazone & Bladder Cancer Risk
  Pharmatimes World News | May 20, 2011
Kevin Grogan
FDA places more restrictions on GSK's Avandia
GlaxoSmithKline's Avandia will not be available in US pharmacies from the middle of November after the Food and Drug Administration imposed further restrictions on the controversial diabetes drug.
The agency restricted access to Avandia (rosiglitazone) in September, though it allowed the drug to remain on the market, unlike its European counterpart which suspended sales, based on data suggesting that it could put patients at an increased risk from heart disease. Now that already-limited access is being cut further.
The FDA says that patients and healthcare providers must now enroll in a special programme in order to prescribe and receive Avandia, Avandamet (rosiglitazone/metformin) and Avaglim (rosiglitazone/glimepride). The new restrictions are part of an updated risk evaluation and mitigation strategy (REMS).
Related Links
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The REMS now limits the use of rosiglitazone medicines to patients already being successfully treated with these drugs and those whose blood sugar cannot be controlled with other anti-diabetic treatments and do not wish to use Takeda's related drug Actos (pioglitazone) and variations thereof. The FDA added that after November 18, the GSK drugs will no longer be available through retail pharmacies.
This latest move looks pretty much like the end of the line for Avandia. Worldwide first-quarter sales slumped 79% to 36 million.
Glaxo's Diabetes Drug Avandia Pulled From U.S. Pharmacies
Bloomberg, By Michelle Fay Cortez - May 18, 2011 5:45 PM ET
GlaxoSmithKline Plc (GSK)'s diabetes drug Avandia will be pulled from U.S. pharmacies in November and available only through a special program, the Food and Drug Administration said.
The restrictions are part of a risk mitigation strategy established in September with a medication guide to limit the use of Avandia after data suggested patients had a higher chance of heart attacks. The drug and combination therapies containing it will no longer be available in retail pharmacies starting Nov. 18, according to the FDA, which is requiring doctors and patients to enroll in a program to prescribe or take them.
Avandia, once the world's best-selling diabetes bill at $3 billion in annual revenue, generated $680 million in sales last year for London-based Glaxo. About 460,500 patients filled a prescription for Avandia, Avandamet or Avandaryl at a retail pharmacy from January to October 2010, the FDA said in a safety announcement posted today on its website.
"Healthcare providers and patients must be enrolled in the Avandia-rosiglitazone Medicines Access Program in order to prescribe and receive rosiglitazone medicines," the agency said, using the chemical name for the drug. Patients will receive their medicines through specially certified mail order pharmacies, the agency said.
Glaxo plans to start telling pharmacists and physicians about the new program within the 60 day window allowed by the FDA, and implement the changes at or before that time, said Mary Anne Rhyne, a company spokeswoman, in an e-mailed statement. Patients shouldn't abruptly stop taking their diabetes medicines without first discussing it with their doctors, she said.
The drugs can be used only by patients who are already taking them successfully and who can't control their blood sugar levels with other diabetes drugs, including Actos from Osaka, Japan-based Takeda Pharmaceutical Co., the agency said.
Use of the medication has fallen by half during the year, with 235,500 patients filling a prescription in January and 119,000 getting the drugs in October, the agency said.
Assessing the Association of Pioglitazone Use and Bladder Cancer Through Drug Adverse Event Reporting - "physicians should pay careful attention to this possible risk."
Diabetes Care Publish Ahead of Print, published online April 22, 2011 CARLO PICCINNI, PHD1 GIULIO MARCHESINI, MD2 DOMENICO MOTOLA, PHD1 ELISABETTA POLUZZI, PHD1
From the 1Department of Pharmacology, University of Bologna, Bologna, Italy; and 2Metabolic Diseases & Clinical Dietetics, Department of Clinical Medicine, University of Bologna, Bologna, Italy.
Corresponding author: Elisabetta Poluzzi, e-mail:
OBJECTIVE-To analyze the association between pioglitazone use and bladder cancer through a spontaneous adverse event reporting system for medications.
RESEARCH DESIGN AND METHODS-Case/noncase bladder cancer reports associ- ated with antidiabetic drug use were retrieved from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) between 2004 and 2009 and analyzed by the reporting odds ratio (ROR).
RESULTS-Ninety-three reports of bladder cancer were retrieved, corresponding to 138 drug- reaction pairs (pioglitazone, 31; insulin, 29; metformin, 25; glimepiride, 13; exenatide, 8; others, 22). ROR was indicative of a definite risk for pioglitazone (4.30 [95% CI 2.82-6.52]), and a much weaker risk for gliclazide and acarbose, with very few cases being treated with these two drugs (6 and 4, respectively).
CONCLUSIONS-In agreement with preclinical and clinical studies, AERS analysis is consistent with an association between pioglitazone and bladder cancer. This issue needs constant epidemiologic surveillance and urgent definition by more specific studies.
A link between pioglitazone and bladder cancer first appeared in preclinical studies and was first reported on the U.S. pioglitazone label in 1999, but experimental studies recently suggested that it might be a rat-specific phenomenon (1). In the large PROactive (PRO- spective pioglitAzone Clinical Trial In macroVascular Events) study, 14 bladder cancers occurred in the pioglitazone arm (0.5%) versus 6 in the placebo arm (0.2%) (2,3), and in September 2010, the U.S. Food and Drug Administration (FDA) announced an ongoing investigation on the possible risk in humans (4). Accordingly, the drug manufacturer is conducting a 10-year observational study to address the long-term risk of bladder cancer asso- ciated with pioglitazone (4).
Very recently, the European Medicines Agency (EMA) suspended the marketing authorization of rosiglitazone (5), and the FDA largely restricted its use because of an increased cardiovascular risk (6). These measures will increase the prescription of pioglitazone; thus, the definition of its benefit/risk profile becomes all the more pressing.
Our aim was to contribute to defining the safety profile of pioglitazone, focusing on cases of bladder cancer recorded in the FDA Adverse Event Reporting System (AERS) database associated with antidia- betic drug treatment.
RESULTS-From 2004 to 2009, 86,987 reports involving antidiabetic drugs were recorded in FDA AERS, corresponding to 599,085 drug-reaction pairs (ob- tained by splitting comedications and multiple reactions reported for each case), with 37,841 reports concerning pioglitazone. Overall, 93 reports of blad- der cancer were retrieved, corresponding to 138 drug-reaction pairs, with 31 concerning pioglitazone; 29 insulin; 25 metformin; 13 glimepiride; 8 exenatide; 6 gliclazide; 5 glipizide; 4 sitagliptin, acarbose and rosiglitazone; 3 glibenclamide; 2 nateglinide and repaglinide; and 1 phenformin and voglibose.
The ROR of bladder cancer was significantly >1 for pioglitazone (ROR 4.30 [95% CI 2.82-6.52]; P , 0.001) as well as for gliclazide and acarbose (Table 1). Among the 31 cases of bladder cancer re- ported in pioglitazone users (mean age, 70 years; range 53-84), 23 occurred in men (3.86 [2.37-6.26]; Supplementary Table A1) and 8 were in women (5.19 [2.15-12.11]). When stratified by age (cutoff, 65), ROR for pioglitazone was only significant in older patients (5.10 [3.14-8.23]). Four cases of bladder can-cer were reported in 2004, three in 2005, nine in 2006, five in 2007, six in 2008, and four in 2009 (ROR not statistically significant in 2005 and 2009; Supplementary Table A2).
Ten cases occurred during clinical studies. The length of drug use, which was recorded in 15 cases, was ,6 months in 6 patients, 6-24 months in 5, and .24 months in 4. Antiplatelet agents (e.g., aspirin and clopidogrel), antihypertensive drugs (e.g., ACE inhibitors and diuretics), lipid-lowering agents (e.g., statins), other antidiabetic drugs (e.g., glimepiride, metformin, and acarbose), and glucocorticoid (fluticasone and mometasone) were the cotreatments most frequently recorded (24 patients). One patient was being treated with cytotoxic therapy (infliximab and methotrexate for psoriatic arthropathy), and one was treated with interferon- b-1a for multiple sclerosis.
CONCLUSIONS-Bladder cancer is the fourth most common cancer and the ninth leading cause of cancer death among U.S. men (10). Cigarette smoking, urinary tract infections, occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, and drugs (e.g., cyclophosphamide) are risk factors for the disease, as might be the systematic use of glucocorticoids (11).
We found a definite signal for bladder cancer associated with pioglitazone use. The demographic characteristics of the selected cases were consistent with blad- der cancer epidemiology (male sex, old age) (10). A weaker signal was also associated with gliclazide, and a much weaker signal was associated with acarbose. Of note, the occurrence of fewer than five events, although resulting in a statistically significant ROR, may be considered clin- ically meaningless because it is too susceptible to reporting biases (12).
Although notoriety bias may have contributed to part of the association between pioglitazone use and bladder cancer (13), we also observed a significant relationship in 2004, which preceded publication of the PROactive study (2) and label revision. Therefore, we do not believe that our findings can be explained by notoriety bias alone. A greater use of pioglitazone could also have influenced this result (14).
Preliminary data found an increasing risk of bladder cancer with pioglitazone exposure, with statistical significance after 24 months (4). This issue could not be confirmed by our analysis, with only four cases of bladder cancer occurring in patients exposed to pioglitazone for more than 2 years and several missing data. In general, the association with bladder cancer does not seem to derive from concomitant drug use or comorbidity, with only two patients receiving treatments potentially favoring carcinogenesis and five patients receiving glucocorticoids.
The ROR analysis has several limitations: generic under-reporting, over- reporting generated by notoriety bias, dependence on the drug-marketing period (Weber effect), missing or misspelled data (7,13,15), and lack of information on patients' habits (smoking) or occupational risks. Despite limitations, the higher-than-expected reporting of bladder cancer for pioglitazone users compared with users of other antidiabetic drugs should stimulate specific case-con- trol studies aimed at verifying the magnitude of the hazard; until the final data of the FDA investigation are available, physicians should pay careful attention to this possible risk.


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