Testimony of Sidney M. Wolfe, M.D. and Larry Sasich, Pharm.D., M.P.H.
Public Citizen Health Research Group
Before The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee
On Petition to Relabel doxazosin (CARDURA)
National Institutes of Health, Bethesda, MD
You are being asked to recommend action to the FDA based on a published analysis of the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT). This trial compared the alpha-blocker drug doxazosin (Cardura), produced by Pfizer Inc. of New York, to the generically available and much less expensive treatment chlorthalidone, a member of the thiazide family of diuretics or ‘water pills’ for the control of high blood pressure. This analysis found that patients taking Cardura were almost twice as likely as those on chlorthalidone to be hospitalized for congestive heart failure, had 25 percent more cardiovascular events, and had a significantly elevated risk of stroke. Patients who had originally been given Cardura in the study greatly benefited from being taken off the drug in order to avoid the excess risks of heart failure, stroke and other cardiovascular events when the above results were made known in January, 2000. Now, almost 17 months later, thanks in part to a massive misinformation and stonewalling campaign by Pfizer, coupled with inadequate action by the FDA, most of the hundreds of thousands of Americans still using the drug have not had the advantage of stopping Cardura and switching to other, safer and usually less expensive drugs such as diuretics and beta blockers. Equally appalling is the likelihood that many patients not previously on Cardura before the results of ALLHAT were known have started using the drug despite the dire warnings of that study.
As physicians being asked by patients to recommend drugs for the treatment of hypertension, it would be highly unlikely for you or for me, knowing what we now know, to recommend an alpha blocker such as Cardura as a first choice drug. More likely, we would relegate it to a fourth or lower choice drug, only after adequate trials of diuretics, beta blockers, or ACE inhibitors, alone and in combination, had been tried without success. If this is what we do for patients who consult us, what can be done so that this evidence-based prescribing decision will be made by other physicians and their patients and that those already on alpha blockers will be switched to other drugs? The task at hand is for you to delineate a series of actions which the FDA can take to maximize the odds that few if any newly diagnosed hypertensive patients are started on alpha blockers such as Cardura and that most, if not all hypertensive patients now using such drugs are safely switched to other agents.
One year ago, in the May 2000 issue of our monthly newsletter Worst Pills, Best Pills News, we warned our 120,000 subscribers against the use of Cardura and other alpha blockers, based on the just-published findings of the ALLHAT study.
The citizen petition asks that: 1) the Food and Drug Administration (FDA) require Pfizer to notify all patients in the U.S. who have taken or are taking Cardura to control their blood pressure and that the FDA issue a press release regarding the interim results of ALLHAT; 2) the FDA require a boxed warning in the professional product labeling or ‘package insert’ for Cardura and its generic versions informing prescribers of the ALLHAT interim results; and 3) that if deemed necessary by the FDA additional labeling changes for Cardura that may include changes in approved uses, warnings, precautions, and contraindications.
Public Citizen strongly supports the fundamental intention of this petition to require notification of physicians and patients of the ALLHAT results but although we support the principle behind this petition, as it stands it will not achieve the desired goal. Therefore, we are urging the committee to make additional recommendations to the FDA such as a mandatory FDA-approved patient guide (Med Guide) to be dispensed with the drug. Before discussing the details of this and other recommendations we would like the committee to first consider Pfizer’s role in ‘stonewalling’ on the ALLHAT results.
Pfizer contributed financially to the ALLHAT study ostensibly to answer an important medical question: Which antihypertensive drugs are the safest and most effective in producing clinically meaningful outcomes for patients? Pfizer did not like the answer and the petition’s authors provide exquisite documentation of corporate ‘damage control’ to protect Cardura, one of Pfizer’s “Magnificent 7” drugs, a $800 million market. The company’s scripting of sales representatives’ elusive responses to ALLHAT questions according to medical speciality coupled with the revelation that sales representatives were not proactively discussing ALLHAT is devoid of scientific and medical ethics.
Because it is clear that Pfizer can not be relied upon to provide scientifically accurate, useful information to patients or physicians, this committee and the FDA must take a much more proactive role to ensure that medical professionals and the public receive such drug information.
FDA Press Releases in Informing the Public About Drug Safety Warnings
We support the FDA’s use of press releases or public health advisories to inform the public immediately about new drug safety warnings. However, at the level of the individual patient this method of informing the public relies primarily on chance and is available for only a short period of time. While serving as an initial alert, a sustained effort to change the opinions of doctors and patients must include permanent educational efforts directed at both groups as will be discussed below.
Drug Safety Labeling Changes
We agree with the petitioners that a black box warning should be required in the professional product labeling for brand and generic versions of Cardura alerting health professionals of the ALLHAT results. However, we would like this committee to note that there is growing body of published evidence that safety labeling changes to a drug’s professional product labeling alone do not protect a large proportion of patients from preventable drug induced injury or death.
The concurrent use of the withdrawn antihistamine terfenadine (Seldane) with contraindicated antibiotics and antifungal drugs before and after safety labeling changes and the issuing of ‘Dear Doctor’ letters has been assessed is several studies. A retrospective review of computerized pharmacy claims from a large New England health insurer found that despite significant declines following reports of life-threatening drug interactions and additional warning in the professional product labeling, concurrent use of terfenadine and contraindicated antibiotics and antifungal drugs continued to occur. Using pharmacy claim data from 1988 through 1994 from state Medicaid programs in Michigan and Ohio it was found that the concomitant use of ketoconazole and erythromycin with terfenadine had fallen by 80 percent. In a retrospective study of pharmacy claims it was found that coprescription of terfenadine with either erythromycin or ketoconazole continued to occur after regulatory action.
The FDA reviewed reports of lactic acidosis associated with the use of the diabetes drug metformin (Glucophage) occurring from May 1995 through June 30, 1996, the drug’s first year on the market in the U.S. Of the 47 patients with a confirmed diagnosis of the adverse drug reaction, 43 (91%) had one or more risk factors for lactic acidosis that were listed in the drug’s professional product labeling at the time of its approval.,
Recently, the effect of June 1998 FDA regulatory actions in the form of a ‘Dear Doctor’ letter and additional safety labeling changes were assessed on the contraindicated prescribing of cisapride (Propulsid). At one state Medicaid site surveyed for the study, in the year prior to new warnings about the drug the use of cisapride was contraindicated in 60 percent of those for whom the drug was prescribed. In the year after the regulatory actions, the proportion of contraindicated patients prescribed this drug had decreased to 58 percent. The authors of the study concluded:
The FDA’s 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.
We strongly agree with this conclusion, particularly as it relates to providing effective communication to patients. The FDA has had the authority since June 1999 to mandate the distribution of Medication Guides by pharmacists for five to ten drugs per year that pose a “serious and significant public health concern” Cardura and the other alpha blockers certainly fit this category when compared to chlorthalidone for the treatment of hypertension.
Additional Labeling Requirements for Patients: Medication Guides
The only way to ensure that patients using Cardura are notified of the ALLHAT results is for the FDA to require a Medication Guide or ‘Med Guide’ for the drug that reflects these results in non-technical language and places the risks in a context that can be used by patients. Medication Guides must not be confused with patient labeling that is a part of a drug’s approved professional labeling that is either voluntarily written by manufacturers or requested by the FDA. The expectation is that these Med Guides for patients would be distributed by pharmacists, as is currently being done for Accutane and thalidomide. Unfortunately, there is indirect evidence that pharmacists have distributed un-regulated information produced by commercial information vendors that are often out-of-date or omit important risk information rather than FDA approved patient information.
Additional Labeling and Med Guide Requirements: Class Labeling for the Alpha Blockers
We also strongly suggest that the advisory committee recommend to the FDA that the black box warning and Med Guide developed for Cardura be the basis for a class black box warning label for all alpha blockers marketed in the U.S. This would include, in addition to Cardura and its generic versions, prazosin (Minipress), terazosin (Hytrin), and tamsulosin (Flomax).
Additional Labeling Requirements: Alpha Blockers as Second Line Therapy for Hypertension
Lastly, we also strongly suggest that the advisory committee recommend to the FDA that all alpha blockers approved be relegated, in labeling and patient guides to second, if not last or almost-last line therapy for hypertension.
 Other alpha-blocker in the U.S. market in addition to doxazosin are prazosin (Minipress), terazosin (Hytrin), and tamsulosin (Flomax).
 At a Washington DC chain pharmacy the retail cost for 30 Cardura 8 milligrams, or a one month supply, was quoted as $44.59. At the same pharmacy, 30 generic chlorthalidone, also a one month supply was quoted as $9.49. This is a difference of $35.10 per month or $421.20 per year. These retail costs were obtained on May 11, 2001.
 Examples of thiazide diuretics available in the U.S. market in addition to chlorthalidone are hydrochlorothiazide (HydroDIURIL, Microzide), bendroflumethiazide (Nagturetin), and benzthiazide (Exna).
 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. Journal of the American Medical Association 2000;283:1967-1975.
 Bernhardt-Liebman Petition at 05 000407. The full text of the citizen petition and its extensive documentation is available on the FDA’s web site at: http://www.fda.gov/ohrms/dockets/dailys/01/Jan01/010901/cp00001.pdf (accessed May 11, 2001).
 Bernhardt-Liebman Petition at 05 000234. The full text of the citizen petition and its extensive documentation is available on the FDA’s web site at: http://www.fda.gov/ohrms/dockets/dailys/01/Jan01/010901/cp00001.pdf (accessed May 11, 2001).
 Bernhardt-Liebman Petition, Deposition of Joseph M. Feczko, page 46. The full text of the citizen petition and its extensive documentation is available on the FDA’s web site at: http://www.fda.gov/ohrms/dockets/dailys/01/Jan01/010901/cp00001.pdf (accessed May 11, 2001).
 Thompson D, Oster G. Use of terfenadine and contraindicated drugs. Journal of the American Medical Association 1996;275:1339-1341.
 Burkhart GA, Sevka MJ, Temple R, Honig PK. Temporal decline in filling prescriptions for terfenadine closely in time with those for either ketoconazole or erythromycin. Clinical Pharmacology and Therapeutics 1997;61:93-96.
 Carlson AM, Morris LS. Coprescription of terfenadine and erythromycin or ketoconazole: an assessment of potential harm. Journal of the American Pharmaceutical Association 1996;NS36(4):263-269.
 Misbin RI, Green L, Stadel BV, et al. Lactic acidosis in patients with diabetes treated with metformin. New England Journal of Medicine 1998;338:265-266.
 Metformin (Glucophage) Professional Product Labeling. Physicians’ Desk Reference 50th ed. Montvale NJ: Medical Economics 1996. The metformin labeling appearing in the 1996 Physicians’ Desk Reference was issued in February 1995.
 Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride. Journal of the American Medical Association 2000;284;3036-3039.
 Department of Health and Human Services, Food and Drug Administration. Prescription Drug Product Labeling; Medication Guide Requirements; Final Rule. Federal Register: December 1, 1998, Volume 63, Number 230, Pages 66377-66400.
 Cavuto NJ, Woosley RL, Sale M. Pharmacies and prevention of potentially fatal drug interactions. Journal of the American Medical Association 1996;275:1086-1087 [letter].
In this study, 50 pairs of terfenadine (Seldane) and erythromycin prescriptions were presented at Washington DC area pharmacies. This combination of drugs was known to increase the risk of potentially fatal heart rhythm disturbances. Sixteen (32%) of the 50 pharmacies filled the two prescriptions without comment. Of the 10 pairs of prescriptions filled at chain pharmacies, 9 were accompanied by written information. Six of the written information leaflets instructed patients to check with the physician if terfenadine and erythromycin were taken together while three suggested “Report any other drugs you take or diseases your have.”
This information contained the following statements:
DO NOT USE SELDANE IF YOU ARE USING KETOCONAZOLE (NIZORAL), ITRACONAZOLE (SPORANOX), ERYTHROMYCIN, CLARITHROMYCIN (BIAXIN), OR TROLEANDOMYCIN (TAO).
“SELDANE has caused IRREGULAR HEARTBEATS which may cause serious problems like fainting, dizziness, cardiac arrest, or death.” (Physicians’Desk Reference 49th ed. Montvale NJ: Medical Economics 1995)
If the pharmacies involved in this study had distributed the FDA approved patient information, rather than the information produced by unregulated information vendors adequate warning about a potentially fatal drug interaction would have been provided 100 percent of the time.