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Petition to Require a Warning on All Calcium Channel Blocking Drugs

November 9, 1995

David A. Kessler, M.D., J.D.
Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

CITIZENS' PETITION TO REQUIRE A WARNING ON ALL CALCIUM CHANNEL BLOCKING DRUGS

Dear Dr. Kessler:

Public Citizen, a nationwide consumer organization with about 90,000 members, hereby petitions the FDA, pursuant to the Federal Food, Drug and Cosmetic Act 21, U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30, to immediately add a box warning and change the labeling on all calcium channel blocking drugs licensed in the United States to include recent evidence linking these drugs to an increased risk for heart attack and death. In 1993, these drugs were prescribed 72 million times to 7 million American for the treatment of hypertension (high blood pressure) or angina pectoris (chest pain).[1],[2] This prescribing continues in the absence of evidence that these drugs prevent heart attack, heart failure, strokes or death and in the face of mounting evidence of their hazards. The FDA should also require patient package inserts for all calcium channel blockers.

A summary of the most recent scientific evidence includes:

* A November 1995 prospective study of older adults with high blood pressure showed the risk of death to be about 1.7 times as great with immediate release nifedipine compared with beta-blockers (another class of drugs for treating high blood pressure).[3]

* In 1995 the pooled results (meta-analysis) of randomized secondary prevention trials found that the use of immediate release nifedipine in high doses was associated with a two to threefold increase in the risk of death compared with placebo. The risk of death increased with increasing doses of nifedipine.[4]

* A 1995 case-control study of the immediate release dosage forms of nifedipine, diltiazem and verapamil, compared with diuretics and beta-blockers in patients with high blood pressure, were consistently associated with about a 60% increase in the risk of heart attack. High doses of calcium channel blockers were associated with increased risk of heart attack.[5]

* The Multicentre Isradipine/Diuretic Atherosclerosis Study (MIDAS) showed in 1994 that the risk of major cardiovascular complications was higher in those taking the calcium channel blocker isfadipine versus patients taking the diuretic (water pill) hydrochlorothiazide to prevent the progression of atherosclerosis.[6]

* Based on this scientific evidence the National Heart, Lung, and Blood Institute declared on August 31, 1995 that ". . . short-acting nifedipine should be used with great caution (if at all), especially at higher doses, in the treatment of hypertension, angina, and MI.", and that the safety of all other calcium channel blockers was "unclear."[7]

These recent studies consistently show a strong link between the use of the calcium channel blocking drug nifedipine (Procardia, Pfizer; Adalat, Bayer) and an increased risk of death and heart attack. Other calcium channel blocking drugs diltiazem (Cardizem, Marion Merrell Dow), isradipine (DynaCirc, Sandoz), and veraparnil (Calan, Searle; Isoptin, Knoll), have also been implicated in increasing the risk of adverse cardiovascular effects in patients with high blood pressure or heart disease. This mounting evidence places in question the safety of the other drugs in this class: amlodipine (Norvasc, Pfizer), bepridil (Vascor, McNeil), felodipine (Plendil, Astra-Merck) and nicardipine (Cardene, Syntex).

The failure to wam doctors and patients of the potential serious effects of this class of drug when safer effective alternatives can be used as initial treatment for high blood pressure and chest pain will contribute to thousands of preventable drug-induced adverse effects annually, including deaths and heart attacks.

The use of calcium channel blocking drugs as the first treatment for high blood pressure or chest pain must be viewed in the light of the following information:

1. The purpose of giving drugs to control high blood pressure is to prevent stroke, heart attack, heart failure and premature death, not simply to lower blood pressure. In addition, to alleviate symptoms the purpose of treating chest pain is to slow or halt progression of coronary artery disease and reduce the risk of heart attack, heart failure or death.

2. No well controlled study has shown convincingly that calcium channel blockers can reduce stroke, heart attack, heart failure or prevent death.

3. The best available scientific evidence links calcium channel blockers to an increased risk of heart attack and death in people using these drugs for high blood pressure and chest pain.

4. The calcium channel blocking drugs are often prescribed for the life of the patient.

5. Although the calcium channel blockers are chemically different, they all share mechanisms of action.

6. We are aware of no specific documented evidence that the long acting dosage forms of calcium channel blockers are safer than the immediate release formulations as far as mortality is concerned.

7. Most important, there are alternative drugs to the calcium channel blockers for the treatment of high blood pressure and chest pain such as the beta-blockers and diuretics that have been proven safe and effective and which reduce--not increase--the risk of death in patients using them.

ACTIONS REQUESTED

We hereby request the following immediate actions:

1. Require a box warning for all immediate release and long acting dosage forms of all calcium channel blocking drugs.

Suggested Warning Label:

Emerging evidence shows a consistent association between the use of the immediate release dosage forms of calcium channel blocking drugs and an increased risk of adverse cardiovascular events including myocardial infarction and death. The evidence to date most strongly implicates the immediate release dosage form of nifedipine in moderate or high doses, but there is no evidence that extended release dosage forms are safer as far as patient mortality is concerned. The three calcium channel blocker sub-types are chemically dissimilar, but they share mechanisms of action. Consequently, it is prudent to consider that this warning should apply to all calcium channel blocking drugs, regardless of chemical class or dosage form (immediate or extended release).

The calcium channel blocking drugs should not be used in those patients with recent myocardial infaretion and congestive heart failure.

Drugs from alternative classes of agents for the initial treatment of stable or unstable angina pectoris or hypertension--diuretics and beta-blockers--have reduced major cardiovascular events and mortality in well controlled trials in hypertensive patients. Other agents, including the calcium channel blockers, have not been shown to reduce the incidence of stroke, myocardial infarction or death. Consequently, the Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends diuretics and beta-blockers as the preferred drugs for treating hypertension.

This new warning should be boxed in bold type and placed at the beginning of the manufacturer's product labeling for amlodipine (Norvasc, Pfizer), bepridil (Vascor, McNeil), diltiazem (Cardizem, Marion Merrell Dow), felodipine (Plendil, Astra-Merck), isradipine (DynaCirc, Sandoz), nicardipine (Cardene, Syntex), nifedipine (Procardia, Pfizer; Adalat, Bayer), nimodipine (Nimotop, Bayer), and verapamil (Calan, Searle; Isoptin, Knoll) and their generic equivalents. This warning should be included in the labeling for both the immediate and extended release forms of these drugs.

2. Require that the indications' section of the manufacturer's product information for all calcium channel blockers licensed for the treatment of essential hypertension state that calcium channel blockers should be used only after an adequate trial of diuretics and/or beta-blockers or in those patients in which diuretics and/or beta-blockers are contraindicated, ineffective or not tolerated.

3. Require that the indications' section of the manufacturer's product information for all calcium channel blockers licensed for the treatment of chronic stable or vasospastic angina pectoris state that calcium channel blockers should only be used after an adequate trial of nitrates and/or beta-blockers or in those patients in which nitrates and/or beta-blockers are contraindicated, ineffective or not tolerated.

4. Immediately inform all U.S. physicians through a "Dear Doctor Letter" about the new warning and labeling changes.

5. Immediately inform all other U.S. professionals through the FDA Medical Bulletin about the new warning and labeling changes.

6. Require that a "Patient Package Insert" be provided with every new and refill prescription dispensed for the immediate and extended release dosage forms of all calcium channel blocking drugs (see below).

PATIENT PACKAGE INSERT -- MEDICATION GUIDES

In the announcement of its proposed Medication Guide (patient package insert) program to provide prescription drug consumers with drug information the FDA stated "FDA believes that improved dissemination of information about prescription drug products is necessary to fulfill patients' need and right to be informed." The FDA also proposed regulations that would require FDA approved Medication Guides for products "that pose a serious and significant public health concern" requiring immediate distribution of FDA-approved patient information.[8]

The scientific evidence presented in this petition clearly identifies the calcium channel blocking drugs as products that "pose a serious and significant public health concern." The following language is suggested as part of the product summary section to be placed at the beginning of the Medication Guide for all calcium channel blocking drugs.

No scientific studies show convincingly that the calcium channel blocking drugs can reduce the risk of stroke, heart attack, heart failure, or prevent death. Recent scientific studies have shown a consistent link between the use calcium channel blocking drugs and an increased risk of heart attack and death in patients with cardiovascular disease. The adverse effects more than offset the assumed benefit of blood pressure lowering in patients with high blood pressure and the symptomatic relief in patients with chest pain. The strongest evidence links the forms of calcium channel blockers that must be taken several times a day with these increased risks. No scientific studies have shown that the once a day forms of calcium channel blockers are safer than the forms that must be taken several times a day.

The calcium channel blocking drugs should not be used in those persons with recent heart attack and heart failure. Safer alternative drugs to the calcium channel blockers are available that can be used for the initial treatment of high blood pressure or chest pain. These. alternatives should be discussed with your doctor before beginning treatment with calcium channel blocking drugs. The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends diuretics and beta-blockers as the preferred drugs for treating high blood pressure.

EVIDENCE FOR INCREASED RISKS WIT14 CALCIUM CHANNEL BLOCKERS

The potential dangers of the calcium channel blockers have been suspected since at least 1989.[9]
The most recent study to raise concerns about the safety of calcium channel blockers is the prospective cohort study published in the November 1995 Journal of the American Geriatrics Society. This study compared the long-term risk of death in 906 adults over 70 years of age with high blood pressure taking beta-blockers, calcium channel blockers, or angiotensin converting enzyme inhibitors. The immediate release dosage form of nifedipine emerged with the highest risk of death compared with the beta-blocking drugs (RR=1.7, 95% Cl 1.1 to 2.7). When the mortality analysis was restricted to those persons with high blood pressure without coronary heart disease and no likely contraindications to taking beta-blocker drugs, all three calcium channel blockers (nifedipine, diltiazem and verapamil) appear to increase the risk of death. The relative risk calculated for nifedipine was 4.2 (RR=4.2, 95% Cl 1.1 to 16.1). The risk of death was not statistically significant with diltiazem (RR=1.6, 95% Cl 0.3 to 7.3) and veraparnil (RR=1.9, 95% Cl 0.4 to 8.2). Higher doses of nifedipine were associated with an increase in deaths. The authors of the study concluded "The present study shows evidence for a decreased survival in older hypertensive persons who use short acting [immediate release] nifedipine."[3]

A meta-analysis, a statistical technique to pool the results of multiple studies, reported in the September 1995 issue of Circulation examined 16 randomized secondary-prevention trials of nifedipine for which dose and mortality data were available. The purpose of this study was to assess the effect of nifedipine dose on increased mortality risk seen in randomized trials that primarily looked at preventing a second heart attack. About 8350 patients were studied, and the doses of nifedipine ranged from 30 to 120 milligrams per day. In daily doses of 30 milligrams to 50 milligrams the risk of death was only slightly increased (risk ratio=1.06, 95% Cl 0.89 to 1.27), and somewhat greater in a dose of 60 milligrams (risk ratio=1.18, 95% Cl 0.93 to 1.50), and at 80 milligrams per day the risk of death had increased almost threefold (risk ratio=2.83, 95% Cl 1.35 to 5.93). In the formal dose response analysis, the risk of mortality was strongly associated with the dose of nifedipine (p = 0.01). The authors of this study state "Regulatory agencies ought to consider whether moderate to high doses of nifedipine capsules should be excluded from the 'approved labeling."[4]

A population based case-control study published in the August 23/30, 1995 Journal of the American Medical Association was restricted to patients without cardiovascular disease other than high blood pressure. The population of patients studied was from a single health maintenance organization (HMO). This method allowed all heart attacks to be identified in the population and provided consistency and completeness in medical and pharmacy records that permitted an unbiased comparison of cases and control. The results showed that compared to diuretics used alone, the calcium channel blocking drugs nifedipine, diltiazem and verapamil, alone or in combination with diuretics, increased the risk of a first heart attack by about 60%. When the use of beta-blocking drugs in patients either with or without cardiovascular disease was used as the comparison group, the risk of first heart attack was still increased by about 60%. A statistically significant dose-response effect for calcium channel blockers and heart attack in this study are similar to the dose-response findings for immediate release nifedipine and mortality in the above mentioned meta-analysis.4 These authors concluded "While high doses of beta -blockers were associated with a decreased risk of myocardial infarction (trend p=.04), high doses of calcium channel blockers were associated with an increased risk (trend p<.Ol)."[5]

The results of the Multicentre Isradipine/Diuretic Atherosclerosis Study (MIDAS) were presented at the 1994 Scientific Meeting of the International Society of Hypertension. The MIDAS study was conducted to compare the effects of isradipine and hydrochlorothiazide on the rate of progression of atherosclerosis. Isradipine showed no overall benefit but the overall incidence of major cardiovascular adverse effects was almost two times higher in those patients taking isradipine, though not statistically different (p=0.07). The number of patients hospitalized for angina was almost four times greater for those taking isradipine than for those taking hydrochlorothiazide, eleven versus three respectively (p<0.05).6 This study has never been published as a full length medical journal article.

The International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT), published in 1990, was a randomized controlled trial to determine if nifedipine would suppress the build-up of plaque in blood vessels of the heart. In this study 425 patients with mild coronary artery disease and stable angina were given 80 mg of immediate release nifedipine or placebo daily. Mortality was not a primary outcome measure in this study but there were 12 deaths in patients taking nifedipine and two in those taking a placebo.[10]

A 1989 systematic review (meta-analysis) of data from all randomized controlled primary and secondary prevention trials of calcium channel blockers found that calcium channel blockers were not of any benefit. In their discussion, the authors of this study said ". . . available randomized trials of calcium channel blockers in myocardial infarction and unstable angina does not indicate any beneficial effect on infarct development, infarct size, reinfarction, or mortality." and ". . . the data suggest a somewhat higher probability of harm than benefit[with calcium channel blockers]."[9]

Three randomized clinical trials of calcium channel blockers have been prematurely terminated when harm was detected at interim analysis:

A 1995 study of nimodipine (Nimotop, Bayer), a calcium channel blocking drug not used for high blood pressure or chest pain, was tested against placebo in a randomized, placebo controlled, double blind clinical trial of patients undergoing cardiac valve replacement. The objective of this study was to determine whether nimodipine would reduce the combined incidence of neurological, neuroophthalmological, and neuropsychological deficits over six months compared with placebo. After enrollment of 149 patients an independent monitoring committee recommended the trial be terminated due to excess mortality in those patients receiving nimodipine compared with the placebo group. Eight of 75 patients died in the nimodipine group compared with one of 74 receiving placebo (small sample odds ratio: 8.6; 95% Cl 1.11 to 392).[11]

The Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT) was done to test whether chronic administration of nifedipine given 7 to 21 days after an acute heart attack would result in a significant reduction in coronary mortality and morbidity in the year following the heart attack.[12] A second trial, SPRINT II, was undertaken at a higher nifedipine dose, given earlier, and in high risk patients only. SPRINT II was prematurely stopped when it was found that there was excess death in those people taking nifedipine versus placebo. Most of the deaths occurred within six days of starting the drug with 43 deaths occurring in those taking nifedipine and 29 in those using placebo during this time.[13]

The 1986 Holland Interuniversity Nifedipine/Metoprolol Trial (HINT), a multicenter, double blind, placebo controlled, randomized trial, studied nifedipine, metoprolol (a beta-blocking drug), and nifedipine and metoprolol in 338 patients with unstable angina not pretreated with a beta-blocker and nifedipine in 177 patients pretreated with a beta-blocker. The major outcomes assessed in HINT were recurrent inadequate circulation of blood to the heart (ischemia) or heart attack within 48 hours. Subject enrollment was stopped when an interim analysis suggested that the risk of heart attack was higher in patients given nifedipine alone than in those treated with the other medications. The dose of nifedipine used in the study was 60 milligrams per 24 hours. For heart attack within 48 hours the nifedipine-placebo rate ratio was 2.0 (95% Cl, 1.1 to 3.6).[14]

The three most recent studies3-5 discussed above meet all of the accepted scientific criteria for supporting a causal link between the calcium channel blockers and harm. (1) The evidence shows a strong association between the use of nifedipine and other calcium channel blockers and the risk of adverse events; (2) this association is consistent across studies; (3) the risk increases with increasing dose; (4) and there are plausible biological explanations of how calcium channel blocking drugs may cause their adverse effects.[4] The evidence is strongest for a link with the immediate release form of nifedipine, but drugs from the three calcium channel blocker sub-types, though chemically different, have been implicated in the same kinds of adverse effects as nifedipine.

Data are lacking to establish the safety of the long acting dosage forms of the calcium channel blockers. The epidemiological data showing the association between calcium channel blockers and adverse cardiovascular events were obtained before the introduction and widespread use of the long acting dosage forms of the calcium channel blockers. To our knowledge, there are no valid long-term scientific studies which demonstrate that extended release dosage forms of calcium channel blockers such as Procardia XL, Cardizem SR or Calan SR are any safer than the immediate acting forms as far as overall mortality or adverse cardiovascular events are concerned.

CONCLUSION

This petition to require a warning on the calcium channel blockers concerns the safety of an estimated seven million Americans using these drugs at present. There is no proof that the calcium channel blockers have a beneficial effect on the major complications of high blood pressure, or that they reduce the risk of death. Lacking proof of benefit and a scientifically valid concern about the safety of calcium channel blockers confirmed in study after study in a biologically plausible fashion, it is unthinkable that physicians and their patients are not adequately informed. This is particularly serious when safer drugs of proven efficacy are available.

We urge the FDA to immediately exercise its public health responsibility by warning the nation's health care professionals about the risks of calcium channel blocking drugs, by requiring a box warning in the labeling for all calcium channel blockers, and by requiring patient package inserts. Millions of Americans take these drugs every year and those that can tolerate proven safe alternatives to the calcium channel blocking drugs are needlessly at risk of potentially life-threatening consequences. Patients should consult with their physician before altering their medication.

CERTIFICATION

We certify that, to the best of our knowledge and belief, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.

Sincerely,

Larry D. Sasich, Pharm.D.
Research Analyst
Public Citizen's Health Research Group

Sidney M. Wolfe, M.D.
Director
Public Citizen's Health Research Group

Peter Lurie, M.D., M.P.H.
Research Associate
Public Citizen's Health Research Group

REFERENCES

1. Manolio TA, Cutler JA, Furberg CD, Psaty BM, Whelton PK, Applegate. Trends in pharmacologic management of hypertension in the United States. Arch Intern Med 1995;155:829-837.

2. IMS America. National Prescription Audit. Ambler, Pa: IMS America; 1993.

3. Pahor M, Guralnik JM, Corti M-C, Foley DJ, Carbonin P, Havlik RJ. Long-term survival and use of antihypertensive medications in older persons. JAm Geriatr Soc 1995;43:1191-1197.

4. Furberg CD, Psaty BM, Meyer JV. Nifedipine dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-1331.

5. Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-625.

6. McClellan K. Unexpected results from MIDAS in atherosclerosis. Inpharma 1994;932:4[abstract].

7. National Heart, Lung, and Blood Institute, Public Health Service, U.S. Department of Health and Human Services. New analyses regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. August 31, 1995.

8. Food and Drug Administration. Prescription drug product labeling; medication guide requirements. Federal Register Vol. 60, No. 164, Thursday, August 24, 1995.

9. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:1187-1192.

10. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW. Retardation of angiographic progression of coronary artery disease by nifedipine. Lancet 1990;335:1109-1113.

11. Wagenknecht LE, Furberg CD, Hammon JW, Legault C, Troost BT. Surgical bleeding: unexpected effect of a calcium antagonist. Br Med J 1995;310:776-777.

12. The Israeli Sprint Study Group. Secondary prevention Israeli nifedipine trial (SPRINT). Eur Heart J 1988;9:354-364.

13. Goldbourt U, Behar S, Reicher-Reiss H, Zion M, Mandelzweig L, Kaplinsky E for the SPRINT Study Group. Early administration of nifedipine in suspected acute myocardial infarction. Arch Intern Med 1993;153:345-353.

14. Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group. Early treatment of unstable angina in the coronary care unit: a randomized, double-blind, placebo controlled comparison of recurrent ischemia in patients treated with nifedipine or metoprolol or both. Br Heart J 1986;56:400-413.

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