Petition to the Food and Drug Administration to immediately stop the distribution of dangerous, misleading prescription drug information to the public. (HRG Publication #1442)
June 9, 1998
Michael A. Friedman, M.D.
CITIZENS' PETITION TO IMMEDIATELY STOP THE DISTRIBUTION OF DANGEROUSLY MISLEADING PRESCRIPTION DRUG INFORMATION TO THE PUBLIC
Dear Dr. Friedman:
There is no question that a substantial proportion of the estimated 100,000 Americans who die each year because of adverse drug reactions and the serious injuries to 2.2 million others(1) could be prevented. One of the most important ways of preventing such tragedies is to ensure that patients are adequately informed about the risks and proper use of prescription drugs. As long ago as 1979, FDA stated that:
". . . oral communication of information about prescription drug products by health professionals cannot be relied upon to provide patients with the information they need to use prescription drug products properly."(2) More recently, the Agency said: "Inadequate access to appropriate patient information is a major cause of inappropriate use of prescription medications, resulting in serious personal injury and related costs to the health care system."(3)
Public Citizen, a nationwide organization representing 120,000 consumers, and Patricia and Ben Christen, whose only son Cory died as a result of unregulated, misleading, commercially produced written patient drug information, hereby petition the Food and Drug Administration (FDA), pursuant to the Federal Food, Drug and Cosmetic Act, to immediately recall, or seize if necessary, unregulated information that is being distributed with prescription drugs that is not consistent with or derived from a drug's FDA approved, regulated professional product labeling, commonly known as the package insert. A large proportion of the patient information leaflets (PILs) produced by commercial information vendors and distributed by pharmacists to millions of consumers when prescriptions are dispensed may contribute to thousands of drug injuries and deaths by giving the public a dangerously false sense of security about the safety of prescription drugs by failing to warn about adverse reactions or proper use including dangerous dosages. FDA's first priority should be to take action by recalling those PILs whose inaccurate information is most likely to cause substantial harm if not corrected.
Seven-year-old Cory Christen's death, from a drug-induced cardiac arrhythmia, was needless and preventable and is directly attributable to his parents being deprived of vital dosing and adverse reaction information, information that was omitted from a PIL produced by an unregulated commercial information vendor, Medi-Span, Inc. of Indianapolis, for the antidepressant drug imipramine (Tofranil). In addition to this tragic example, the FDA is in possession of other evidence demonstrating that dangerous informational deficiencies exist in the PILs for other drugs.
Forty-one thousand patients are hospitalized and an estimated 3,300 die each year from gastrointestinal bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs), used for treating arthritis or pain. Studies have shown that if patients are not adequately informed to stop the use of such drugs if they develop abdominal pain and therefore do not identify the pain as an adverse reaction to the NSAID, they are much more likely to have serious bleeding sufficient to require hospitalization. Given that many physicians do not routinely provide this kind of information to their patients, the routine use of accurate and complete PILs would save hundreds of lives lost to NSAID-induced gastrointestinal bleeding and thousands of hospitalizations. As discussed below, FDA's own study has shown serious deficiencies in PILs and a recent Public Citizen's Health Research Group survey of PILs for 15 NSAIDs found that only a small fraction warned patients to stop using the drug if they developed abdominal pain.
This petition is based on the following which will be discussed in greater detail:
THE FDA HAS JURISDICTION OVER DRUG INFORMATION INTENDED FOR USE BY THE PUBLIC WHICH ACCOMPANIES THE DISPENSING OF PRESCRIPTION DRUGS
Patient Information Leaflets (PILs) meet the legal definition of drug labeling
Section 201(m) of the Food Drug and Cosmetic Act defines "labeling" as "all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article."(4) Patient information leaflets fall under part (2) of this definition, and thus constitute "labeling" under the Act.
Drugs are considered misbranded if they are accompanied by PILs which are misleading (fail to reveal important facts, including adverse reactions) or fail to include adequate directions for use, including warnings against unsafe dosages.
Because patient information leaflets are "labeling," the FDA has jurisdiction to regulate their content pursuant to two separate provisions of the Act:
1. Under section 502(a) of the Act, a drug is misbranded if its labeling is "false or misleading in any particular."(5) In determining whether labeling is "misleading," section 201(n) instructs the Agency to take into account, both representations made or suggested and "the extent to which the labeling . . . fails to reveal facts material in light of such representations or material with respect to consequences which may result from the use prescribed in the labeling . . . or under such conditions as are customary or usual."(6)
2. Under section 502(f), a drug is misbranded if its labeling does not include adequate directions for use and "adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users... ."(7)
FDA can regulate PILs in order to enforce the labeling provisions of the law
Section 701(a) of the Act authorizes the Agency to promulgate regulations for the efficient enforcement of the Act.(8) The above two misbranding provisions, in combination with section 701(a), empower the Agency to issue and enforce regulations to ensure that patient information leaflets are accurate and not misleading both in terms of what information is included and in terms of what information is omitted. Although there are currently no regulations on PIL content, the PILs with the most flagrant violations, which are more likely to result in harm to patients, could be recalled or, if necessary, seized because they clearly violate the above-cited sections of the Food , Drug and Cosmetic Act.
COMMERCIAL INFORMATION VENDORS, PHARMACISTS, AND DRUG COMPANIES ARE ALL RESPONSIBLE FOR THE INFORMATION CONTAINED IN PILs
The Responsibility of Companies Producing PILs
First, section 301(k) of the Act prohibits doing any act with respect to a drug, while the product is held for sale after shipment in interstate commerce, that results in the drug being misbranded.(9) A company that makes and distributes a misleading patient information leaflet causes a product to be misbranded, and thus commits a prohibited act. (Although the company's act may in some cases precede the shipment of the specific item purchased by the consumer, the act comes after the drug in general has entered interstate commerce.)
The Responsibility of Pharmacists
Second, a pharmacist could be held accountable under this same theory. That is, that the pharmacist has rendered the product misbranded by giving the consumer a misleading patient information leaflet at the time of sale.
The Responsibility of Drug Companies
Third, if a drug manufacturer knows that a patient information leaflet concerning its product is misleading, the Agency should hold the manufacturer responsible for the consequent misbranding, even if a manufacturer is not involved in producing or distributing the leaflet. (It is highly unlikely that drug manufacturers are unaware of the content of the PILs which are being dispensed with their drugs.) The Agency's "intended use" regulation provides precedent for holding drug manufacturers accountable for what a third party says about or does with the manufacturer's product. See 21 C.F.R. § 201.128 ("if a manufacturer knows, or has knowledge of facts that would give him notice, that a drug introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug which accords with such other uses to which the article is to be put.")
THE NEEDLESS DEATH OF CORY CHRISTEN RESULTED FROM CRITICAL SAFETY INFORMATION BEING OMITTED FROM AN UNREGULATED PIL FOR THE DRUG IMIPRAMINE (TOFRANIL AND GENERICS)
Cory was diagnosed with Attention Deficient Hyperactivity Disorder (ADHD) on December 8, 1995 and referred to a psychiatrist on May 10, 1996 who prescribed three drugs for Cory: (1.) imipramine (Tofranil), a tricyclic antidepressant, a drug that is not approved by the FDA for the treatment of ADHD(10); (2.) divalproex (Depakote), a drug approved for mania and epilepsy, not for ADHD(11); and (3.) pemoline (Cylert), a drug that is approved by the FDA for Attention Deficit Disorder(12).
Cory's parents did not know that imipramine could cause serious potentially fatal heart rhythm disturbances (see Appendix I). This information was omitted from the Medi-Span PILs given to Cory's parents by the pharmacist. If this information had been made available to his parents, Cory would not have been given the drug.
Cory was started on a dose of imipramine of 2.2 milligrams per kilogram (a total of 50 milligrams per day) on May 21, 1996. By the time he died on September 19, 1996 his doctor had increased his dose to 8.8 milligrams per kilogram (a total of 200 milligrams per day). The package insert for imipramine clearly states that a dose of 2.5 milligrams per kilogram per day should not be exceeded in childhood (see Appendix I). Cory was receiving 3.5 times the recommended dose of imipramine when he died. As seen in Appendix I, this information about maximum childhood dose is in the package insert but was not in the PIL which Cory's parents were given with the prescription.
During the four months that Cory was taking imipramine his parents had reported to his doctor on three separate occasions that he had experienced hallucinations (6/10/96), headache and "seeing an eye" (6/27/96), and a fine tremor in his hands and he was staring off into space (8/29/96). Again, the package insert lists hallucinations and tremors as adverse reactions for imipramine (see Appendix I). But, Cory's parents did not know these were adverse reactions to imipramine, this vital information was not contained in the Medi-Span PIL (see Appendix I).
On the morning of September 19, 1996 Cory went to school. At 8:15 AM he complained to his teacher that he had a headache. After lunch, Cory was on his way to his physical education class when he stopped at a water fountain where he collapsed. His teacher administered cardiopulmonary resuscitation (CPR) within minutes. Cory was transported to the local emergency and pronounced dead at 1:41 PM.
The Medical Examiner's Report concluded:
Based on the anatomic findings at autopsy, and investigation information available at this time, it is my conclusion that CORY CHRISTEN, a 7 year-old white male died as a result of toxic effects of imipramine overdose, causing cardiac arrhythmia (heart rhythm disturbance).(13)
The Medi-Span PIL given to Cory's parents omitted the most important information, the potentially serious and deadly adverse effects of this drug. Instead, Medi-Span only warned of the minor, nuisance effects of imipramine which are expected to go away with the use of the drug. Cory's parents were deprived of information they had a right to know in order to make an informed decision about their child's medical care. The effect was to give Cory's parents a false sense of security about the safety of imipramine and this led directly to Cory's death.
If Cory's parents had been given an imipramine PIL that was consistent with or derived from the drug's approved product labeling they would have known four critical pieces of information, any one of which might have saved the life of their son:
1. That imipramine can cause heart rhythm disturbances that are potentially fatal.
2. That the imipramine prescribed for their son was for an "off-label" use, a use that was not approved by the FDA. Imipramine is approved only for depression and pediatric enuresis (bed wetting), not ADHD.
3. That Cory had been prescribed a dose of imipramine that was 3.5 times greater than the maximum dose recommended for children in the imipramine approved product labeling.
4. That the hallucinations and tremors experienced by Cory were actually adverse drug reactions. .
AN FDA SURVEY OF PILs HAS FOUND SUBSTANTIAL DIFFERENCES BETWEEN COMMERCIAL INFORMATION VENDORS IN THE QUALITY OF INFORMATION PROVIDED, INCLUDING THE OMISSION OF WARNINGS WHICH COULD BE LIFE-SAVING.
The FDA has compared the PILs produced by eight commercial information vendors for three commonly prescribed prescription drugs for consistency with the drugs' approved product labeling. The PILs were produced by the American Society of Health-Systems Pharmacists, Clinical Reference Systems, Ltd., Facts and Comparisons, First Data Bank, Medi-Span, Inc., Medi CHEX, Inc., Pharmex, and the United States Pharmacopeia. The specificity of the information communicated was judged on the basis of whether the directions for use were clear and whether the risk information conveyed the significance of the risk, how to recognize negative consequences, and the proper response to take should they occur.(14)
The FDA found substantial differences between the commercial vendors and the quality of information provided. For example, none of the eight vendors mentioned the contraindications for the use of the high blood pressure lowering drug enalapril (Vasotec), i.e., allergic reactions or swelling (angioedema) on previous treatment with other drugs in the same family. Two vendors failed to warn the patient about the symptoms of angioedema, a potentially deadly allergic reaction. Of the six vendors including such symptoms (i.e., swelling of the face, extremities, eyes, lips, tongue or difficulty in swallowing or breathing), only one advised the patient experiencing such symptoms to take no more drug and to seek medical attention immediately.
PILS CONTAIN INCOMPLETE SAFETY INFORMATION
Public Citizen's Health Research Group has conducted two studies of the information content of PILs being distributed by pharmacists to the public. In the first, we examined the PILs for 15 nonsteroidal anti-inflammatory drugs (NSAIDs) for sufficient information for patients to reduce their likelihood of severe NSAID-associated gastrointestinal (GI) toxicity should it occur. PILs were assessed for the following information: (1) GI toxicity is identified as a potentially serious adverse effect; (2) GI toxicity is identified as potentially life-threatening; (3) the symptoms of NSAID associated GI toxicity are listed; and (4) instruction is given to stop the NSAID and contact the prescriber should symptoms of GI toxicity appear. None of these PILs produced by commercial information vendors met all four criteria and only 15 out of 59 (25.4%) warned about stopping the drug if symptoms of GI toxicity such as abdominal pain occur.(15)
In the second study, the content of four categories of information in PILs for five fluoroquinolone antibiotics ( drugs such as ciprofloxacin (Cipro) and ofloxacin (Floxin)) were compared to the information given in the approved product labeling for these drugs (package insert). The information content of the fluoroquinolone PILs contained less than one-half of the information listed in the approved product labeling for these drugs.(16)
INFORMED PATIENTS CAN AVOID SERIOUS DRUG INDUCED INJURY
GI bleeding and perforation are common and serious adverse effects of the non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin), nabumetone (Relafen), and oxaprozin (Daypro).
Wynne and Long(17) studied 50 consecutive patients with arthritis admitted to the hospital with acute GI bleeding who had taken any of four commonly used (NSAIDs) in the preceding three day and 100 control patients matched for age, gender, NSAID, and dosage who had not experienced GI bleeding. All patients were visited in their homes by a nurse to assess their knowledge of their arthritis treatment. The nurse asked whether the patients had received any information about the possible adverse effects of NSAIDs, if so from where, and what they been told to do if an adverse effect occurred. The nurse asked the patients who had bled, "Did you have any stomach problems, such as indigestion or pain before your stomach bleed?" And the patients who had not bled, "Have you had any stomach problems, such as indigestion or pain?" The nurse also asked the patients to estimate how much of the prescribed dose they actually took and, if it was less than prescribed, why.
The patients whose use of these drugs had led to bleeding knew less about the adverse effects of their NSAIDs or what to do when they occurred than did the patients who had not bled. The patients who bled were also more compliant with their prescribed dosage of drug. Fewer patients who bled (16%) than patients who had not bled (41%) remembered having been told of the possible adverse effects of their drug or about what to do if they developed an adverse reaction (4% vs. 21%). In addition, 18 (36%) of the patients who bled experienced stomach pain before bleeding and all but two had continued to take their drug, whereas only 15 (15%) of the patients who did not bleed had stomach upset, of whom 10 had reduced their dosage of drug.
One of the world's most respected drug safety experts, Dr. Andrew Herxheimer, commented on this study: ". . . it looks as if ignorance about side effects led to failure to recognize warning symptoms and to inappropriate compliance [by NSAID users]."(18)
VOLUNTARY REGULATION OF PILS CANNNOT WORK
Voluntary self-regulation by the warnings companies such as Medi-Span, Inc. has proven to be unsuccessful. Companies selling these warnings are willing to omit information about deadly adverse effects resulting in inadequately-educated patients who are therefore less reluctant to use or question their prescribed medications. Medi-Span, Inc. has testified through its vice-president of operations, that it allowed the marketplace to help determine the content of its warnings. Several documents attributable to Medi-Span, Inc. indicate that the Medi-Span, Inc. monographs (PILs) are intended to "stand alone" in the absence of counseling, and are considered a safety net in terms of risk management. The dangerously deficient sheets demonstrate the dangers of not requiring scientifically-based regulation: In claiming that "no consistently inferior product would survive in the marketplace", a company abdicates even its voluntarily-assumed responsibility to "insure accuracy". The marketplace should not judge the quality of these items; scientists should.
The majority of PILs now being distributed contain incomplete safety information. Incomplete, inaccurate or out-of-date safety information misrepresents the risks of prescription drugs and thus presents a hazard to the public's health that is leading to needless drug induced deaths and injury and, in the case of Cory Christen, the tragic, preventable death of a seven-year-old child.
The FDA has attempted since 1979 to require the distribution of objective prescription drug information written for consumers in non-technical language, but their efforts have been consistently thwarted by the drug industry and professional trade associations, such as the American Medical Association (A.M.A.) and the American Pharmaceutical Association (A.Ph.A). These groups have effectively prevented the Agency from requiring the distribution of vital, potentially life-saving, information to prescription drug consumers.
After Congress killed the FDA's 1995 effort to ensure the public had useful written drug information, a legislatively mandated voluntary process produced guidelines for the information content of PILs that were agreed to by representatives of the drug industry, medicine, pharmacy, and consumers in 1996 and these guidelines were accepted by the Secretary of the Department of Health and Human Services in early 1997.(19) Central to these guidelines is useful written information for consumers which for the purposes of the guidelines was defined, in part, as being scientifically accurate or "information consistent with or derived from FDA approved labeling . . .."
The drug industry and the professional trade associations maintain a patently disingenuous stance by saying on the one hand they support the distribution of high quality, objective drug information to the public, while on the other they will only support the voluntary implementation of the agreed upon guidelines. These groups know full well that the Congressionally mandated plan that created the voluntary guidelines is unenforceable. This means no useful drug information in the hands of the public for the foreseeable future.
Distinguishable from the issue of the current inability of the FDA to require PILs to be dispensed with prescriptions is the issue raised in this petition: If PILs are going to be voluntarily provided with a prescription, as they currently are for the majority of prescriptions being dispensed, the FDA has the legal authority, indeed is required by law, to ensure that the content of the PILs is not dangerously incomplete and misleading as in the cases found by FDA's own study, in the studies done by Public Citizen's Health Research Group and in the case of Cory Christen.
The safety of any prescription drug to the individual consumer cannot be separated from the quality of information that accompanies the drug. By being incomplete, unregulated PILs increase the risks of adverse drug reactions by misleading consumers about the safety of their drugs.
The FDA clearly stated in 1995 that it believes that: "Inadequate access to appropriate patient information is a major cause of inappropriate use of prescription drugs resulting in serious personal injury and related costs to the health care system."12 Cory Christen's death was a needless and tragic example of the effect of inappropriate patient information in the form of unregulated PILs distributed by a pharmacist. Had Cory's parents received a PIL that was consistent with or derived from imipramine's approved product labeling Cory's parents would have made the decision not to administer the drug and Cory would be alive today. There will continue to be more 'Corys' until the public is guaranteed access to objective information, written in non-technical language, that places the risks of prescription drugs in a context that is useful to the general public.
The Agency has the clear legal authority and mandate to ensure that when the public receives PILs, the information is written in non-technical language that is consistent with or derived from a drug's approved product labeling and must do so now.
We certify that, to the best of our knowledge and belief, this petition includes all information and views on which this petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.
Larry D. Sasich, Pharm.D., M.P.H., FASHP
Sidney M. Wolfe, M.D. Director,
Allison Zieve, Attorney
The bolding in the imipramine professional product labeling was added for emphasis. It is present in the FDA-approved labeling but was missing in the Medi-Span PIL.
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients. JAMA 1998;279:1200-05.
2. Food and Drug Administration. Prescription Drug Products: Patient Labeling Requirements. Federal Register Vol. 44:40016, July 6, 1979.
3. Department of Health and Human Services. Food and Drug Administration. Prescription Drug Product Labeling; Medication Guide Requirements. Federal Register Vol. 60, No. 164, Thursday, August 24, 1995.
4. 21 U.S.C. § 321(m)
5. 21 U.S.C. § 352 (a)
6. 21 U.S.C. § 321(n)
7. 21 U.S.C. § 352(f)
8. 21 U.S.C. § 371(a)
9. 21 U.S.C. § 331(k)
10. Tofranil (imipramine) Professional Product Labeling. Physicians' Desk Reference 1996. Montvale NJ: Medical Economics Company, 1996.
11. Depakote (divalproex) Professional Product Labeling. Physicians' Desk Reference 1996. Montvale NJ: Medical Economics Company, 1996.
12. Cylert (pemoline) Professional Product Labeling. Physicians' Desk Reference 1996. Montvale NJ: Medical Economics Company, 1996.
13. Medical Examiner's Report for Cory Christen, Colorado County, Texas signed by Elizabeth Peacock, MD, Deputy Medical Examiner, dated October 29, 1996.
14. Department of Health and Human Services. Food and Drug Administration. Prescription Drug Product Labeling; Medication Guide Requirements. Federal Register Vol. 60, No. 164, Thursday, August 24, 1995.
15. Sasich LD, Wolfe SM. Deficiencies in patient information leaflets concerning gastrointestinal complications of nonsteroidal anti-inflammatory drugs. Journal of General Internal Medicine 1997;12(suppl):79[abstract].
16. Bradley LR, Sasich LD. The information content of patient medication information leaflets: examination of five fluoroquinolone antibiotics. Journal of the American Pharmaceutical Association 1998;38:278-279[abstract].
17. Wynne HA, Long A. Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs). British Journal of Clinical Pharmacology 1996;42:253-256.
18. Herxheimer A. Many NSAID users who bleed don't know when to stop. British Medical Journal 1998; 316:492[editorial].
19. Action Plan for the Provision of Useful Prescription Medicine Information presented to the Honorable Donna E. Shalala, Secretary of the Department of Health and Human Services by the Steering Committee for the Collaborative Development of a Long-Range Action Plan for the Provision of Useful Prescription Medicine Information, December 1996.