Legally regulated drug labels approved by the Food and Drug Administration (FDA) 1 contain valuable information about adverse drug reactions. The information provided in these labels is gained from clinical trials and postmarketing surveillance. FDA-approved drug labeling text has been a rich resource for the study of concerns regarding drug-related safety and toxicity 2. For example, studies based on drug labeling have shown that drugs receiving black-box warnings appear more often in certain therapeutic categories than others 3.
Recently, there has been growing concern among psychiatrists regarding the increase in black-box warnings for psychiatric medications, as 794 unique drugs were approved by FDA. Thirty-five percent (279) of these had a boxed warning, the most severe label associated with adverse drug reactions 4.
Between 2004 and 2005, the FDA required 91 products to have ‘black boxes’ – the agency’s most serious level of warning for patients. This was more than double the 45 black boxes required during the 25 years from 1975 to 2000. In fact, more than 300 active ingredients with black-box warnings are currently on the market 5.
Aim of the work
This review was carried out to (a) define black-box warnings and the drugs included, (b) search for the causes of warnings for psychiatric medications, (c) develop strategies to deal with black-box warnings, and finally, (d) study the effects of those warnings on our practice with regard to current drug regulations in Egypt.
To achieve the above-mentioned objectives, we conducted a search of the literature for all published papers and data on Pubmed, MD consult, About.com Guide, and WebMD Health News. We used keywords such as black-box warning and drug regulation Egypt.
Results and discussion
Several articles were found in the web sites mentioned. We excluded irrelevant articles and chose the relevant ones. After reviewing the chosen articles, we decided on the following subtitles.
A black-box warning, also known as a ‘black label warning’ or a ‘boxed warning,’ is so named because of the black border surrounding the text of the warning that appears on the package insert, label, and other literature describing the medication (e.g. magazine advertising). It is the most serious medication warning required by the FDA 6.
The FDA requires a black-box warning for one of the following three situations: (a) the medication can cause serious undesirable effects (such as a fatal, life-threatening, or permanently disabling adverse reaction) compared with the potential benefits of the drug; (b) a serious adverse reaction can be prevented, reduced in frequency, or reduced in severity by proper use of the drug; for example, a medication may be safe for use in adults, but not in children; or (c) the drug may be safe for use in adult women who are not pregnant 6. The FDA requires the boxed warning to provide a concise summary of the adverse side effects and risks associated with use of the medication.
Not only psychiatric drugs but others also carry the label. However, more than 300 drugs carry black-box warning. The Drug Information Center of the Kansas University Medical Center maintains an online listing of all medications that have a black-box warning 7.
Sometimes, an entire class of drugs carries a black-box warning, as may also be the case with certain psychiatric drugs such as the use of selective serotonin reuptake inhibitors by individuals younger than 25 years of age or the use of antipsychotic drugs by the elderly, or even with the use of antiepileptic drugs. In other cases, the label may be for a single drug such as for atomoxetine, a nonstimulant that is used to treat attention deficit hyperkinetic disorder (ADHD).
In 2004, the FDA communicated about suicidality among children and adolescents using all classes of antidepressant drugs and placed the following warning ‘antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders’ 8.
Antipsychotic drugs in elderly
After a meta-analysis of 17 trials on the use of atypical antipsychotics in elderly patients with dementia-related psychosis, in 2005, the FDA issued a black-box warning of an increased risk of mortality with the use of atypical antipsychotics compared with a placebo (relative risk 1.6–1.7). The mortality rate in antipsychotic-treated patients was about 4.5% compared with about 2.6% in the placebo group. Although the causes of death varied, most were due to cardiovascular reasons (heart failure, sudden death) or infections (pneumonia). A black-box warning was placed on atypical antipsychotics as a class 9.
In 2008, the FDA placed a black-box warning on all antiepileptic drugs because of fears about the risk of suicidal thoughts and behavior associated with the use of epilepsy drugs. The FDA wanted to place the warning even for those drugs that did not have documented risk factors 10.
A black-box warning was also placed on Topiramate as it was found to cause ‘A syndrome consisting of acute myopia associated with secondary angle closure glaucoma’ 11.
In 2005, the FDA issued a public health advisory about rare reports of suicidal thinking in children and adolescents taking atomoxetine, a drug approved for the treatment of ADHD in adults and children 12.
Consequences of a black-box warning
After the communication from the FDA and the subsequent black-box warnings for serotonin reuptake inhibitors and newer antidepressants in March 2004, prescriptions decreased by 4.23% per month (95% confidence interval: −8.44–0.18%, P=0.06). It then stabilized, with no significant changes in the number of prescriptions from July 2004 to March 2005. Since then, the number of prescriptions has steadily increased again 13.
In addition, there was a switch from general practitioners to psychiatrists to obtain prescriptions. This switch from general practitioners to psychiatrists may have an impact on access to care for children and teenagers 13.
Gibbons et al.14 indicated that there is a link between a 22% decrease in prescriptions after warnings were issued by the FDA and the 14% increase in suicide rates among youth between 2003 and 2004 14. The same results were reported by a study that showed a steady high rate of suicides among youth in 2005 15.
Psychosis affects approximately 40% of patients with Alzheimer disease, whereas at least 80% of patients with dementia experience agitation at some point in the illness 16. Furthermore, for many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms such as depression, sleep disturbance, psychosis, and aggression. Little evidence supports nonpharmacological treatments of aggression and psychosis in dementia 17. Meanwhile, no drug has been FDA approved for the treatment of the neuropsychiatric symptoms of dementia; thus, psychiatrists often prescribe off-label psychotropics – especially antipsychotics – to ameliorate.
FDA and public safety!
By law, the FDA must inform consumers if there have been side effects or complications due to the use of a particular drug 18. Therefore, the rationale behind black-box warnings is that they will prompt physicians to carefully consider the risks of the medication before prescribing them and determine whether the use of the drug is warranted or whether there is another option. Also, black-box warnings should prompt discussions between the doctor and the patient about the potentially serious side effects. Finally, by being aware of the potential risk of the medication, patients themselves can make important decisions as to their level of comfort with the medication.
However, the FDA approves drugs on the basis of whether they work better than an inactive placebo pill. The FDA is trying to ensure long-term safety studies are conducted after a drug is initially approved based on data from relatively small groups, but pharmaceutical companies are dragging their feet before they finalize follow-up safety studies. Furthermore, it relies on drug companies to perform all premarket testing on drugs for safety and efficacy 19. Thus, if the FDA is concerned about safety, marketing of drugs should not be allowed before safety studies are conducted by its own team. Furthermore, prescription of any drug should be based on strong indications; otherwise, there is no need to prescribe such drugs. In addition, there should be a discussion between the doctor and the patient about the drug to be prescribed and patients should share in the decision-making process.
Another point in terms of a black-box warning is the pressure imposed by the media. In some cases, such as in the case of stimulants, some experts believe that ADHD is being overdiagnosed and that stimulant medicines are being overused. The FDA’s drug safety and risk management advisory committee recommended that ADHD stimulant drugs receive a black-box warning due to their possible risks of causing high blood pressure, stroke, and sudden death 18. However, to date, stimulants do not have this warning.
Does the FDA use black-box warnings to get drug manufacturers off the hook? Some may ask this question 19. Does the FDA seek to protect them against the legal claims of patients and caregivers? This is another question that remains unanswered. The experience with Avandia may provide some answers to the above questions. Safety concerns over Avandia, an antidiabetic drug that was approved by the FDA in 1999, did not arise until 2007, after the sales of Avandia pills exceeded 3 billion USD a year. Avandia was linked to a 43% increase in heart attacks compared with other medications or placebo 19.
How can psychiatrists solve the problems related to black-box warnings?
Sometimes the effort of experts and institutes as AACAP may help to prevent unnecessary addition of black box warning as in case of stimulant. Hence the American Academy of Child and Adolescent Psychiatry (AACAP) and the American Psychiatric Association rapidly face the FDA and Dr Laurence Greenhill said, when he testified in front of an FDA committee on behalf of the AACAP and the American Psychiatric Association: ‘Stimulant medications offer many benefits to a wide range of children, and have proven to be safe over a half-century of use’. It is not known whether this is why the FDA did not place a warning. However, on other occasions, the AACAP has urged the FDA to balance the impact of stronger warnings on current practice and the demonstrated effectiveness of antidepressants to treat individuals with depression 18.
In addition, the President of the AACAP stated that ‘I understand that the FDA is struggling with the issue about whether or not antidepressants are safe and effective treatments for people living with mental illnesses’. The AACAP’s position is that antidepressants are effective in the treatment of depression and is concerned that the stigma surrounding the diagnosis and treatment of mental illnesses will increase with the increase in the literature of the current black-box warning 20. However, despite this, the FDA extended the warning to include patients younger than 25 years of age.
With so many warnings out there, won’t people just start ignoring the warnings?
This is definitely one possible problem with all of the recent warnings. Many doctors and parents may simply become so accustomed to the warnings that they may not even consider them when deciding whether a child should take a medicine 18. Although ignoring the warnings will not decrease the stigma, it may facilitate compliance or absolve the legal responsibility of the doctors.
What do we actually need as psychiatrists or even as psychiatric patients and their care givers?
First, as doctors, we should be up to date on all recent studies on psychiatric drugs, especially those funded by nonpharmaceutical agencies. We should properly weigh the risks versus benefits of prescribing a particular drug to a patient. Second, pharmaceutical companies should disseminate information appropriately as it is crucial to fully disclose the results of clinical studies, the data on appropriate use, patient types, and clear and concise information on the risks of drugs. Unfavorable or negative information should not be withheld as it will ultimately be revealed 2. Third, and most importantly, a good rapport should be established with patients and their families as they have to have faith and trust in us for good compliance.
Drug regulations in Egypt
Although we have the Egyptian Drug Authority, which is the pharmaceutical regulatory body of the Egyptian Ministry of Health, the officials of the Egyptian health industries state that FDA approval is key to having medical products registered in Egypt 21.
So should Egypt and other developing countries follow American FDA instructions?
This is a difficult question that has both a political and a scientific aspect. To answer this question, we have to find a solution to several others. First, do we contribute to the decision made by the FDA through local research conducted on our patients or through expert views in panel discussions of the FDA? Second, do we have our own agreement about drug regulations in Egypt regarding the algorithms, priority, and safety of drugs? Third, what other countries as European and Asian did regarding FDA instructions and warning? Fourth, what would occur if we do not follow these regulations? Finally, do we need an after-sale research to ensure the efficacy, tolerability, and safety of manufactured or imported drugs on our population, and if so, who will be responsible for the design and funding of these investigations?
Conclusion and implications
In Egypt, currently, there is a huge emphasis on human rights and on laws of mental health that regulate how to deal with mentally ill patients. Therefore, inevitably, we will be questioned by our patients and perhaps their lawyers about the safety of the drugs we prescribe and we should have evidence-based answers to the question ‘why did you give me this drug with a black-box warning?’.
Conflicts of interest
There are no conflicts of interest.
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. [Accessed on 24 December 2011]