Академический Документы
Профессиональный Документы
Культура Документы
& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Review Article
Strategies for the Prescription of Psychotropic Drugs
with Black Box Warnings
Jonathan R. Stevens, M.D., M.P.H., Tiana Jarrahzadeh, D.O.,
Rebecca Weintraub Brendel, M.D., J.D., Theodore A. Stern, M.D.
Received July 8, 2013; revised August 21, 2013; accepted August 26,
2013. From Henry Ford Health Systems, Dearborn, MI; Wayne State
University, Detroit, MI; Michigan State University, East Lansing, MI;
Red Sox Foundation and Massachusetts General Hospital (MGH),
Home Base Program, Boston, MA; Harvard Medical School (HMS),
Boston, MA; Avery D. Weisman Psychiatry Consultation Service
at MGH, Boston, MA. Send correspondence and reprint requests
to Jonathan Stevens, M.D., M.P.H., Henry Ford Health Systems,
5111 Auto Club Road, Suite 112, Dearborn, MI 48126; e-mail:
jsteven8@hfhs.org
& 2014 The Academy of Psychosomatic Medicine. Published by
Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org
123
All amphetamines
All rst-generation (typical) and second-generation (atypical)
antipsychotics
Carbamazepine
Clozapine and carbamazepine
Clozapine
Clozapine
Clozapine and umazenil
Lamotrigine
Lithium
Valproic acid
Valproic acid
Naltrexone, dantrolene, and valproic acid
Thioridazine, mesoridazine, and droperidol
Levothyroxine
Methadone
Disulram
Midazolam
n
Does not include psychotropics already withdrawn from the market because of safety concerns (e.g., pemoline, nefazodone, or
propoxyphene).
www.psychosomaticsjournal.org
Stevens et al.
pharmaceutical companies on adverse events. Those
events serve as early warning signals for possible
serious adverse reactions that may lead to a BBW.
The FDA may convene a public advisory committee
to determine the signicance of a safety signal. If a
safety concern emerges from clinical trial data or
consistent reports made to the AERS, an interdisciplinary team convenes with representatives from the
Ofce of Surveillance and Epidemiology and the
Ofce of New Drugs.1 This collaborative team then
decides whether to continue monitoring, require a
boxed warning, or withdraw the drug from the market.
Despite this monitoring system, the FDA has not
articulated clearly its rationale and basis for issuing a
BBW.
In the absence of such guidance, Beach et al.4
devised a classication scheme to analyze what it takes
for the FDA to create a BBW. Based on their analysis
of the wordings of 375 BBWs of 206 drugs, they
identied the following 6 criteria that seem to inuence
the FDAs decision to have BBWs added to the
labeling of drug products: (1) identication of an
adverse event that can be prevented through early
detection and intervention; (2) a clearly categorized
patient cohort for whom the treatment is particularly
dangerous; (3) a situation in which the risk of treatment likely outweighs its benets (in certain circumstances); (4) identied issues of dosing or drug
interaction, or both, that are critical to the risk;
(5) situations involving special settings or training of
physicians that are critical to the safe administration of
a drug; and (6) situations in which the method of drug
administration requires exceptional care. In addition,
they4 classied the type of evidence for supporting a
boxed warning into 4 categories: patterns of postmarketing reports (52.4%); clinical trials that were part
of the new drug application (28.7%); epidemiologic
surveys (9.4%); and, occasionally, miscellaneous bases
(9.4%).
According to their report, the most frequent
warning (25%) was for the identication and avoidance of high-risk patients. Dosing considerations or
harmful drug interactions were the next most common
purpose of the warnings (20%).
HOW EFFECTIVE IS THE BBW SYSTEM?
The results of the study by Beach et al.4 indicated that
more than half of the BBWs were discovered after the
Psychosomatics 55:2, March/April 2014
125
www.psychosomaticsjournal.org
Stevens et al.
in children and adolescents taking SSRI antidepressants added complexity to an already challenging
treatment situation. The FDA action both reected
and fueled public suspicion of pediatric psychopharmacology. It is perhaps one of the best-known and
most controversial examples of a BBW on a psychotropic medication.
To detail how the pediatric antidepressant advisories affected prescribing practices, the chronologic
development of this BBW has been reviewed. In 2003,
the United Kingdoms Medicines and Healthcare
Regulatory Agency, a regulatory agency analogous
to the FDA initiated an investigation into the safety of
antidepressant medications. This investigation was
triggered by anecdotal reports regarding withdrawal
reactions, suicidal ideation, and suicidal behavior
from adult and pediatric patients taking paroxetine.22,23 Within the year, the Medicines and Healthcare Regulatory Agency, FDA, and European
Medicines Agency all issued advisories regarding
reports of suicidality in young patients given antidepressants. They advised against using paroxetine to
treat depression in children and adolescents. Those
advisories were a consequence of post hoc analyses
that found a statistically signicant increase in suicidal
behavior with paroxetine treatment.22,23 Further (in
2003), the UKs Committee on the Safety of Medicines
conducted a review of antidepressants and concluded
that clinicians should prescribe uoxetine for
depressed children and adolescents.22,24 In 2004, after
the FDA held a public hearing and issued a public
health advisory, they advised that Health care
providers should carefully monitor patients receiving
antidepressants for possible worsening of depression
or suicidality, especially at the beginning of therapy or
when the dose either increases or decreases.25 The
FDA also determined that uoxetine was the only
SSRI noted to be helpful in treating depression in the
pediatric population.26 In October 2004, the FDA
issued a BBW describing the probable risk of increased
suicidality in children and adolescents and suggested
close monitoring for side effects and response in youth.
The following year (2005), antidepressant manufacturers were required to include a BBW on antidepressant product labels.25 Then, in May 2007, the FDA
updated the BBW on antidepressants to include young
adults (aged 1824 years) during initial antidepressant
treatment. The warning stated that patients of all ages
who were started on antidepressant therapy should be
Psychosomatics 55:2, March/April 2014
127
www.psychosomaticsjournal.org
Stevens et al.
warnings do not appear to have changed the prescribing practices. Korneld et al.46 analyzed a nationally
representative audit of ofce-based providers between
2000 and 2008 and noted that FDA advisories for
stimulants and atomoxetine had little effect on
prescribing use.
Case Study #3Antipsychotic Medication and
Increased Mortality in the Elderly
In addition to children and adolescents, the elderly
are another potentially vulnerable population that
may be disproportionately affected by regulatory
agency advisories and warnings. One recent example
is the BBW on antipsychotics in elderly patients with
dementia. Dementia results in progressive and irreversible loss of cognitive abilities. Alzheimers disease
is the most common dementia, currently estimated to
affect 5.2 million Americans of all ages.53 Patients with
dementia may have associated behavioral dysregulation, agitation, and assaultiveness, all behaviors that
pose a clinical dilemma (as there are no FDAapproved medicines to treat these symptoms). Atypical antipsychotics became a commonly used class to
treat the elderly with behavioral and psychologic
symptoms of dementia (albeit on an off-label basis)
after several clinical trials showed benets in this
population.54,55 However, safety concerns were quick
to follow, rst about an increased risk of stroke (linked
to risperidone) after a MedWatch warning in 2003. In
2004, emerging links with hyperglycemia and newonset diabetes compounded concerns about the safety
of atypical antipsychotics.56,57
In 2005, the FDA issued a warning based on a
meta-analysis of 17 randomized controlled trials stating that second-generation antipsychotic treatment of
the behavioral disturbances resulting from dementia
was associated with an increased mortality as compared with placebo.56 The mortality rate owing to heart
failure or sudden death was about 1.61.7 times higher
with atypical antipsychotics than it was with placebo.57
In 2008, the FDA extended the BBW to rst-generation, or typical, antipsychotic medications.58
Gill et al.57 found that atypical antipsychotic use
was associated with a small but signicant increase in
mortality among older adults with dementia. The risk
became apparent within a month and lasted up to
6 months. They also noted that conventional
Psychosomatics 55:2, March/April 2014
129
www.psychosomaticsjournal.org
Stevens et al.
References
1. OConner NR: FDA boxed warnings: how to prescribe
drugs safely. Am Fam Physician 2010; 81:298303
2. Code of federal regulations: specic requirements on content and format of labeling for human prescription drug and
biological products described in 201.56 (b) (1), 21 C.F.R
Sect. 201. 57, 2000
3. Murphy S, Roberts R: Black box 101: how the food and
drug administration evaluates, communicates, and manages
drug benet/risk. J Allergy Clin Immunol 2006; 117:3439
4. Beach JE, Faich GA, Bormel FG, Sasinowski FJ: Black box
warnings in prescription drug labeling: results of a survey of
206 drugs. Food Drug Law 1998; 53:403411
5. Lurie P, Sasich LD: Safety of FDA-approved drugs. J Am
Med Assoc 1999; 282:22972298
6. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU,
Wolfe SM, Bor DH: Timing of new black box warnings and
withdrawals for prescription medications. J Am Med Assoc
2002; 287:22152220
7. Wagner AK, Chan KA, Dashevsky I, et al: FDA drug
prescribing warnings: is the black box half empty or half
full? Pharmacoepidemiol Drug Saf 2006; 15:369386
8. Lasser KE, Seger DL, Yu DT, et al: Adherence to black box
warnings for prescription medications in outpatients. Arch
Intern Med 2006; 166:338344
9. Marcus SC, Olfson M, Pincus HA, Zarin DA, Kupfer DJ:
Therapeutic drug monitoring of mood stabilizers in Medicaid patients with bipolar disorder. Am J Psychiatry 1999;
156:10141018
10. Halloran K, Barash PG: Inside the black box: current
policies and concerns with the United States food and drug
administrations highest drug safety warning system. Curr
Opin Anaesthesiol 2010; 23:423427
11. [Internet] [cited 2013 June 20]. Available from: http://www.
aacap.org/galleries/PsychiatricMedication/APAAACAPlet
ter9-05.pdf
12. Costello EJ, Egger H, Angold A: 10-year research update
review: the epidemiology of child and adolescent psychiatric
disorders: I. Methods and public health burden. J Am Acad
Child Adolesc Psychiatry 2005; 44:972986
13. Costello EJ, Erkanli A, Angold A: Is there an epidemic of
child or adolescent depression? J Child Psychol Psychiatry
2006; 47:12631271
14. Birmaher B, Brent D, Bernet W, et al: AACAP Work
Group on Quality Issues. Practice parameters for the
assessment and treatment of children and adolescents with
depressive disorders. J Am Acad Child Adolesc Psychiatry
2007; 46:15031526
15. Hawton K, van Heeringen K: Suicide. Lancet 2009; 373:
13721381
16. Hazell P, OConnell D, Heathcote D, Robertson J, Henry D:
Efcacy of tricyclic drugs in treating child and adolescent
depression: a meta-analysis. Br Med J 1995; 310:897901
17. Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M:
Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database Syst Rev 2007; 3:CD004851
www.psychosomaticsjournal.org
131
132
www.psychosomaticsjournal.org
Stevens et al.
62. Glezer A, Stern TA, Mort EA, Atamian S, Abrams JL,
Brendel RW: Documentation of decision-making capacity,
informed consent, and health care proxies: a study of
surrogate consent. Psychosomatics 2011; 52:521529
63. Brendel RW, Wei MH, Schouten R, Edersheim JG: An
approach to selected legal issues: condentiality, mandatory
reporting, abuse and neglect, informed consent, capacity
decisions, boundary issues, and malpractice claims. Med
Clin North Am 2010; 94:12291240
64. Melonas JM: Preventing and reducing professional liability
risk related to psychopharmacology. Psychiatric Times
www.psychosomaticsjournal.org
133