Definition/Introduction

Boxed warnings (formerly known as Black Box Warnings) are the highest safety-related warnings that medications can have assigned by the Food and Drug Administration. These warnings are intended to bring the consumer’s attention to the major risks of the drug. Medications can have a boxed warning added, taken away, or updated throughout their tenure on the market. Over 400 different medications currently have boxed warnings.[1]

Boxed warnings typically apply to a particular drug cohort rather than one specific drug; this is because, commonly, the severe risk is associated with the mechanism of action and its undesired effects on the body, therefore applying to several medications within a class.[2]

Issues of Concern

Medications with boxed warnings associated with them may have adverse financial consequences as these warnings can affect the marketability of the drug and generate negative news reports.

Clinicians must use their clinical judgment on whether or not to prescribe medications with these warnings to their patient's care. Boxed warnings are not meant to be absolute contraindications for drugs, but instead, to bring the attention to the clinician and pharmacist on potential severe side effects.[3][4]

In rare instances, a drug may be the subject of a recall from the market. The most serious type of recall (Class I) is when the use of a medication may cause severe health detriments or even possible death.

Clinical Significance

Examples of medications with boxed warnings[5][6][7][8][9]:

• Fluoroquinolone antimicrobials: increased risk of tendinitis and/or tendon rupture
• Rosiglitazone: increased risk of heart failure or myocardial infarction if the patient has current heart disease
• Selective serotonin reuptake inhibitors (SSRIs): increased risk of suicidal thinking and behavior in pediatric patients
• Celecoxib: cardiovascular and gastrointestinal risks
• Medroxyprogesterone: decreased bone density with long-term use

Examples of medications with warnings that have been updated[10]

• Varenicline: the FDA removed the warning in 2009; original reports of depression, suicidal thoughts, and actions

The Food and Drug Administration uses a program, i.e., MedWatch, that helps to track adverse events associated with medications. There is an online program accessible to clinicians and patients to enter the adverse effects of a medicine.[1]

Nursing, Allied Health, and Interprofessional Team Interventions

The healthcare team, i.e., clinicians, nurses, and pharmacists, must work together to make sure that patients on pharmacotherapy correctly take their medications, e.g., ciprofloxacin, and importantly, to discuss any serious drug side effects they encounter, e.g., tendinitis, etc. This includes knowledge of any FDA-boxed warnings. A complete medication list for the patient is necessary before prescribing medications to prevent clinically significant drug interactions, and a pharmacist can perform medication reconciliation to answer any questions or address concerns other healthcare team members may have. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Buckley NA, Rossi S. Bringing greater transparency to "black box" warnings. Clin Toxicol (Phila). 2011 Jul;49(6):448-51. [PubMed: 21824055]

2.

Panagiotou OA, Contopoulos-Ioannidis DG, Papanikolaou PN, Ntzani EE, Ioannidis JP. Different black box warning labeling for same-class drugs. J Gen Intern Med. 2011 Jun;26(6):603-10. [PMC free article: PMC3101972] [PubMed: 21286838]

3.

O'Connor NR. FDA boxed warnings: how to prescribe drugs safely. Am Fam Physician. 2010 Feb 01;81(3):298-303. [PubMed: 20112888]

4.

Martin CM, Borgelt L. Black box warnings: what do they mean to pharmacists and patients. Consult Pharm. 2012 Jul;27(7):482-92. [PubMed: 22910129]

5.

Tanne JH. FDA adds "black box" warning label to fluoroquinolone antibiotics. BMJ. 2008 Jul 15;337(7662):a816. [PMC free article: PMC2483892] [PubMed: 18632714]

6.

Tanne JH. FDA places "black box" warning on antidiabetes drugs. BMJ. 2007 Jun 16;334(7606):1237. [PMC free article: PMC1892463] [PubMed: 17569906]

7.

Kondro W. FDA urges "black box" warning on pediatric antidepressants. CMAJ. 2004 Oct 12;171(8):837-8. [PMC free article: PMC522639] [PubMed: 15477614]

8.

Lenzer J. FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke. BMJ. 2005 Feb 26;330(7489):440. [PMC free article: PMC549650] [PubMed: 15731142]

9.

Green W. The FDA, contraceptive marketing approval and products liability litigation: Depo-Provera and the risk of osteoporosis. Food Drug Law J. 2013;68(2):115-35, i. [PubMed: 24640465]

10.

Mohammadi D. Black-box warnings could be removed from varenicline. Lancet Respir Med. 2016 Nov;4(11):861. [PubMed: 27742352]

Disclosure: Claire Delong declares no relevant financial relationships with ineligible companies.

Disclosure: Charles Preuss declares no relevant financial relationships with ineligible companies.