Boxed warning

Examples

Boxed warnings on drugs have received increased media attention in the United States since 2004. Among some of the more widely covered stories:

• In October 2004, the FDA began requiring that boxed warnings be placed on all antidepressant medications, warning they may result in an increased risk of suicidal tendencies in children and adolescents. In May 2006, the boxed warning was expanded to young adults aged 18–24 years old.
• , the FDA has required a boxed warning on the Depo-Provera contraceptive injection, due to the risk of significant loss of bone density with long-term use.
• In April 2005, FDA advisors requested that Pfizer place a boxed warning on their non-steroidal anti-inflammatory drug Celebrex (celecoxib) for cardiovascular and gastrointestinal risks.
• In 2005, the FDA issued a boxed warning regarding the risk of atypical antipsychotics being prescribed among elderly patients with dementia. This advisory was associated with a decrease in use of antipsychotics, especially in elderly patients with dementia.
• , natalizumab (marketed as Tysabri) received a boxed warning on its packaging due to increased risk of developing progressive multifocal leukoencephalopathy (PML). Tysabri was pulled from the market in 2004, shortly after its introduction, after three cases of the rare disease were linked to its use. PML has affected approximately 212 Natalizumab recipients in 2012 (or 2.1 in every 1000 patients). Tysabri is now distributed under a controlled prescription program called TOUCH (Tysabri Outreach: Unified Commitment to Health).
• , the FDA added a boxed warning to the anticoagulant warfarin due to the risk of bleeding to death.
• In February 2006, the FDA's Drug Safety and Risk Management Advisory Committee voted to include boxed warnings on methylphenidate formulations used to treat attention deficit hyperactivity disorder, such as Ritalin (methylphenidate), due to possible cardiovascular side-effects. A month later, the agency's Pediatric Advisory Committee effectively rejected recommending boxed warnings for both cardiovascular and psychiatric adverse effects.
• On November 14, 2007, the FDA added a boxed warning to the diabetes medication Avandia (rosiglitazone), citing the risk of heart failure or heart attack to patients with underlying heart disease, or are at a high heart attack risk.
• On July 8, 2008, the FDA ordered a boxed warning on certain antibiotic medications containing fluoroquinolone, which has been linked to tendon ruptures and tendinitis. Included were the popular drugs Cipro (ciprofloxacin), Levaquin (levofloxacin), Avelox (moxifloxacin), Noroxin (norfloxacin) and Floxin (ofloxacin).
• On July 1, 2009, the FDA required Chantix (varenicline) to carry a boxed warning due to public reports of side effects including depression, suicidal thoughts, and suicidal actions. , the warning has been removed on the basis of updated evidence.
• On October 27, 2010, the FDA issued a boxed warning regarding the use of Metacam (meloxicam) oral suspension in cats in the United States. Meloxicam is a non-steroidal anti-inflammatory drug that is approved in the U.S. for a single post-operative injection in cats.
• , the FDA issued a boxed warning regarding the use of thyroid hormone stimulating agents in treatment of obesity. Data does not indicate any benefits to using these agents for weight loss. Data does indicate an increased risk of life-threatening cardiovascular events when high levels of these agents are used in hypothyroid populations. Euthyroid populations demonstrate increased CV risk at clinical doses. Hypothyroid agents should not be used in combination with sympathomimetic agents including: stimulants, and diet pills, due to increased CV risks.
• In July 2013, the FDA issued a boxed warning for the antimalarial drug mefloquine, noting the drug's adverse neuropsychiatric side effects, and emphasizing neurological effects from the drug could "occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent".

In other jurisdictions

In China, a warning text (警示语) may be added to a package insert, either voluntarily by the manufacturer or at the request of NMPA (formerly CFDA, the Chinese counterpart of FDA). Although no formatting requirement is found in law, the typical formatting is similar to the American counterpart with boxed text at the top of the insert. The CFDA/NMPA has used its power to mandate a warning on fluoroquinolones, ceftriaxone, aciclovir, and pioglitazone.

Health Canada terms its version of boxed warnings "serious warnings and precautions box". The formatting is similar to the US counterpart; an example for Paxlovid can be seen on Pfizer's website.

References

References

1. "The heading and the summary must be contained within a box and bolded." 21CFR201.57 Subpart B (a)(4)
2. "Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format". U.S. [[Food and Drug Administration]].
3. "Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers". National Institute of Mental Health.
4. (November 2010). "Responding to an FDA warning--geographic variation in the use of rosiglitazone". The New England Journal of Medicine.
5. (April 2010). "Changes in glitazone use among office-based physicians in the U.S., 2003-2009". Diabetes Care.
6. (2019). "The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?". Frontiers in Psychiatry.
7. (June 2012). "Antidepressants and the FDA's black-box warning: determining a rational public policy in the absence of sufficient evidence". The Virtual Mentor.
8. "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection".
9. (April 7, 2005). "COX-2 Selective (includes Bextra, Celebrex, and Vioxx)".
10. (August 2, 2005). "Celebrex to Get 'Black Box' Label on Heart Risks".
11. (January 2010). "Impact of FDA black box advisory on antipsychotic medication use". Archives of Internal Medicine.
12. (May 2012). "Risk of natalizumab-associated progressive multifocal leukoencephalopathy". The New England Journal of Medicine.
13. "TOUCH Program". Biogen Idec.
14. "Black Box for Warfarin".
15. (February 10, 2006). "Strongest warning suggested for ADHD drugs". [[CNN]].
16. (March 22, 2006). "'Black Box' ADHD Drug Warning Rejected". [[CBS News]].
17. (March 22, 2006). "MINUTES OF THE PEDIATRIC ADVISORY COMMITTEE".
18. (November 14, 2007). "Glaxo's Avandia to carry heart-attack warning".
19. (July 8, 2008). "FDA orders 'black box' label on some antibiotics". CNN.
20. FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban".
21. (October 27, 2010). "FDA Announces Addition of Boxed Warning to METACAM® (meloxicam) Labels".
22. "Thyrolar (liotrix) dosing, indications, interactions, adverse effects, and more".
23. (July 29, 2013). "FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects".
24. (2014). link
25. (December 2017). "Comparison of the safety information on drug labels in three developed countries: The USA, UK and Canada". Saudi Pharmaceutical Journal.
26. "PAXLOVID".