Boxed warning

In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it is formatted with a 'box' or border around the text[1] to emphasize it is of utmost importance.[2] The FDA can require a pharmaceutical company to place a boxed warning. It is the strongest warning that the FDA requires, and signifies that medical studies indicate that the drug carries a significant risk of preventable, serious or even life-threatening adverse effects.[2][3]

Economists and physicians have thoroughly studied the effects of FDA boxed warnings on prescription patterns. It is not necessarily true that a physician and patient will have a conversation about a drug's boxed warning after it is issued.[4] For instance, an FDA-mandated boxed warning decreased rosiglitazone use by 70%, but that still meant 3.8 million people were given the drug. Later research indicated that after receiving an FDA advisory, there was a decrease in rosiglitazone use, due to a combined effect of media exposure, advisory, and scientific publications, whereas pioglitazone (with a similar advisory but less media exposure) did not similarly decrease in use.[5]

Examples

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

  • The FDA has required that boxed warnings be placed on all antidepressant medications warning they may result in increased risk of suicidal tendencies in children, adolescents, and young adults aged 18–24 years old.
  • FDA advisors have recommended that Pfizer be required to place a boxed warning on their non-steroidal anti-inflammatory drug Celebrex (celecoxib) for cardiovascular and gastrointestinal risks.
  • As of November 17, 2004, 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.[6]
  • 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.[7]
  • As of 2006, 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).[8] Tysabri is now distributed under a controlled prescription program called TOUCH (Tysabri Outreach: Unified Commitment to Health).[9]
  • As of October 9, 2006, the FDA added a boxed warning to the anticoagulant warfarin due to the risk of bleeding to death.[10]
  • 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.[11] A month later, the agency's Pediatric Advisory Committee effectively rejected recommending boxed warnings for both cardiovascular and psychiatric adverse effects.[12] (Minutes and transcripts of the relevant meetings are available on the FDA website.)[13][14]
  • 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.[15]
  • 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).[16]
  • 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. As of 2016, the warning has been removed on the basis of updated evidence.[17]
  • 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.[18]
  • As of May 2013, the FDA issued a boxed warning regarding the use of thyroid hormone stimulating agents in treatment of obesity.[19] 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".[20]

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 black-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.[21]

Health Canada terms its version of boxed warnings "serious warnings and precautions box".[22] The formatting is similar to the US counterpart; an example for Paxlovid can be seen on Pfizer's website.[23]

France uses color-coded pictographs to indicate levels of drugs countraindicated in driving. Japan uses pictographs and text.[21]

References
  1. "The heading and the summary must be contained within a box and bolded." 21CFR201.57 Subpart B (a)(4)
  2. U.S. Food and Drug Administration. "Guidance for industry. Even in the context of clinical research, human subjects are often not informed about the risks included in boxed warnings for drugs they are being given. For protocols involving drugs with boxed warnings, 63% of consent forms did not disclose 1 or more boxed warning risks. Warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products—content and format" (PDF). Food and Drug Administration. Retrieved February 21, 2010.
  3. National Institute of Mental Health, Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers Archived March 1, 2010, at the Wayback Machine."
  4. Shah ND, Montori VM, Krumholz HM, Tu K, Alexander GC, Jackevicius CA. Geographic Variation in the Response to FDA Boxed Warnings for Rosiglitazone. N Engl J Med. 2010;22:2081-2084.
  5. Cohen A, Rabbani A, Shah N, Alexander GC. Changes in glitazone use among office-based physicians in the United States, 2003-2009. Diabetes care. 2010;33:823-825.
  6. "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection". Food and Drug Administration. Archived from the original on August 9, 2007. Retrieved August 15, 2007.
  7. Dorsey R, Rabbani A, Gallagher SA, Conti R, Alexander GC. The impact of boxed warnings on the use of atypical antipsychotic medicines. Archives of Internal Medicine. 2010;170:96-103. Archived July 27, 2011, at the Wayback Machine
  8. Bloomgren, Gary; Richman, Sandra; Hotermans, Christophe; Subramanyam, Meena; Goelz, Susan; Natarajan, Amy; Lee, Sophia; Plavina, Tatiana; Scanlon, James V. (May 17, 2012). "Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy". New England Journal of Medicine. 366 (20): 1870–1880. doi:10.1056/NEJMoa1107829. ISSN 0028-4793. PMID 22591293.
  9. "TOUCH Program". TOUCH On-Line. Biogen Idec. Retrieved September 8, 2016.
  10. "Black Box for Warfarin". Retrieved August 15, 2007.
  11. "Strongest warning suggested for ADHD drugs". CNN. Associated Press. February 10, 2006. Archived from the original on August 18, 2007. Retrieved August 15, 2007.
  12. "'Black Box' ADHD Drug Warning Rejected". CBS News. March 22, 2006. Retrieved August 15, 2007.
  13. Pediatric Advisory Committee documentation available at: "2006 FDA Advisory Committees Meeting Documents by Center". U.S. Food and Drug Administration. February 5, 2007. Retrieved August 15, 2007.
  14. Drug Safety and Risk Management documentation available at: "CDER 2006 Meeting Documents". U.S. Food and Drug Administration. February 1, 2007. Retrieved August 15, 2007.
  15. "Glaxo's Avandia to carry heart-attack warning". MarketWatch. November 14, 2007. Retrieved November 14, 2007.
  16. "FDA orders 'black box' label on some antibiotics". CNN. July 8, 2008. Retrieved July 8, 2008.
  17. FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Food and Drug Administration. Archived from the original on October 19, 2010. Retrieved July 1, 2009.
  18. "FDA Announces Addition of Boxed Warning to METACAM® (meloxicam) Labels". October 27, 2010.
  19. "Thyrolar (liotrix) dosing, indications, interactions, adverse effects, and more".
  20. "FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects". July 29, 2013.
  21. Hong Lan; Zhu Jun-yi (2014). 国内外药品说明书和标签管理中有关警示语的比较研究 [Comparison of Related Content of Warnings in Drug Labels and Package Inserts at Home and Abroad] (PDF). 中国药房. 33. doi:10.6039/j.issn.1001-0408.2014.33.29.
  22. Alshammari, TM; Devadasu, VR; Rathnam, RP (December 2017). "Comparison of the safety information on drug labels in three developed countries: The USA, UK and Canada". Saudi Pharmaceutical Journal. 25 (8): 1103–1107. doi:10.1016/j.jsps.2017.07.006. PMC 6111122. PMID 30166896.
  23. "PAXLOVID". Pfizer Medical Information - Canada.
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