boxed warning
{{short description|Type of warning that appears on the package insert for certain prescription drugs}}
{{Use mdy dates|date=May 2019}}
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File:Boxed warning in context FDA example.jpg{{Globalize|date=March 2025|2=United States}}
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"The heading and the summary must be contained within a box and bolded." 21CFR201.57 Subpart B (a)(4) to emphasize its importance. 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.{{cite web |url=https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075096.pdf|archive-url=https://web.archive.org/web/20090617012246/http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075096.pdf|url-status=dead|archive-date=June 17, 2009|title=Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format | work = 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| publisher = U.S. Food and Drug Administration |access-date=February 21, 2010 }}{{cite web |work = National Institute of Mental Health | url = http://www.nimh.nih.gov/health/topics/child-and-adolescent-mental-health/antidepressant-medications-for-children-and-adolescents-information-for-parents-and-caregivers.shtml | title = Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers | archive-url = https://web.archive.org/web/20100301063959/http://www.nimh.nih.gov/health/topics/child-and-adolescent-mental-health/antidepressant-medications-for-children-and-adolescents-information-for-parents-and-caregivers.shtml | archive-date = 1 March 2010 }}
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.{{cite journal | vauthors = Shah ND, Montori VM, Krumholz HM, Tu K, Alexander GC, Jackevicius CA | title = Responding to an FDA warning--geographic variation in the use of rosiglitazone | journal = The New England Journal of Medicine | volume = 363 | issue = 22 | pages = 2081–2084 | date = November 2010 | pmid = 21083379 | doi = 10.1056/NEJMp1011042 }} 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.{{cite journal | vauthors = Cohen A, Rabbani A, Shah N, Alexander GC | title = Changes in glitazone use among office-based physicians in the U.S., 2003-2009 | journal = Diabetes Care | volume = 33 | issue = 4 | pages = 823–825 | date = April 2010 | pmid = 20103549 | pmc = 2845035 | doi = 10.2337/dc09-1834 }}
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.{{cite journal | vauthors = Fornaro M, Anastasia A, Valchera A, Carano A, Orsolini L, Vellante F, Rapini G, Olivieri L, Di Natale S, Perna G, Martinotti G, Di Giannantonio M, De Berardis D | display-authors = 6 | title = The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits? | journal = Frontiers in Psychiatry | volume = 10 | issue = | pages = 294 | date = 2019 | pmid = 31130881 | pmc = 6510161 | doi = 10.3389/fpsyt.2019.00294 | quote = On October 2004, the FDA required a so-called boxed warning for antidepressant drugs of any class. That warning became effective in January 2005. In 2006, the FDA warning extended to young adults aged up to 25 years, an announcement that followed a slew of media reports about the link between antidepressant drug use and suicide, possibly culminating in an exaggerated alarmist message. | doi-access = free }}{{cite journal | vauthors = Ho D | title = Antidepressants and the FDA's black-box warning: determining a rational public policy in the absence of sufficient evidence | journal = The Virtual Mentor | volume = 14 | issue = 6 | pages = 483–488 | date = June 2012 | pmid = 23351264 | doi = 10.1001/virtualmentor.2012.14.6.pfor2-1206 }}
- {{as of|2004|November|17|df=US}}, 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.{{cite web|url=https://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html |title=Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection |website=Food and Drug Administration |access-date=August 15, 2007 |archive-url=https://web.archive.org/web/20070809090332/https://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html |archive-date=August 9, 2007 }}
- 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.{{cite web |title=COX-2 Selective (includes Bextra, Celebrex, and Vioxx) |website=U.S. Food and Drug Administration |date=April 7, 2005 |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory |archive-url=https://web.archive.org/web/20190928144031/https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory |url-status=dead |archive-date=September 28, 2019 |access-date=January 2, 2024}}{{cite web | vauthors = Corbett J |title=Celebrex to Get 'Black Box' Label on Heart Risks |website=The Wall Street Journal |date=August 2, 2005 |url=https://www.wsj.com/articles/SB112292615442301776 |access-date=January 2, 2024}}
- 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.{{cite journal | vauthors = Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC | title = Impact of FDA black box advisory on antipsychotic medication use | journal = Archives of Internal Medicine | volume = 170 | issue = 1 | pages = 96–103 | date = January 2010 | pmid = 20065205 | pmc = 4598075 | doi = 10.1001/archinternmed.2009.456 | url = http://www.rwjf.org/healthpolicy/product.jsp?id=55809 | archive-url = https://web.archive.org/web/20110727225144/http://www.rwjf.org/healthpolicy/product.jsp?id=55809 | archive-date = July 27, 2011 }}
- {{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).{{cite journal | vauthors = Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C | display-authors = 6 | title = Risk of natalizumab-associated progressive multifocal leukoencephalopathy | journal = The New England Journal of Medicine | volume = 366 | issue = 20 | pages = 1870–1880 | date = May 2012 | pmid = 22591293 | doi = 10.1056/NEJMoa1107829 | doi-access = free }} Tysabri is now distributed under a controlled prescription program called TOUCH (Tysabri Outreach: Unified Commitment to Health).{{Cite web|url=https://www.touchprogram.com/TTP/|title=TOUCH Program|website=TOUCH On-Line|publisher=Biogen Idec|access-date=September 8, 2016}}
- {{as of|2006|October|9|df=US}}, the FDA added a boxed warning to the anticoagulant warfarin due to the risk of bleeding to death.{{cite web |url=http://www.medscape.com/viewarticle/545727 |title=Black Box for Warfarin |access-date=August 15, 2007 }}
- 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.{{cite news | url = http://www.cnn.com/2006/HEALTH/02/09/attention.deficit.ap | title = Strongest warning suggested for ADHD drugs | agency = Associated Press | date = February 10, 2006 | access-date = August 15, 2007 | publisher = CNN | archive-url = https://web.archive.org/web/20070818192248/http://www.cnn.com/2006/HEALTH/02/09/attention.deficit.ap/ | archive-date = August 18, 2007 }} A month later, the agency's Pediatric Advisory Committee effectively rejected recommending boxed warnings for both cardiovascular and psychiatric adverse effects.{{cite web | url = https://www.cbsnews.com/news/black-box-adhd-drug-warning-rejected/ | title = 'Black Box' ADHD Drug Warning Rejected | date = March 22, 2006 | access-date = August 15, 2007 | work = CBS News}}{{Cite web |date=March 22, 2006 |title=MINUTES OF THE PEDIATRIC ADVISORY COMMITTEE |url=https://www.fda.gov/ohrms/dockets/ac/oc06.htm |url-status=dead |archive-url=https://wayback.archive-it.org/7993/20170404053633/https://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4210m_Minutes%20PAC%20March%2022%202006.pdf |archive-date=April 4, 2017 |access-date=August 15, 2007 |website=FDA |quote=The committee members were asked if they felt that based on the data for the pediatric population, there was a need for a boxed warning regarding cardiovascular risks. None on the committee expressed a need for this.}}
- 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.{{cite web |date=November 14, 2007 |title=Glaxo's Avandia to carry heart-attack warning |url=http://www.marketwatch.com/news/story/glaxos-avandia-carry-heart-attack/story.aspx?guid=%7B8819DDE2-9FD7-484E-A829-E73118A3E302%7D |url-status=dead |archive-url=https://web.archive.org/web/20080112044223/http://www.marketwatch.com/news/story/glaxos-avandia-carry-heart-attack/story.aspx?guid=%7B8819DDE2-9FD7-484E-A829-E73118A3E302%7D |archive-date=January 12, 2008 |access-date=November 14, 2007 |website=MarketWatch}}
- 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).{{cite news |url=http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html|title=FDA orders 'black box' label on some antibiotics |access-date=July 8, 2008 |work=CNN | date=July 8, 2008}}
- 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.{{cite web|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm|author=FDA|title=Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban|website=Food and Drug Administration |access-date=July 1, 2009|archive-url=https://web.archive.org/web/20101019032042/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm|archive-date=October 19, 2010}}
- 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.{{Cite web |date=October 27, 2010 |title=FDA Announces Addition of Boxed Warning to METACAM® (meloxicam) Labels |url=https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm231254.htm |url-status=dead |archive-url=https://web.archive.org/web/20101030020153/https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm231254.htm |archive-date=October 30, 2010 |website=FDA}}
- {{as of|2013|May}}, the FDA issued a boxed warning regarding the use of thyroid hormone stimulating agents in treatment of obesity.{{Cite web | url=http://reference.medscape.com/drug/thyrolar-liotrix-342737#5 | title=Thyrolar (liotrix) dosing, indications, interactions, adverse effects, and more}} 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".{{Cite news |url=https://www.fda.gov/drugs/drugsafety/ucm362227.htm |archive-url=https://web.archive.org/web/20130801032958/http://www.fda.gov/Drugs/DrugSafety/ucm362227.htm |url-status=dead |archive-date=August 1, 2013 |title=FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects |date=July 29, 2013}}
In other jurisdictions
{{Broader|Medication package insert#Sections of the Prescribing Information}}
In China, a warning text ({{lang|zh|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.{{cite journal | vauthors = Lan H, Jun-yi Z |script-title=zh:国内外药品说明书和标签管理中有关警示语的比较研究 |trans-title=Comparison of Related Content of Warnings in Drug Labels and Package Inserts at Home and Abroad |script-journal=zh:中国药房 |date=2014 |volume=33 |doi=10.6039/j.issn.1001-0408.2014.33.29 |doi-broken-date=February 22, 2025 |url=http://www.china-pharmacy.com/zzlw/2015/2/201502271623429345.pdf}}
Health Canada terms its version of boxed warnings "serious warnings and precautions box".{{cite journal | vauthors = Alshammari TM, Devadasu VR, Rathnam RP | title = Comparison of the safety information on drug labels in three developed countries: The USA, UK and Canada | journal = Saudi Pharmaceutical Journal | volume = 25 | issue = 8 | pages = 1103–1107 | date = December 2017 | pmid = 30166896 | pmc = 6111122 | doi = 10.1016/j.jsps.2017.07.006 }} The formatting is similar to the US counterpart; an example for Paxlovid can be seen on Pfizer's website.{{cite web |title=PAXLOVID |url=https://www.pfizermedicalinformation.ca/en-ca/paxlovid?section=3-serious-warnings-and-precautions-box&tab=pm |website=Pfizer Medical Information - Canada}}
References
{{reflist|25em}}
External links
- [http://blackboxrx.com Black Box Warnings] by FormWeb.
Category:drug marketing and sales