Public Citizen Urges FDA To Strengthen Warning on Labeling of BOTOX and Related Drugs

Manufacturers of onabotulinumtoxinA (BOTOX, BOTOX COSMETIC) and related drugs — known as botulinum-toxin drugs — often tout them as safe and devoid of serious adverse effects, despite evidence to the contrary.

On Dec. 12, 2023, Public Citizen petitioned the Food and Drug Administration (FDA) to promptly emphasize the risk of iatrogenic botulism and related symptoms on the labeling of these drugs.[1] Iatrogenic botulism is a muscle-paralyzing disease that can occur as a complication of treatment with botulinum-toxin drugs due to their potential for diffusion and systemic spread beyond injection sites.

Specifically, our petition asked the agency to revise the black-box warning (the most prominent warning the FDA can require) on the labeling of both cosmetic and therapeutic botulinum-toxin drugs to make it clear that they are associated with systemic iatrogenic botulism, even when used at recommended doses, in initial or subsequent (repeated) treatment.

In addition, we asked the FDA to remove misleading promotional claims from the labeling of Botox and Botox Cosmetic that negate the risks included in the black-box warning.

About botulinum-toxin drugs

Botulinum toxin is a poison derived from the bacterium Clostridium botulinum, which causes botulism. The FDA has approved several injectable drugs that are purified from botulinum toxin (see Table, below, for a list of these drugs). In 2022, the global market for botulinum-toxin drugs was $5.9 billion. By 2033, their global market is projected to reach nearly $13 billion.[2]

Injection of botulinum-toxin drugs temporarily blocks the nerve signals that cause muscles to contract. Therefore, the FDA approved some of these drugs to treat certain conditions, including cervical dystonia (involuntary contraction of the neck muscles), severe underarm sweating, blepharospasm (abnormal spasm of the eyelids), certain types of urinary incontinence, spasticity of limb muscles and strabismus (certain types of eye-muscle problems), as well as for preventing chronic migraine headaches. The FDA also approved some of these drugs to treat certain cosmetic conditions: smoothing crow’s feet lines, forehead lines and frown lines.

Often, however, botulinum-toxin drugs are used for neuromuscular conditions and cosmetic uses that the FDA has not approved.

Table. FDA-Approved Botulinum-Toxin Products

Evidence of harm supporting Public Citizen’s petition

Our petition discussed several published drug-safety case reports and case series showing that systemic iatrogenic botulism has occurred with recommended doses of botulinum-toxin drugs for various approved uses.

We also analyzed data from the FDA Adverse Event Reporting System (FAERS), a database that contains voluntary reports of drug-related adverse events. From this database, we identified 5,414 reports with serious outcomes — such as death, life-threatening events, hospitalization or disability — in which a botulinum-toxin drug was the only primary suspect. These reports were received by the FDA through March 2021.

Among 5,414 reports with serious outcomes, 121 (2%) specified botulism as an adverse reaction; of those, 89 involved therapeutic uses of botulinum-toxin drugs and 32 involved cosmetic uses. Several of the 121 botulism reports involved botulinum-toxin doses that were within the recommended dose range for the specified uses. For example, seven of 27 botulism reports involving Botox Cosmetic indicated that the injected doses ranged from 10 to 30 units. In addition, five of the 66 botulism reports involving therapeutic uses of Botox indicated that the injected doses were 50 or fewer units (the maximum recommended dose ranges from 100 to 400 units).

We also found that 2,817 (52%) of the 5,414 serious reports included signs or symptoms that are suggestive of iatrogenic botulism, consistent with the effect of botulinum-toxin drugs. We grouped these signs or symptoms into six categories: 1) those involving the bladder, 2) those involving muscle weakness or paralysis in the extremities, 3) those involving the eyes, 4) those involving the oropharynx (the area in the back of the mouth and upper throat), 5) those involving breathing and 6) those involving certain abnormal sensations. Many of these reports involved small doses of botulinum-toxin drugs.

Most likely, our analysis greatly underestimated the true extent of serious adverse effects associated with botulinum-toxin drugs, including those of iatrogenic botulism and its suggestive signs or symptoms, due to the voluntary reporting of adverse events to the FAERS database. For example, a systematic review estimated that only 6% of the adverse events of drugs are reported to spontaneous reporting systems, such as the FAERS database.[3]

Details of Public Citizen’s requests to the FDA

In 2008, Public Citizen petitioned the FDA to require the addition of a black-box warning on the labeling of botulinum-toxin drugs regarding the risk of distant spread of the toxin (spread beyond the site of local injection to other parts of the body).[4] In 2009, the agency granted our request.[5] The current black-box warning, however, fails to explicitly mention the risk of “systemic iatrogenic botulism.”[6] Although the current warning acknowledges that distant spread has occurred in injections of botulinum-toxin drugs for “approved indications… at doses comparable to those used to treat cervical dystonia and spasticity and at lower doses,” it does not explicitly state that iatrogenic botulism and botulism-related symptoms have occurred after both initial and subsequent injections of recommended botulinum-toxin doses for various approved uses. Therefore, in our December 2023 petition, we asked the FDA to make these risks clear in the black-box warning of all approved botulinum-toxin drugs.

We also asked the FDA to make it clear that cases of systemic iatrogenic botulism associated with recommended doses of botulinum-toxin drugs may require prompt administration of botulinum antitoxin to avoid disease progression and serious outcomes, including temporary muscle paralysis, hospitalization and death.

Lastly, we asked the FDA to require the removal of three misleading promotional statements from the labeling of Botox and Botox Cosmetic. These statements claim that “[n]o definitive serious adverse event reports of distant spread of toxin effect” were associated with the use of recommended doses of these drugs to treat four therapeutic indications (blepharospasm, chronic migraine, severe underarm sweating and strabismus) and certain approved cosmetic uses.[7],[8] We noted in our petition that these statements are not included on the labeling of these drugs in other countries, such as Canada and the United Kingdom.[9],[10],[11] We also stated that our analysis of the FAERS database negates these claims. Specifically, of 639 serious reports in which Botox was the primary suspect when used to treat one of the four therapeutic indications listed in the misleading claims, 269 (42%) included adverse reactions that were suggestive of iatrogenic botulism. Many of those 269 reports involved recommended initial or repeated doses of Botox. Likewise, of 934 reports in the FAERS database in which Botox Cosmetic was the primary suspect, at least 140 initial or single-dose reports and at least 24 repeated-dose reports involved doses of 30 units or less; some reports involved doses as low as six units.

What You Can Do

Do not use any botulinum-toxin drug to smooth skin wrinkles or fine lines. If you are considering any of these products for an FDA-approved use, discuss with your clinician whether their potential benefits outweigh their risks and how often you will need to be injected with these drugs. Let your clinician know right away if you develop any serious adverse effects, such as those affecting your breathing, eyelids, speech or swallowing, or you experience weakness within hours to weeks after injections with these drugs.

Do not use botulinum-toxin drugs for any condition that is not approved by the FDA. Never receive any injection of botulinum-toxin drugs from an unlicensed health care professional.

Report all serious adverse events associated with the use of botulinum-toxin drugs to the FDA’s MedWatch adverse-event reporting program by visiting www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Public Citizen. Petition to the FDA to strengthen safety warning for Botox and related drugs and remove misleading claims from Botox/Botox Cosmetic labeling. December 12, 2023. https://www.citizen.org/article/petition-to-the-fda-to-strengthen-safety-warning-for-botox-and-related-drugs-and-remove-misleading-claims-from-botox-botox-cosmetic-labeling. Accessed January 5, 2024.

[2] Persistence Market Research. Botulinum toxin market. https://www.persistencemarketresearch.com/market-research/botulinum-toxin-market.asp. Accessed January 5, 2024.

[3] Hazell L, Shakir SAW. Under-reporting of adverse drug reactions: A systematic review. Drug Saf. 2006;29(5):385-396.

[4] Public Citizen. Petition requesting regulatory action concerning the spread of botulinum toxin (Botox, Myobloc) to other parts of the body. January 23, 2008. https://www.citizen.org/article/petition-requesting-regulatory-action-concerning-the-spread-of-botulinum-toxin-botox-myobloc-to-other-parts-of-the-body/. Accessed January 5, 2024.

[5] Food and Drug Administration. Response to Public Citizen’s 2008 petition requesting regulatory action concerning the spread of botulinum toxin (Botox, Myobloc) to other parts of the body. Docket no. FDA-2008-P-0061. April 30, 2009. https://www.citizen.org/wp-content/uploads/FDA_April-2009.-Response-to-Public-Citizen-petition.pdf. Accessed January 5, 2024.

[6] Public Citizen. Petition to the FDA to strengthen safety warning for Botox and related drugs and remove misleading claims from Botox/Botox Cosmetic labeling. December 12, 2023. https://www.citizen.org/article/petition-to-the-fda-to-strengthen-safety-warning-for-botox-and-related-drugs-and-remove-misleading-claims-from-botox-botox-cosmetic-labeling. Accessed January 5, 2024.

[7] Allergan, Inc. Label: onabotulinumtoxinA (BOTOX). August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103000Orig1s5325Correctedlbl.pdf. Accessed January 5, 2024.

[8] Allergan, Inc. Label: onabotulinumtoxinA (BOTOX COSMETIC). February 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=485d9b71-6881-42c5-a620-a4360c7192ab&type=display. Accessed January 5, 2024.

[9] AbbVie Corporation. Product monograph: onabotulinumtoxinA (BOTOX COSMETIC). November 4, 2022. https://www.abbvie.ca/content/dam/abbvie-dotcom/ca/en/documents/products/BOTOXCOSMETIC_PM_EN.pdf. Accessed January 5, 2024.

[10] Allergan Inc. Monograph: Product monograph: onabotulinumtoxinA (BOTOX). March 11, 2021. https://pdf.hres.ca/dpd_pm/00060199.PDF. Accessed January 5, 2024.

[11] AbbVie Inc. Summary of product characteristics for healthcare professionals: botulinum toxin type A (BOTOX). June 2023. https://www.medicines.org.uk/emc/product/859/smpc/print. Accessed January 5, 2024.