BOTOX -- Black Box Warning

 Updated 3/2017-- photos and all links removed as many are no longer active and it's easier than checking each one.

The U.S. Food and Drug Administration recently announced that safety label changes including a boxed warning and a Risk Evaluation and Mitigation Strategy (REMS) will now be required for all botulinum toxin products.  The agency took the action because of two main reasons.  The first one is the potential for serious risks that may occur from the spread of the botulinum toxin beyond the injection site.  The second reason is associated with the lack of interchangeability among the three licensed botulinum toxin products.

When the botulinum toxin spreads beyond the area of injection, symptoms similar to botulism may occur.  These symptoms include unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids.

This “spreading effect” has been reported in both children and adults.  It has been reported most often in children with cerebral palsy being treated with the products for muscle spasticity.  Treatment of muscle spasticity is an off-label use of the drug.  The “spreading effect” has been reported in patients being treated for both approved and unapproved uses.

Botulinum toxin products include:

• Botox and Botox Cosmetic (botulinum toxin type A), marketed by Allergan
• Myobloc (botulinum toxin type B), marketed by Solstice Neurosciences
• Dysport (abobotulinumtoxinA),  a new FDA-approved product marketed by Ipsen Biopharm Ltd.

All are approved by the FDA for the treatment of  cervical dystonia.  Botox Cosmetic and Dysport are approved by the FDA for treatment of glabellar frown lines.  Botox is approved for the treatment of severe underarm sweating (primary axillary hyperhidrosis), crossed eyes (strabismus), and abnormal tics and twitches of the eyelids (blepharospasm).    All other uses are considered off-label.

The FDA has not identified any definitive serious adverse event reports of a distant spread of toxin effect producing symptoms consistent with botulism when these products are used in accordance with the approved label.

It is important for those of us who use botulinum toxins to remember that the dosage strength between the products is not the same.  One unit of Botox is not equal in strength (potency) as one unit of Myobloc or Dysport. 

BOTOX® Cosmetic Insert (pdf)

Dilution Technique:  Using a 21-gauge needle and an appropriately sized syringe draw up a total of 2.5 mL/100 Unit vial or 1.25 mL/50 Unit vial of 0.9% sterile saline without a preservative…….
Injection Technique: Glabellar 

Using a 30-gauge needle, inject a dose of 0.1 mL into each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose of 20 Units. Typically the initial doses of  reconstituted BOTOX® Cosmetic induce chemical denervation of the injected muscles one to two days after injection, increasing in intensity during the first week.

MYOBLOC® Insert (pdf)

The recommended initial dose of MYOBLOC® for patients with a prior history of tolerating botulinum toxin injections is 2500 to 5000 U divided among affected muscles. Patients without a prior history of tolerating botulinum toxin injections should receive a lower initial dose.  The duration of effect in patients responding to MYOBLOC® treatment has been observed in studies to be between 12 and 16 weeks at doses of 5000 U or 10,000 U.

Dysport®  Insert 

The units of Dysport are specific to the preparation and are not interchangeable with other preparations of botulinum toxin.

Glabellar lines Dosage

The dosage is dependant on the severity of the lines and the specific muscle being treated.

For the corrugator and procerus muscles 40 to 60 units divided between injection sites as follows:

8 to 12 units in each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose of 60 units

Improvement of severity of glabellar lines generally occurs within 72 hours after treatment and persists for 3 to 6 months.

It is important for us to educate patients and their caregivers of the potential adverse effects.  Some of these effects have been reported as early as several hours and as late as several weeks after treatment.  Patients should seek immediate medical attention if they develop any of these symptoms  --  unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids.

Adverse events may be reported by health care professionals and/or consumers to the FDA's MedWatch Adverse Event Reporting program   by four ways:

• Online: www.fda.gov/MedWatch/report.htm
• Regular Mail: use postage-paid FDA form 3500 available at: www.fda.gov/MedWatch/getforms.htm and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: 800-FDA-0178 (the same form you would mail)
• Phone: 800-FDA-1088

REFERENCES

FDA News (April 30, 2009)

BOTOX® Injections; eMedicine Article, Sept 25, 2008; Robert A Hauser, MD, MBA, Mervat Wahba, MD, Theresa McClain, MSN, ARNP