US Pharm. 2010;35(3):HS-22-HS-24.

Botox, which is a purified form of the toxin botulinum produced by the bacterium Clostridium botulinum, has several medical applications. The C botulinum toxin causes a life-threatening type of food poisoning called botulism.¹ Recently, the FDA issued some new guidelines and revisions with regard to Botox applications. In August 2009, the FDA issued a special alert regarding changes to the generic names and revisions to the prescribing information for botulinum toxin types A and B, including the newly approved abobotulinumtoxinA (Dysport) and rimabotulinumtoxinB (Myobloc).²

The FDA issued a boxed warning regarding the risk of a potentially life-threatening spread of the toxin’s effect from the local injection site. In addition, it required provision of a medication guide to explain risks to patients and caregivers. The FDA also placed emphasis on the differences in potency among the products (TABLE 1).³

MECHANISM OF ACTION

OnabotulinumtoxinA (previously known as botulinum toxin type A) is a neurotoxin produced by C botulinum, a spore-forming anaerobic bacillus. In humans, onabotulinumtoxinA appears to affect only the presynaptic membrane of the neuromuscular junction, where it prevents the calcium-dependent release of acetylcholine and produces a state of denervation. Muscle inactivation persists until new fibrils grow from the nerve and form junction plates on new areas of the muscle-cell walls.^1,4

INDICATIONS AND USES

Botox products are categorized as neuromuscular blockers and ophthalmic agents. They are used to treat a variety of conditions.

Labeled Indications and Dosing

Reduction of Glabellar Lines: Botox Cosmetic is used for the temporary improvement of the appearance of facial lines and wrinkles due to moderate-to-severe glabellar lines (lines between the eyebrows) in adult patients up to 65 years of age. For an effective intramuscular (IM) dose, the clinician must observe the patient’s ability to activate the superficial muscles injected. The location, size, and use of muscles may vary between individuals. A dose of 4 U (0.1 mL) is injected into each of five sites, two in each corrugator muscle and one in the procerus muscle, for a total dose of 20 U (0.5 mL). The dose may be repeated every 3 to 4 months to achieve the desired result.⁴

Cervical Dystonia: This is a neurologic disorder that causes severe neck- and shoulder-muscle contractions. In patients aged 16 years and older, the mean IM dose in patients previously treated with botulinum toxin is 236 U divided among the affected muscles; the initial dose in previously untreated patients should be lower. Subsequent dosing should be based on the position of the patient’s head and neck, localization of pain, patient response, and previous adverse reactions. To reduce the risk of the occurrence of dysphagia, the starting dose should be no more than 100 U.⁵

Strabismus: This condition involves a constant lack of parallelism of the visual axes of the eyes, or misaligned eyes. In this case, administration of local anesthetic and ocular decongestant drops is recommended several minutes prior to IM injection. The initial dose for vertical muscles and for horizontal strabismus less than 20 prism diopters (PD) is 1.25 U to 2.5 U in any one muscle; for horizontal strabismus of more than 20 to 50 PD, the initial dose is 2.5 U to 5 U in any one muscle.⁶

Blepharospasm: Blepharospasm is an uncontrollable winking associated with dystonia. In patients aged 12 years and older, an initial IM dose of 1.25 U to 2.5 U is injected into the medial and lateral pretarsal orbicularis oculi of the upper lid and the lateral pretarsal orbicularis oculi of the lower lid; the dose may be increased up to twice the previous dose if the response from the initial dose lasted 2 months or less; maximum dose per site is 5 U. Tolerance may occur if treatments are given more often than every 3 months, but the effect usually is not permanent. The cumulative dose should be no more than 200 U in a 30-day period.⁷

Axillary Hyperhidrosis: This condition involves severe, excessive underarm sweating that is not adequately controlled with topical treatments. In adults, the intradermal dose is 50 U per axilla. The injection area should be defined by standard staining techniques. Injections should be evenly distributed across multiple (10–15) sites 1 cm to 2 cm apart and administered in aliquots of 0.1 mL to 0.2 mL. Additional doses may be administered when the clinical effect diminishes.⁸

In all of the above cases, no dose adjustment is required in renal or hepatic impairment. All doses are reconstituted with preservative-free 0.9% sodium chloride to the units required.

Investigational Uses

Botox has a number of investigational uses, including the treatment of oromandibular, laryngeal, and other dystonias; the treatment and prophylaxis of migraine; and the treatment of dynamic muscle contracture in pediatric patients with cerebral palsy. These uses, however, will not be reviewed in this article.

SAFETY

In some cases, the botulinum toxin’s effects may spread to areas of the body beyond the injection site, thereby causing symptoms of botulism. In addition, dysphagia and breathing difficulties can occur and may be life-threatening. Other symptoms, which may develop within hours or weeks of injection, include blurred vision; dysarthria (trouble saying words clearly); dysphonia (hoarseness, change, or loss of voice); generalized muscle weakness; and urinary incontinence. The risk likely is greatest in children treated for spasticity (unapproved use). Immediate medical attention is required if respiratory, speech, or swallowing difficulties appear.⁹

CONTRAINDICATIONS

Botox is contraindicated if the patient is hypersensitive to albumin, botulinum toxin, or any component of the formulation. Another contraindication is infection at the proposed injection site(s). Higher doses or more frequent administration may result in neutralizing antibody formation and loss of efficacy.¹⁰

CAUTIONS

Botox use carries a number of cautions. For example, Botox should be used with caution in patients with neuromuscular diseases such as myasthenia gravis or neuropathic disorders (e.g., amyotrophic lateral sclerosis).

Reduced blinking from injection of the orbicularis muscle can lead to corneal exposure and ulceration when treating blepharospasm. For this reason, caution should be exercised in patients with angle-closure glaucoma. Careful testing of corneal sensation, avoidance of lower-lid injections, and treatment of epithelial defects are necessary.

Extreme caution should be exercised in patients with preexisting respiratory disease; treatment of cervical dystonia with botulinum toxin may weaken accessory muscles that are necessary for these patients to maintain adequate ventilation. Extreme caution also should be taken in patients receiving other agents that may interfere with neuromuscular transmission (e.g., aminoglycosides, neuromuscular blocking agents).¹⁰

PREGNANCY CONSIDERATIONS

No studies have been conducted on the human reproductive system, but Botox use should be avoided in pregnancy. Based on limited case reports, adverse fetal effects have not been observed with inadvertent administration during pregnancy. It is currently recommended that adequate contraception be ensured in women of childbearing potential. Excretion in breast milk is unknown, so Botox should be used with caution in nursing women.¹¹

MONITORING

Botox should be used with caution in the presence of disease that affects neuromuscular transmission or coagulation. Prior to administration, the potential for interactions with other medications the patient may be taking (e.g., anything that may affect neuromuscular transmission) should be evaluated. Therapeutic effects and adverse response should be assessed following each treatment. Adverse events may occur several hours after injection or be delayed up to several weeks. The patient should be instructed about necessary aftercare, possible side effects and appropriate interventions, and adverse symptoms that must be reported.¹¹

PATIENT EDUCATION

The patient should be advised that this medication is administered by injection. Aftercare instructions should be followed precisely. The patient should be informed that Botox, when used to improve appearance of facial lines or wrinkles, may cause headache; dry, painful, watery, or bloodshot eyes; a feeling of something in the eye; increased sensitivity to light; or slightly blurred vision. With other uses, the patient should be made aware that Botox may cause headache, dizziness, drowsiness, gastrointestinal upset, neck pain, upper respiratory infection, sore throat, or rhinitis. The patient should report immediately any difficulty swallowing, breathing, or speaking or any muscle weakness, vision problems, loss of bladder control, worsening symptoms, or other persistent or acute adverse symptoms, even if these occur several weeks following treatment.¹²

REFERENCES

1. Kukreja R, Singh BR. Botulinum neurotoxins: structure and mechanism of action. In: Proft T, ed. Microbial Toxins: Current Research and Future Trends. Norfolk, UK: Caister Academic Press; 2009.
2. FDA. OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc) Information. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm175011.htm. Accessed February 17, 2010.
3. FDA. FDA’s MedWatch Safety Alerts: June 2009. www.fda.gov/ForConsumers/ConsumerUpdates/ucm164442.htm. Accessed February 17, 2010.
4. Rzany B, Dill-Müller D, Grablowitz D, et al. Repeated botulinum toxin A injections for the treatment of lines in the upper face: a retrospective study of 4,103 treatments in 945 patients. Dermatol Surg.
5. Velickovic M, Benabou R, Brin MF. Cervical dystonia: pathophysiology and treatment options. Drugs. 2001;61:1921-1943.
6. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004;20:981-990.
7. Hsiung GY, Das SK, Ranawaya R, et al. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord. 2002;17:1288-1293.
8. Eisenach JH, Atkinson JL, Fealey RD. Hyperhidrosis: evolving therapies for a well-established phenomenon. Mayo Clin Proc. 2005;80:657-666.
9. Coté TR, Mohan AK, Polder JA, et al. Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. J Am Acad Dermatol.
10. Carruthers J, Carruthers A. Complications of botulinum toxin A. Facial Plast Surg Clin North Am. 2007;15:51-54.
11. Mejia NI, Vuong KD, Jankovic J. Long-term botulinum toxin efficacy, safety, and immunogenicity. Mov Disord. 2005;20:592-597.
12. MedlinePlus. Botox. www.nlm.nih.gov/medlineplus/botox.html. Accessed February 17, 2010.

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