Botulinum Toxin Type A

Class: Other Miscellaneous Therapeutic Agents
Brands: Botox

Special Alerts:

[UPDATED 08/03/2009] FDA notified healthcare professionals of changes to the established drug names for botulinum toxin Type A (Botox/Botox Cosmetic, Dysport) and botulinum toxin Type B (Myobloc) to reinforce individual potencies and prevent medication errors, and provided recommendations for healthcare professionals to consider, plus information for patients, family members, and caregivers. For more information visit the FDA website at: and .

The marketed trade names and the product formulations have not changed.

Summary of FDA-Approved Botulinum Toxin Products

Trade Name	NEW Drug Name	OLD Drug Name	Indication
Botox	OnabotulinumtoxinA	Botulinum toxin type A	Cervical dystonia, Severe primary axillary hyperhidrosis, Strabismus, Blepharospasm
Botox Cosmetic	OnabotulinumtoxinA	Botulinum toxin type A	Temporary improvement in the appearance of moderate to severe glabellar lines
Dysport	AbobotulinumtoxinA	Botulinum toxin type A	Cervical dystonia, temporary improvement in the appearance to moderate to severe glabellar lines
Myobloc	RimabotulinumtoxinB	Botulinum toxin type B	Cervical dystonia

[Posted 04/30/2009] FDA notified healthcare professionals that after an ongoing safety review initiated in February 2008, the manufacturers of licensed botulinum toxin products [botulinum toxin Type A (Botox and Botox Cosmetic) and botulinum toxin Type B (Myobloc)] will be required by FDA to strengthen warnings in product labeling and add a boxed warning regarding the risk of adverse events when the effects of the toxin spread beyond the site where it was injected.

FDA will also require that manufacturers develop and implement a Risk Evaluation and Mitigation Strategy [REMS], including a communication plan to provide more information regarding the risk for distant spread of botulinum toxin effects after local injection, as well as information to explain that botulinum toxin products cannot be interchanged. The REMS would also include a Medication Guide that explains the risks to patients, their families, and caregivers. FDA is requiring the manufacturers to submit safety data after multiple administrations of the product in a specified number of children and adults with spasticity to assess the signal of serious risk regarding distant spread of toxin effects.

FDA’s evaluation of the data continues to support the recommendations made in the 2008 Early Communication. For more information visit the FDA website at: , and .

REMS:

FDA approved a REMS for onabotulinumtoxina (formerly botulinum toxin a) to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of onabotulinumtoxina (formerly botulinum toxin a) and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Neurotoxin produced by Clostridium botulinum;^{1 3 5 31 37 70 73 79} 7 structurally similar but antigenically and serologically distinct serotypes (A, B, C, D, E, F, and G) exist.^{3 31 32 37 70 73 75 79}

Botulinum toxin disrupts neurotransmission by inhibiting release of acetylcholine at cholinergic nerve terminals of the peripheral nervous system and at ganglionic nerve terminals of the autonomic nervous system, inducing a chemical denervation and flaccid paralysis and inhibiting glandular secretion.^{1 2 3 5 31 32 37 43 72 73 75 194}

Uses for Botulinum Toxin Type A

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Botulinum toxin type A (Botox, Botox Cosmetic) and type B (Myobloc) currently are commercially available in the US;^{1 2 5} types C and F reportedly under clinical investigation in other countries.⁴

Cervical Dystonia

Management of cervical dystonia (also referred to as spasmodic torticollis) to decrease the severity of associated abnormal head position and neck pain;^{1 3 4 9 14 16 29 30 32 35 37 40 54 65 69 85 95 96 122 123} designated an orphan drug by FDA for this use.⁸¹

Considered first-line therapy for cervical dystonia because of its efficacy, relatively low incidence of adverse effects, and temporary dose-related therapeutic effects (compared with surgery).^{3 15 30 33 34 35 54 83 86 90 296 297 298}

Comparative safety and efficacy of botulinum toxin types A and B in cervical dystonia have not been established.^{14 69}

Blepharospasm and Associated Facial Nerve Disorders

Management of blepharospasm associated with dystonia, including benign essential blepharospasm and seventh cranial (facial) nerve disorders; ^{1 3 24 29 30 33 34 35 37 89 90 94 98 99 100 101 102 103 104 105 106} considered a first-line therapy.^{9 29 33 34 54 65}

Designated an orphan drug by FDA for treatment of blepharospasm associated with dystonia in adults and children ≥12 years of age.⁸¹

Management of Meige’s syndrome† (idiopathic blepharospasm with facial and oromandibular dystonias).^{7 24 90 98 100 102 104 309}

Strabismus and Nystagmus

Management of dystonia-associated strabismus;^{1 4 9 29 30 33 34 35 37 54 65 81 85 89 108 109 110 111 112 113 114 115 123 138 296 297 298} designated an orphan drug by FDA for this use.⁸¹ An effective alternative or adjunct to surgery in selected adults and children with congenital or acquired strabismus.^{33 37 109 296 297 298}

Also has been used in vertical strabismus in dysthyroid ophthalmopathy for which surgery is inappropriate.^{9 33 37 109 110 115 180}

Safety and efficacy not established for treatment of ocular deviations >50 prism diopters†,^{1 115} restrictive strabismus†,^{1 113 115} or Duane’s syndrome with lateral rectus weakness†.^{1 113}

Has been used in surgically overcorrected or undercorrected strabismus;^{4 107 113 115} however, efficacy not established in strabismus secondary to prior surgical overrecession of the ocular antagonist muscle.^{1 115 296 297 298}

Not effective in chronic paralytic strabismus except as an adjunct to surgical repair to reduce ocular antagonist muscle contracture.^{1 4 33 115 296 297 298}

Spasmodic Dysphonia (Laryngeal Dystonia)

Treatment of choice for management of spasmodic dysphonia† (laryngeal dystonia) despite occasional complications and possible risk of reflex laryngeal stridor.^{9 35 54 65 83 85 116 247 296 297 298 308 317} Spasmodic dysphonia involving the adductor muscles appears to be more common;^{30 35 37 83 116} a limited number of patients with abductor muscle spasm have obtained some benefit from EMG-guided injections of the toxin into the posterior cricoarytenoid muscle.^{9 30 35 37 207 308 317}

Oromandibular Dystonias

Has been used successfully in the management of various oromandibular dystonias† (e.g., Meige’s syndrome†);^{3 4 9 29 30 33 34 35 37 84 90 104 118 119 120 309} considered a treatment of choice by some clinicians, although efficacy evidence from well-controlled studies is lacking.^{9 29 33 34 35 37 84 104 118 119 120 296 297 298 309}

Focal Limb Dystonias

Has been used for the management of focal limb dystonias (e.g., writer’s cramp†);^{9 30 33 37 54 65 175 176 177 178} considered first-line therapy.^{9 37 174 175 176 177 178 296}

Tremor

Has been used for the management of various types of tremor†,^{35 36 65 194 195 196 197 248} including hand tremor†.^{36 194 195 196 197}

Axillary Hyperhidrosis

Management of severe primary axillary hyperhidrosis that has not responded adequately to conservative treatments (e.g., topical antiperspirants).^{1 137 138 157 158 159 160 161 162 163 164 170 237 259 277}

Requires repeated treatment but avoids associated morbidity (e.g., pneumothorax, Horner’s syndrome, compensatory hyperhidrosis) of surgical procedures.^{137 162 163 164 170 296}

Gustatory Sweating

Used with good results in patients with gustatory sweating† (e.g., Frey syndrome, diabetic gustatory sweating);^{4 50 157 168} considered a treatment of choice by some clinicians, although efficacy data are limited.^{50 157 296 297 298}

Cosmesis of Glabellar Facial (“Frown”) Lines

Used for temporary improvement in the appearance of moderate to severe glabellar facial (“frown”) lines associated with corrugator and/or procerus muscle activity.^{5 37 64 68 79 85 123 140 141 142 143 144 145 146 147 148 149 150 157 305}

A treatment of choice in individuals wishing to avoid major procedure.^{145 296 297 298}

Cosmetic effects generally persist at least 4–6 months.^{140 143 144 146 150}

May not be appropriate when a wide range of facial expressions is required for professional or personal reasons.^{145 296 297 298}

Cosmesis of Lateral Canthal Wrinkles (“Crow’s Feet”)

Has been used for temporary improvement in the appearance of facial wrinkles associated with hyperactivity of the orbiculus oculi muscle† (lateral canthal wrinkles†, also known as “crow’s feet”†).^{66 68 123 140 141 146 152 153 311}

Cosmesis of Horizontal Forehead Lines

Has been used for temporary improvement in the appearance of hyperfunctional facial lines caused by frontalis muscle hyperactivity† (horizontal forehead lines).^{142 143 146 183 186 303}

Young individuals (usually females) with expressive horizontal forehead lines reportedly exhibit the best response.^{143 296 297 298}

Spasticity Associated with Cerebral Palsy

Has been used for the treatment of dynamic muscle contracture in pediatric patients with cerebral palsy†;^{155 166 169 229 230 231 232 233 234 269 270 271 272 273 275 279 280 281 315 321} designated an orphan drug by the FDA for this use.⁸¹ Some clinicians suggest conjunctive use of physical therapy and orthotics (e.g., casting).^{155 166 169 229 270 315 342 343}

Also has been used as an adjunct to analgesics for relief of postoperative pain secondary to muscle spasm associated with cerebral palsy† following orthopedic surgery.^{219 229 275}

Spasticity Associated with Stroke

Has been used to decrease spasticity, improve posture and range of motion, and relieve painful muscle spasms in patients with spasticity associated with stroke†.^{218 219 220 221 223 224 225 226 236 276 296 297 298 341}

Spasticity Associated with Multiple Sclerosis

Has been used for treatment of spasticity associated with multiple sclerosis† (e.g., hip adductor spasms†, spastic ankles†).^{37 123 166 198 204 219 220 223 224 229 235 236 276 297 360}

Anal Sphincter Disorders

Has been used effectively to treat uncomplicated cases of chronic anal fissure†;^{123 124 125 126 127 128 129 130 131 132 133 134 217 286} circumvents potential complications of surgery.^{125 126 127 128 129 130 133 217 296 297 298 365 366}

Has been used for pain reduction following hemorrhoidectomy†, presumably as a result of reducing spasm of the anal sphincter.²⁵⁶

Neurogenic Voiding Dysfunction

Has been used for the treatment of detrusor-sphincter dyssynergia† (generally detrusor-external sphincter dyssynergia†) associated with spinal cord disease or injury.^{33 34 35 37 85 123 199 200 201 202 203 206 208 209 210 211 212 296 297 298}

Voiding Dysfunction Associated with Benign Prostatic Hyperplasia

Has been used to treat voiding dysfunction associated with benign prostatic hyperplasia† (benign prostatic hypertrophy, BPH).²⁶⁸

Achalasia

Has been used successfully in a limited number of patients to relieve dysphagia, pain, and regurgitation¹⁸⁹ associated with achalasia†;^{34 35 37 85 123 184 185 187 188 189 190 191 192 193 296 297 298} much less effective in achalasia secondary to gastroesophageal junction carcinoma or other malignancy than in idiopathic achalasia.^{188 189}

Musculoskeletal Pain Disorders

Has been used for pain relief in a variety of pain disorders of musculoskeletal origin, including myofascial pain syndrome†,^{34 47 120 240 241 242 243 293 313 324 329} chronic neck pain†,^{313 331} chronic lower back pain†,^{35 85 240 241 243 244 245 313 324 332 333} and whiplash-associated disorder†.^{243 313 336}

Has also been used for treatment of tennis elbow†.^{35 97 322}

Prophylaxis of Disabling Headache

Has been used to reduce the frequency of and/or pain associated with migraine headache† in certain patients who require an alternative to conventional drug therapies because of inefficacy, intolerance, contraindications, and/or poor compliance.^{296 313 327 328}

Has been used with relatively inconsistent benefit in post-whiplash (cervicogenic) headache†.^{238 241 267 324 330 334}

Botulinum Toxin Type A Dosage and Administration

General

• 
  

  Adjust dosage carefully according to response and particular condition treated.^{4 120}

  
  


• 
  

  Generally, the effective IM dose depends on muscle mass: the larger the muscle, the higher the required dose.^{4 120}

  
  


• 
  

  Individual susceptibility to the toxin varies;⁴ and optimal dosages for a number of conditions have not been fully elucidated.^{37 133 138 142 156 218 219 238 243 301 302 313 321 337 338}

  
  


• 
  

  Lower doses may be required in patients with preexisting weakness or when there is concern about weakness, in those with milder disease severity, and in women and patients with lower body weights.⁴

  
  


• 
  

  If a patient fails to respond, consider possibility of an inadequate drug dose, incorrectly reconstituted and/or improperly stored drug solution, and/or misinjection.^{65 296 348}

  
  


• 
  

  Manufacturer recommends ≥12 weeks between treatment sessions for cosmesis.⁵

  
  


• 
  

  Some clinicians state strict adherence to recommended treatment interval of 12 weeks is not critical with low doses administered for cosmesis (e.g., 100 units total dose); such clinicians repeat injections after 2 weeks if desired results are not achieved after initial treatment.^{5 143 296 297 298}

  
  


• 
  

  Some clinicians suggest a treatment interval ≥8–12 weeks for noncosmetic indications.⁵

  
  

Administration

Administer by IM injection into affected muscles,^{1 3 4 5 120} intradermally^{30 35 60 67 79 85 123 157 158 160 170 259} , intracutaneously†,^{60 157 163 164 165 296 297 298} sub-Q†,^{60 157 163 164 165 296 297 298} or directly into affected glands†.^{4 320}

IM Administration

Administer by IM injection into affected muscles.^{1 3 4 5 120}

Just before administration, withdraw a volume of reconstituted drug slightly greater than the volume of the intended dose into an appropriately sized sterile syringe and expel any air bubbles in the syringe barrel; attach a new needle appropriate for the injection site to the syringe and confirm needle patency.^{1 5}

Reconstitution

Formulations of Botox and Botox Cosmetic of botulinum toxin type A are identical and are interchangeable provided the appropriate dilutions and administration techniques for a given indication are used.²⁹⁸

For noncosmetic uses, reconstitute vial containing 100 units of vacuum-dried drug with 1, 2, 4, or 8 mL of 0.9% sodium chloride injection without preservatives to provide a solution containing 10, 5, 2.5, or 1.25 units per 0.1 mL, respectively.^{1 298}

For cosmetic uses, reconstitute 50- or 100-unit vials of vacuum-dried drug with 1.25 mL or 2.5 mL, respectively, of 0.9% sodium chloride injection without preservatives to provide solutions containing 4 units of botulinum toxin type A per 0.1 mL. ^{5 64 296 298}

Use a new, sterile needle and syringe to enter the vial during reconstitution and for withdrawal of each dose.^{1 5}

To prevent possible toxin inactivation,²⁹⁸ allow stopper of vial to dry thoroughly after cleansing with alcohol before entering vial with a needle.^{121 142 296 297}

Vials may be reentered to treat the same patient within 4 hours of reconstitution; refrigerate during this time.^{1 5 298}

Direct 0.9% sodium chloride diluent toward side of vial using an appropriately sized syringe with a 21-gauge, 2.5-inch needle.^{1 5 121 296 297 298} Gently swirl to avoid excessive foaming of solution; do not shake.^{1 5 121 296 297 298}

Record date and time of reconstitution on drug vial.^{1 5}

Carefully dispose of all used vials, including expired vials and/or equipment used in preparation and administration, as medical waste.^{1 5}

Dilution

The optimum dilution to produce maximal effect not established;²²⁹ however, some clinicians state that use of concentrated solution (e.g., 100 units/mL) avoids many complications related to more extensive spread of toxin when less concentrated solutions (e.g., 10 units/mL) used.¹⁴¹

Prepare desired dose for administration by using a fixed concentration of the drug (e.g., 20–100 units/mL) and varying the volume of the injection to obtain the appropriate dose (e.g., decrease administered injection volume from 0.1 mL to 0.05 mL per dose to decrease dose by 50%, or increase administered injection volume from 0.1 mL to 0.15 mL to increase dose by 50%) or by diluting the appropriate dose in a fixed volume (e.g., 2–4 mL) of diluent (e.g., 0.9% sodium chloride injection without preservatives).^{1 5 229 270 298}

Lidocaine reportedly used as diluent to reduce pain on injection†;^{138 296 297 298 323} however, manufacturer states that diluents other than 0.9% sodium chloride injection without preservatives are not recommended because of potential for unknown interactions or adverse effects of other components.^{1 2 5 298}

Bacteriostatic (i.e., preserved with benzyl alcohol) 0.9% sodium chloride injection used as a diluent† reportedly is associated with less pain upon injection.^{62 64 138 296 298} However, manufacturer states that diluents other than 0.9% sodium chloride injection without preservatives are not recommended.^{1 5 298}

IM Injection Techniques

Targeting injection to the appropriate muscle(s) may be facilitated by active electromyography (EMG), ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks (e.g., evidence of muscular hypertrophy, stiffness, tenderness, visible abnormal muscular activity).^{4 120 147 229}

EMG-guided injections often recommended to ensure optimal placement of toxin for efficacy, particularly in patients who have not responded adequately to previous injections, and to minimize adverse effects on nonaffected tissue.^{120 140 143 147 296 297 298}

EMG guidance may allow more accurate identification of neural motor end plate, facilitating more precise injection and improving effectiveness of lower doses.^{240 360}

Injection into the midbelly of larger muscles where the motor end plates are located may enhance benefit.^{240 296 360}

Cervical Dystonia

Total dose administered at each treatment session is given as several injections divided among affected muscles.^{1 65}

Identify affected muscles by careful clinical evaluation, including physical examination and palpation (e.g., for areas of hypertrophy, pain).^{9 33 65} Palpation of contracting muscles while the patient’s head is placed in the position most favored by dystonic pulling of the neck muscles reportedly is helpful.^{9 65}

EMG guidance also may be useful in delineating involved muscles for injection, particularly in obese patients or for muscles difficult to identify by palpation.^{1 35 37 39 56 65}

Blepharospasm and Hemifacial Spasm

For the treatment of blepharospasm, the initial recommended dose is injected at each site without EMG guidance into the medial and lateral pretarsal orbicularis oculi of the upper lid and into lateral pretarsal orbicularis oculi of the lower lid.^{1 4 65}

Reduce or prevent ecchymosis of adnexa by using very fine-gauge needles (e.g., 30- , 32-gauge), limiting repeat use of needles to ≤4 times, appropriate discontinuance of medications and supplements that affect platelet function (e.g., aspirin, vitamin E) prior to injection, and by applying pressure and/or ice to the injection site immediately post-injection.^{1 296}

Reduce risk of ptosis by avoiding injection near the levator palpebrae superioris.^{1 22 37 141 296 297 298}

Reduce risk of diplopia by avoiding medial lower lid injections, thereby reducing drug diffusion into the inferior oblique muscle.¹

Treatment of hemifacial spasm, which sometimes occurs in conjunction with blepharospasm,^{3 9 20 29 30 33 34 35 37 65 83 100 102 106} should be individualized.²⁶³ Initially inject only those muscles considered most disturbing to the patient, such as the orbicularis oculi (as for blepharospasm); affected muscles of the lower face may respond through drug diffusion or cessation of eyelid contractions that act as a trigger for spasm.^{4 21 37}

Strabismus

To ensure optimum placement of the needle within targeted extraocular muscles, injection with EMG guidance or into exposed muscles during surgery is recommended;^{1 56 296} however, some clinicians suggest that the drug can be safely administered by clinicians with sufficient experiential knowledge of orbital anatomy.²⁹⁶

Spasmodic Dysphonia Involving the Adductor Muscles

Inject into the thyroarytenoid vocalis complex via the cricothyroid cartilage with EMG guidance;^{4 9 35 37 65 83 117 296 297 298 308 317} use a hollow, Teflon-coated needle.^{9 35 37 83 116 117 308}

Also has been given by indirect laryngeal endoscopy (without EMG guidance) in some (e.g., post-surgical) patients.^{4 35 117 296 297 298 308}

While injections have been given into both vocal cords,^{9 35 37 83 308} some clinicians prefer unilateral injections to minimize adverse effects;^{6 65 83 205 296 297 298} controversy exists regarding the optimal method.²⁹⁶

Spasmodic Dysphonia Involving the Abductor Muscles

Inject into the posterior cricothyroid muscle using EMG guidance.^{37 116 117}