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The MS hug: Learn what causes it and how to get relief

Generic Name: Botulinum Toxin Type A
Class: Other Miscellaneous Therapeutic Agents

Warning(s)

  • Distant Spread of Toxin Effects
  • Effects of any botulinum toxin may spread from local sites of injection, producing symptoms consistent with the mechanism of action of botulinum toxin.1 5 (See Distant Spread of Toxin Effects under Cautions.)

  • Symptoms reported hours to weeks following injection.1 5

  • Swallowing and breathing difficulties may be life-threatening; deaths reported.1 5

  • Children treated for limb spasticity probably at highest risk; however, such effects also can occur in adults, particularly those with underlying predisposing conditions.1 5 (See Pediatric Use under Cautions.)

  • In both labeled and unlabeled (e.g., spasticity in children) uses, symptoms consistent with the spread of toxin effect reported at doses comparable to or lower than those used in cervical dystonia.1 5

Introduction

Neurotoxin produced by Clostridium botulinum;1 3 5 31 37 70 79 disrupts neurotransmission by inhibiting release of acetylcholine from peripheral cholinergic and ganglionic nerve terminals.1 3 5 31 32 37 194 384

Uses for Botox

Currently, 3 botulinum toxin type A preparations (abobotulinumtoxinA [Dysport], incobotulinumtoxinA [Xeomin], and onabotulinumtoxinA [Botox, Botox Cosmetic]) and one botulinum toxin type B preparation (rimabotulinumtoxinB [Myobloc]) are commercially available in the US.1 2 5 403 These preparations are not interchangeable;1 2 5 381 384 403 410 assay methods used to determine potency of these various toxins are specific to each individual manufacturer and/or formulation.1 2 5 However, Botox and Botox Cosmetic formulations are identical, and the manufacturer states that these preparations may be used interchangeably provided appropriate dilutions and administration techniques for a given indication are used.298

Overactive Bladder

Management of overactive bladder, with symptoms of urge urinary incontinence, urgency, and frequency, in patients who have an inadequate response to or are intolerant of anticholinergic drug therapy.1 443 444 450 451 454

Reduces the frequency of urinary incontinence episodes and increases the volume voided per micturition.1 443 444 450 451 454

Detrusor Overactivity Associated with a Neurologic Condition

Management of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis) in patients who have an inadequate response to, or are intolerant of, anticholinergic drug therapy.1 33 34 35 37 123 199 200 201 202 203 206 208 209 210 211 212 296 298 447

Also may be useful in patients with spinal cord injury who perform self-catheterization and who do not wish to undergo surgery (e.g., sphincterotomy).33 34 35 37 123 199 200 201 202 203 206 208 209 210 211 212 296 298 447

Relaxes the external urethral sphincter and promotes voiding; decreases urethral and bladder pressure during voiding and reduces postvoiding residual volume and the need for anticholinergic drug therapy.201 202 206 298 447 449 454

Voiding Dysfunction Associated with Benign Prostatic Hyperplasia

Has been used for the management of voiding dysfunction associated with benign prostatic hyperplasia (BPH).268 453

Anal Sphincter Disorders

Has been used to treat uncomplicated cases of chronic anal fissure, thought to be related to sustained high resting anal sphincter tone and associated anodermal ischemia.123 125 126 127 128 129 130 131 132 133 217 May be more effective and cause fewer adverse effects than topical nitroglycerin ointment.125 127 217

Has been used for pain reduction following hemorrhoidectomy.256

Achalasia

Has been used successfully in a limited number of patients to relieve dysphagia, pain, and regurgitation189 associated with achalasia.34 35 37 123 184 185 187 189 190 191 192 193 296 298

Optimum candidates include patients with symptomatic achalasia who have concomitant illness and/or who are at high risk for complications such as esophageal reflux or perforation (generally geriatric patients, who may be more likely to respond than younger patients),187 190 those who have not responded to prior myotomy, those who have had esophageal perforation associated with pneumatic dilatation, and those with an epiphrenic diverticulum.185 187 189 190 191 192 296 298

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Chronic Migraine Prophylaxis

Prophylaxis of headaches in patients with chronic migraine (defined as headache lasting ≥4 hours per day on ≥15 days per month).1 423 424 425 426 427 428 429 430

Reduces mean frequency of headache days, number of moderate and severe headache days, number of headache or migraine episodes, and total cumulative hours of headache on headache days.1 423 424 425 426 428

Manufacturer states that safety and efficacy for prophylaxis of episodic migraine (≤14 headache days per month) not established.1

Upper Limb Spasticity

Management of upper limb spasticity to decrease the severity of increased muscle tone in elbow flexors (biceps brachii), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis); safety and efficacy based on studies in adults who had experienced a stroke ≥6 weeks previously.1 221 222 438

Decreases spasticity, improves posture and range of motion, and relieves painful muscle spasms in adults with stroke-related spasticity;1 3 37 218 219 221 223 224 225 226 360 438 442 296 298 341 has been suggested as first-line therapy for upper limb spasticity in adults.440

Manufacturer states that safety and efficacy not established for the management of other upper limb muscle groups, and not shown to improve upper extremity functional abilities or range of motion at a joint affected by a fixed contracture.1

Not intended to substitute for usual standard-of-care rehabilitation regimens.1

Spasticity Associated with Cerebral Palsy

Has been used for the management of upper-extremity deformities associated with cerebral palsy (e.g., shoulder internal rotation and/or adduction, persistent thumb-in-palm or thumb adduction, wrist or elbow flexion, forearm pronation).229 230 321

Some clinicians suggest conjunctive use of physical therapy and orthotics (e.g., casting).169 229 270 315 342 343

Manufacturer states that safety and efficacy not established for the management of lower limb spasticity in adults or pediatric patients.1 441 However, has been used successfully in the management of cerebral palsy-associated spasticity and deformities (e.g., equinus foot deformity, spastic hemiplegia, relief of postoperative pain secondary to muscle spasm) involving the lower limbs.37 123 169 218 219 223 224 229 231 232 233 234 270 275 280 285 296 341 343 360

Designated an orphan drug by FDA81 for the treatment of dynamic muscle contracture in pediatric patients with cerebral palsy.169 229 230 231 232 233 234 269 270 271 272 275 280 315 321

Cervical Dystonia

Management of cervical dystonia (spasmodic torticollis) to reduce the severity of associated abnormal head position and neck pain;1 3 9 14 16 29 32 35 37 65 69 123 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 33 34 35 86 90 296 298

Spasmodic Dysphonia (Laryngeal Dystonia)

Considered treatment of choice for management of spasmodic dysphonia despite occasional complications and possible risk of reflex laryngeal stridor.9 35 65 116 247 296 298 308 317

Spasmodic dysphonia involving the adductor muscles appears to be more common;35 37 116 a limited number of patients with abductor muscle spasm have obtained some benefit from electromyogram (EMG)-guided injections of the toxin into the posterior cricoarytenoid muscle.9 35 37 207 308 317

Oromandibular Dystonias

Has been used successfully in the management of various oromandibular dystonias (e.g., Meige’s syndrome);3 7 9 24 29 33 34 35 37 90 98 100 104 118 119 120 309 considered a treatment of choice by some clinicians, although efficacy evidence from well-controlled studies is lacking.9 29 33 34 35 37 104 118 119 120 296 298 309

Primary Axillary Hyperhidrosis

Management of severe primary axillary hyperhidrosis that is inadequately managed with topical agents.1 35 79 123 137 138 157 159 160 161 162 164 170 237 259 277

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

Palmar Hyperhidrosis

Manufacturer states that safety and efficacy for the management of hyperhidrosis in body areas other than axillae not established.1 However, has been useful in some patients with focal palmar hyperhidrosis.35 49 79 123 137 138 157 164 165 167 259 277 452

Blepharospasm and Associated Facial Nerve Disorders

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

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

Also has shown clinical benefit in patients with hemifacial spasm (unilateral eyelid and facial movement disorder), which may occur in association with blepharospasm.3 9 20 29 33 34 35 37 56 65 100 106 Results reported to be comparable to those of microvascular decompression of the facial nerve, with less risk of serious complications (e.g., facial paralysis, deafness, stroke).9 37 98

Strabismus

Management of dystonia-associated strabismus;1 9 29 33 34 35 37 65 81 108 109 110 111 112 113 114 115 123 138 296 298 designated an orphan drug by FDA for this use in adults and children ≥12 years of age.81 An effective alternative or adjunct to surgery in selected patients with congenital or acquired strabismus.33 37 109 296 298

Has been used in vertical strabismus in dysthyroid ophthalmopathy for which surgery is inappropriate.9 33 37 109 110 115

Safety and efficacy not established for treatment of ocular deviations >50 prism diopters,1 115 restrictive strabismus,1 113 115 strabismus secondary to prior surgical overrecession of the ocular antagonist muscle,115 296 298 or Duane’s syndrome with lateral rectus weakness.1 113

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

Cosmesis of Glabellar Facial Lines

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 79 123 140 141 142 143 144 145 146 147 148 149 150 157 305

A treatment of choice in individuals wishing to avoid major procedures.145 296 298

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.145 296 298

Cosmesis of Lateral Canthal Lines

Temporary improvement in the appearance of moderate to severe lateral canthal lines (“crow’s feet”) associated with orbicularis oculi activity.5 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.143 296 298

Myofascial Pain Syndrome

Has been used in musculoskeletal pain disorders such as myofascial pain syndrome;34 120 240 241 242 313 324 329 may provide better and more prolonged relief than corticosteroids (e.g., methylprednisolone).240 241 242 296 298 313 324

Tremor

Has been used for the management of various types of tremor,35 36 65 194 196 197 including essential hand tremor.36 194 196 197

Botox Dosage and Administration

General

  • Thorough knowledge of diagnosis, management, and regional anatomy of the treated disorder, careful dose selection, and accomplished injection techniques critical for obtaining therapeutic benefit and minimizing adverse effects.1 5 56

  • Working knowledge of EMG techniques required for treatment of strabismus and upper limb spasticity; also may be useful for accurate injection of target muscles in patients with cervical dystonia.1 35

  • Some experts recommend limiting use of botulinum toxins to clinicians with specialized training.37 65 296 298

  • Adjust dosage carefully according to response and particular condition treated.120

  • Generally, the effective IM dose depends on muscle mass: the larger the muscle, the higher the required dose.120

  • Optimal dosages for a number of conditions have not been fully elucidated.37 133 138 142 156 218 219 313 321 337 338

  • 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.5 143 296 298

  • Some clinicians suggest a treatment interval ≥8–12 weeks for noncosmetic indications.296 298

Controlling Injection Pain

  • Pretreatment with ice packs or topical or local anesthetics (e.g., lidocaine/prilocaine cream and an occlusive dressing, proparacaine ophthalmic solution) has been recommended prior to injection, particularly when preexisting muscle pain exists or when injecting extrinsic ocular muscles.120 140 275 296

  • Other clinicians report topical or local anesthetics are not useful to prevent injection pain since they do not penetrate underlying muscles and/or require additional injections.270 296 298

  • Dilution with 0.9% sodium chloride injection containing a preservative (benzyl alcohol) has been reported to reduce pain on injection;62 64 138 157 however, the manufacturer recommends use of 0.9% sodium chloride injection without preservatives for reconstitution and/or dilution.1 5 298

  • IV sedation or general anesthesia may be needed prior to injection in some patients (e.g. those in considerable pain, those with urologic conditions, pediatric patients receiving multiple injections in the hand).120 296 298

Administration

Administer by IM injection into affected muscles,1 3 5 120 intradermally35 60 79 123 157 160 170 259 , intracutaneously,60 157 164 165 296 298 sub-Q,60 157 164 165 296 298 or directly into affected glands.320

IM Administration

Administer by IM injection into affected muscles.1 3 5 120

Reconstitution

Must reconstitute commercially available vacuum-dried onabotulinumtoxinA (Botox, Botox Cosmetic) prior to administration.1 5 298

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

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

Vials are for single use only; discard any unused portions.1 5

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

For noncosmetic uses except detrusor overactivity associated with a neurologic condition, reconstitute 100- or 200-unit vials of vacuum-dried drug with an appropriate amount of 0.9% sodium chloride injection without preservatives to provide a solution containing the desired dose of onabotulinumtoxinA per 0.1 mL.1 298 (See Tables 1 and 2.)

Except for detrusor overactivity associated with a neuromuscular condition; see text for details on reconstituting onabotulinumtoxinA for that use.

Use 0.9% sodium chloride injection without preservatives only.

Table 1. Resultant Dose of OnabotulinumtoxinA (Botox) Following Reconstitution for Noncosmetic Uses

Resulting Dose (units/0.1 mL)

Diluent Volume

100-Unit Vial

200-Unit Vial

1 mL

10 units

20 units

2 mL

5 units

10 units

4 mL

2.5 units

5 units

8 mL

1.25 units

2.5 units

10 mL

1 unit

2 units

Use 0.9% sodium chloride injection without preservatives only.

Table 2. Reconstitution of OnabotulinumtoxinA for Noncosmetic Uses1

Use

Vial Size (Diluent Volume)

Overactive bladder

100 units (10 mL)

Chronic migraine

200 units (4 mL) or 100 units (2 mL)

Upper limb spasticity

200 units (4 mL) or 100 units (2 mL)

Cervical dystonia

200 units (2 or 4 mL) or 100 units (1 or 2 mL), depending on injection volume and number of injection sites

Primary axillary hyperhidrosis

100 units (4 mL)

Blepharospasm

100 units (4 or 8 mL)

Strabismus

100 units (4 or 8 mL)

Detrusor overactivity associated with a neurologic condition

See text

For detrusor overactivity associated with a neurologic condition, reconstitute one 200-unit vial with 6 mL of diluent (0.9% sodium chloride injection without preservatives); after gentle mixing, withdraw 2 mL of drug solution into each of three 10-mL syringes and add 8 mL of same diluent to each syringe.1 Each syringe contains approximately 67 units of drug (for total dose of 200 units).1 Use immediately after reconstitution in syringe; dispose of any unused diluent.1

Alternatively, for detrusor overactivity associated with a neurologic condition, reconstitute two 100-unit vials with 6 mL of diluent (0.9% sodium chloride injection without preservatives) per vial; after gentle mixing, withdraw 4 mL of drug solution from each vial into each of two 10-mL syringes, then withdraw remaining 2 mL of drug solution from each vial into a third 10-mL syringe (for total of 4 mL in each syringe).1 Add 6 mL of same diluent to each syringe.1 Each syringe contains approximately 67 units of drug (for total dose of 200 units).1 Use immediately after reconstitution in syringe; dispose of any unused diluent.1

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

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

Record date and time of reconstitution on drug vial.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;138 296 298 323 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

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

IM Injection Techniques/Precautions (General)

Targeting injection to the appropriate muscle(s) may be facilitated by active 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).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.120 140 143 147 296 298

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

Injection Techniques/Precautions (Overactive Bladder or Detrusor Overactivity Associated with a Neurologic Condition)

Manufacturer recommends administration into the detrusor muscle of the bladder via a flexible or rigid cystoscope.1 Also has been administered by transperineal injection guided by EMG or by transrectal ultrasound.1 199 201 202 203 206 296 298

Patients must not have a urinary tract infection at time of treatment.1 Administer antibiotic prophylaxis 1–3 days before treatment, on day of treatment, and for 1–3 days after treatment; avoid aminoglycosides.1 448 (See Specific Drugs under Interactions.)

Discontinue antiplatelet therapy ≥3 days prior to procedure; manage patients receiving anticoagulant therapy appropriately to reduce bleeding risk.1

May use an intravesical instillation of diluted local anesthetic with or without sedation prior to injection of onabotulinumtoxinA.1 If local anesthetic instillation used, drain anesthetic from bladder and irrigate with enough sterile 0.9% sodium chloride injection prior to drug injection to allow adequate visualization for injection while avoiding overdistention.1

Prime needle with approximately 1 mL (depending on the needle length) of reconstituted onabotulinumtoxinA to remove air prior to injection.1 Inject onabotulinumtoxinA into detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone.1

For overactive bladder, insert needle approximately 2 mm into detrusor muscle and administer dose as 20 injections of 0.5 mL each given approximately 1 cm apart.1 As final injection, inject approximately 1 mL of sterile 0.9% sodium chloride solution so remaining onabotulinumtoxinA in needle is delivered to bladder.1 After drug administration, observe patient for at least 30 minutes and until spontaneous void has occurred.1

For detrusor overactivity associated with a neurologic condition, insert needle approximately 2 mm into detrusor muscle and administer dose as 30 injections of 1 mL each given approximately 1 cm apart.1 As final injection, inject approximately 1 mL of sterile 0.9% sodium chloride injection so remaining onabotulinumtoxinA in needle is delivered to bladder.1 After drug administration, drain 0.9% sodium chloride injection used for bladder wall visualization and observe patient for at least 30 minutes.1

Injection Techniques/Precautions (Anal Sphincter Disorders)

Inject both lateral and distal to the fissure; local anesthesia before injection generally not necessary.217 296 298 315

Inject internal or external anal sphincter; optimal injection site not determined.217 Some clinicians prefer injection of the internal sphincter because spasm of this muscle contributes to chronic anal fissure and because of its ease of palpation and injection.316

Other clinicians prefer injection of the external sphincter because of concerns that inaccurate localization of the injection in the internal sphincter may result in fecal and/or flatulence incontinence attributable to drug diffusion into the intrasphincteric space.217 296 298

Avoid deep injections that may enter the puborectalis muscle; such injections may be associated with a high risk of incontinence.217 296 298

Injection Techniques/Precautions (Chronic Migraine Prophylaxis)

Divide injections among 7 specific head/neck muscle areas; consult manufacturer's labeling or specialized references for details on recommended injection sites.1 Administer as 0.1-mL injections in each site using a sterile 30-gauge, 0.5-inch needle; a 1-inch needle may be needed in the neck region for patients with thick neck muscles.1 Inject the procerus muscle at one site (midline); inject all other muscles bilaterally, with half of the injections administered on the left and half on the right side of the head and neck.1

Injection Techniques/Precautions (Upper Limb Spasticity)

Inject superficial muscles using an appropriately sized needle (e.g., 25- to 30-gauge); may use a longer 22-gauge needle for deeper musculature.1

Manufacturer recommends localization of involved muscles with EMG guidance or nerve stimulation techniques.1

Injection Techniques/Precautions (Cervical Dystonia)

Manufacturer states that clinicians administering onabotulinumtoxinA must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any anatomic alterations due to prior surgical procedures.1

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 56 65

Injection Techniques/Precautions (Spasmodic Dysphonia [Laryngeal Dystonia])

For spasmodic dysphonia involving the adductor muscles, inject into thyroarytenoid vocalis complex via cricothyroid cartilage with EMG guidance;9 35 37 65 117 296 298 308 317 use hollow, Teflon-coated needle.9 35 37 116 117 308 Also has been given by indirect laryngeal endoscopy (without EMG guidance) in some (e.g., postsurgical) patients.35 117 296 298 308 While injections have been given into both vocal cords,9 35 37 308 some clinicians prefer unilateral injections to minimize adverse effects;6 65 205 296 298 optimal method controversial.296

For spasmodic dysphonia involving the abductor muscles, inject into posterior cricothyroid muscle using EMG guidance.37 116 117 308 Injection of abductor muscles technically complicated33 35 37 117 308 and has potential to cause serious adverse effects (e.g., bilateral abductor paralysis with airway obstruction).33 116 117 308

Injection Techniques/Precautions (Oromandibular Dystonia)

Use EMG and/or palpation to select for injection the muscles responsible for the particular type of oromandibular dysfunction (e.g., jaw closing, jaw opening).120 296 298 308

Injection Techniques/Precautions (Blepharospasm and Associated Facial Nerve Disorders)

For the management of blepharospasm, inject initial dose 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 65

Reduce or prevent ecchymosis of adnexa by using very fine-gauge needles (e.g., 27- to 32-gauge), limiting repeat use of needles to ≤4 times, appropriately discontinuing drugs and supplements that affect platelet function (e.g., aspirin, vitamin E) prior to injection, and applying pressure and/or ice to the injection site immediately postinjection.1 296

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

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

Individualize treatment of hemifacial spasm, which sometimes occurs in conjunction with blepharospasm.3 9 20 29 33 34 35 37 65 100 106 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.37

Injection Techniques/Precautions (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 While some clinicians have suggested that the drug can be injected directly by clinicians with sufficient experiential knowledge of orbital anatomy,296 the manufacturer states that injection without EMG guidance or surgical exposure should not be attempted.1

Injection Techniques/Precautions (Facial Cosmesis)

Clinicians using a botulinum toxin for facial cosmesis should understand the relevant neuromuscular and/or orbital anatomy of the therapeutic area and the effects of any changes to the anatomy from prior surgical procedures.5 143

EMG-guided injection has been recommended to more accurately target certain facial muscle(s) (e.g., platysma, in the lower face, or where there is facial asymmetry), but some clinicians suggest that EMG may be of limited benefit when muscles to be injected are difficult to identify by palpation and/or visualization.143 147 296 298

When used for facial cosmesis, inject affected facial muscles with a 30-gauge needle and tuberculin syringe; ensure that the correct injection volume and concentration are administered.5

Minimize the risk of ptosis by avoiding injections near the levator palpebrae superioris, especially in individuals with larger brow-depressor complexes.5 137 140 141 142 296 298

Injection sites in the lateral corrugator muscle should be ≥1 cm above the bony supraorbital ridge5 37 and should not be injected <1 cm above the central eyebrow.5

Injections in the forehead area should always be made above the lowest fold produced when the individual is asked to elevate their forehead, or ≥2 cm above the brow.143

In older individuals, do not inject the lower portion of the brow (this muscle is used to raise the eyebrows in order to see).143

Do not treat entire forehead and glabellar lines during a single session; high risk of ptosis.143 157 296 298

When injections in the midpupillary line are made in individuals with large brow-depressor complexes, inject 1 cm above the bony superior orbital margin; dose should not exceed 5 units.141 142

Avoid eyelid ptosis by asking the individual to remain upright (e.g., avoid naps in the reclining position) for 4 hours following treatment, avoid rubbing or massaging the treated area for 4 hours (to prevent excess diffusion and possible weakness of adjacent muscles), and frown and smile repeatedly for at least ≥1–4 hours143 296 298 immediately following treatment.60 66 140 141 143 296 298

Apply digital pressure at the border of the supraorbital ridge while injecting the corrugator muscle to minimize the potential for diffusion into the levator muscle and resultant weakening.143

When injection sites are marked (e.g., with a ball-point pen) to ensure optimal targeting,140 296 298 avoid injecting directly into the marked areas to prevent tattooing of the skin.298

Before injection, instruct the individual to accentuate specific facial lines to be treated by frowning (for glabellar lines), squinting (for lateral canthal wrinkles), or elevating the brow (for horizontal forehead lines).140

When treating lateral canthal wrinkles (“crow’s feet”), avoid injecting too close to the eyelids to avoid delayed eye closure, decreased blinking, excessive tearing, and lateral rectus muscle weakness.140 Manufacturer recommends administering the first injection approximately 1.5–2 cm temporal to the lateral canthus and just temporal to the orbital rim; consult manufacturer's labeling for recommended sites of injection if lateral canthal lines are above or below the lateral canthus or primarily below the lateral canthus.5 Some clinicians suggest injection 1 cm outside the bony lateral orbital margin or 1.5 cm lateral to the lateral canthus to minimize risk of transient strabismus or diplopia.141 296 Avoid making injections below the zygomaticus muscle to avoid ptosis of the upper lip.141 143

Inject as superficially as possible in a series of continuous blebs to avoid ecchymoses in the periorbital area, with each injection at the advancing border of the previous one to avoid hitting blood vessels.143 296

Vary volume and concentration of injections according to the area being treated (e.g., lateral canthal wrinkles, glabellar lines, platysma).121 Low-volume, concentrated solutions are recommended to paralyze specific facial muscles; larger volumes of less-concentrated solutions may be used to smooth lateral canthal wrinkles (“crow’s feet”) or the brow area.121 296 298 However, larger, less-concentrated volumes of solution reported to result in unacceptably short durations of improvement and larger areas of undesired paralysis.121 141 157 296 298

Some clinicians suggest that toxin injected in the procerus muscle be massaged toward the depressor supercilii muscle following injection (i.e., to decrease activity of the depressor muscle and its contribution to facial lines).157 296 298

Effects appear to last longer with repeated treatments in some individuals.140 143 144 146 296 Attributed to behavioral modification (i.e., avoiding certain facial movements that produce excessive pleating of facial skin)140 143 or to some degree of fibrosis or atrophy of injected muscles.29 146 150 No histologic evidence of permanent degeneration or atrophy to date.143 149 296 298

As the individual squints in an exaggerated manner, administer the toxin at several sites located 1 cm lateral to the bony rim or 1.5 cm lateral to the lateral canthus; inject at 1- to 1.5-cm intervals into the raised folds of skin in an arc from just beneath the lateral edge of the eyebrow down to the lateral infraorbital rim.66 68 140 296

Inject sites laterally in an arc away from the brow, with the most lateral injection placed vertically above the midpupil to retain some frontalis muscle function for facial expression.140 142 143 296 298

A second treatment session may be needed for optimal results if several rows of deep hyperfunctional forehead lines are present.140 296

Firmly massage sites laterally following injection.68 140 143 157 296 298

Intradermal Injection

Administer by intradermal injection for treatment of hyperhidrosis.1 44 60 138 143 268 274 296

Primary Axillary Hyperhidrosis

Use standard staining techniques (e.g., Minor’s iodine starch test) to identify axillary hyperhidrotic area for injection.1 44 60 138 143 268 274 296

Consult manufacturer’s labeling or specialized references for instructions on how to perform Minor’s iodine starch test.1

Make injections at a 45° angle to the skin surface and as superficially as possible to ensure intradermal administration, minimize leakage, and allow optimum diffusion into the eccrine gland.1 143 296

If injection sites are marked with ink, avoid direct injection into marked areas to prevent permanent tattooing of the skin.1

Careful compression of treated skin area suggested to promote drug penetration.160

The effects of the drug may involve a ring of up to approximately 2 cm in diameter.1 To minimize area of no effect, evenly space injections.1

Intraglandular Injection

Administer by injection directly into affected gland(s).268 274 320

Voiding Dysfunction Associated with Benign Prostatic Hyperplasia

Injections into the prostate gland may be administered using transrectal ultrasonography (TRUS) guidance.268 274

Dosage

All doses refer to units of Botox or Botox Cosmetic; these preparations have equivalent potency on a unit-for-unit basis.1 5

Botox and Botox Cosmetic formulations are identical; manufacturer states that these preparations may be used interchangeably provided the appropriate dilutions and administration techniques for a given indication are used.298 (See Reconstitution under Dosage and Administration.)

Units of biologic activity for different serotypes or formulations of botulinum toxin cannot be compared with or converted to units of other botulinum toxins.1 2 5 Data on several different serotypes (e.g., botulinum toxin types A, B, C, F) and/or formulations of botulinum toxin have been reported;1 2 5 assay methods used to determine potency of these various toxins are specific to each individual manufacturer and/or formulation.1 2 5

Carefully individualize onabotulinumtoxinA dosage according to patient response and particular condition being treated.1 120 Use lowest recommended dose when initiating treatment.1

Pediatric Patients

Blepharospasm
Pediatric Patients ≥12 Years of Age
IM

Initially, 1.25–2.5 units at each site injected with a sterile, 27- or 30-gauge needle without EMG guidance into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid.1 65

This dose represents an injection volume of 0.05–0.1 mL at each injection site using a solution containing 25 units/mL.1 65

Dose during subsequent treatment sessions may be increased by up to twofold if initial response is insufficient (e.g., the duration of effect is <2 months);1 however, little additional benefit from doses >5 units per site.1

Tolerance may occur, especially if injections for blepharospasm are administered at <3-month intervals.1

Alternatively, some clinicians recommend a dose of 15–20 units per eye divided among injection sites with a total cumulative dosage <100 units during any 30-day treatment period.296

Manufacturer states that the total cumulative dosage should not exceed 200 units during any 30-day treatment period;1 some clinicians report routine use of considerably lower cumulative dosages (e.g., <100 units).296

Initial effect generally occurs within 3 days of injection (range: 2–7 days),137 and maximal benefit occurs 1–2 weeks after treatment.1 The duration of effect is approximately 3 months and is rarely permanent.1

Strabismus
Pediatric Patients ≥12 Years of Age
IM

Several minutes prior to injection, instill several drops of a topical ophthalmic anesthetic (e.g., 0.5% proparacaine hydrochloride) and an ocular decongestant (e.g., 2.5% phenylephrine hydrochloride) into the affected eye(s).1 296

Strabismus involving vertical extraocular muscles or horizontal strabismus of <20 prism diopters: 1.25–2.5 units initially injected into any one muscle.1

Horizontal strabismus of 20–50 prism diopters: 2.5–5 units initially into any one muscle; some clinicians suggest dividing this dose between the muscles of both affected eyes.1 296

Persistent sixth-nerve palsy lasting ≥1 month: 1.25–2.5 units initially injected into the medial rectus muscle.1

Use lower dose in each dose range for treatment of small deviations and larger doses only for large deviations.1

The volume injected for the treatment of strabismus should be 0.05–0.15 mL per muscle.1

Paralysis of injected muscles generally begins 1–2 days after injection and increases in intensity during the first week after injection.1 Paralysis generally lasts 2–6 weeks and gradually resolves over a similar time period.1

Overcorrections exceeding 6 months in duration have been reported rarely.1

Reexamine patients 7–14 days after each injection to evaluate response and to determine need for additional or larger doses.1 296

Subsequent injections will be required in approximately 50% of patients because of inadequate initial response, mechanical factors (e.g., large deviations or restrictions), and/or lack of binocular motor fusion to stabilize the alignment.1

If subsequent injections are required, administer a dose comparable to the initial dose in patients who experience adequate paralysis of the target muscle.1 For patients experiencing incomplete paralysis of the target muscle after the initial injection, increase dose up to twofold compared with the previously administered dose.1 296

Do not administer subsequent injections until the effects of the previous dose have dissipated as evidenced by substantial return of function in the injected and adjacent muscles.1 296

Maximum dose as a single injection into any one muscle is 25 units.1

Spasticity Associated with Cerebral Palsy
IM

Optimal treatment regimen, including optimal dose, dilution, and number of injection sites, has not been determined.229 296

Base dose on the size of muscles to be injected, number of muscles to be injected concurrently, and patient's body weight; other considerations include general health of the patient, target muscle strength, antagonist muscle strength, potential number of neuromuscular junctions in target muscle, degree of joint function and/or deformity, patient age, concern for excessive muscular weakness, anticipated duration of therapy, and previous response to therapy.229 296 315

Based on clinical experience, 1–6 units/kg per muscle has been recommended.229 232 269 270 271 298 315

Maximum dose per treatment session: 3–6 units/kg for large muscles, 1–2 units/kg for small muscles; maximum dose of 50 units per injection site.229 232 269 270 271 298 315

Maximum recommended total dose administered during a single treatment session should not exceed 12 units/kg or 400 units, whichever is less.315 Alternatively, maximum dose of 6 units/kg per treatment session suggested by some clinicians.298

Largest total dose injected at one treatment session reportedly 29 units/kg, divided among several large muscles of the lower extremities.229 272

Maximum dose of 10–12 units/kg per treatment session has been recommended when only 1 or 2 muscles are injected.229 271

Onset of muscle weakness following injection generally occurs within 2–3 days and reaches a peak after about 3–4 weeks; reassess patients 6 weeks after initial treatment session.219 315 Muscle weakness generally wears off after 3 months; functional improvement may last considerably longer.230 234 280 315

Adults

Overactive Bladder
IM

100 units per treatment, given as 20 separate injections of 0.5 mL each into the detrusor muscle (avoiding the trigone) via a flexible or rigid cystoscope.1

Consider reinjection when clinical effect of previous bladder injection has diminished, but no sooner than 12 weeks after previous injection.1 444 Median time until patients qualified for second treatment in clinical trials was 169 days (approximately 24 weeks).1

Detrusor Overactivity Associated with a Neurologic Condition
IM

200 units per treatment, given as 30 separate injections of approximately 6.7 units each into the detrusor muscle (avoiding the trigone) via a flexible or rigid cystoscope.1 447 454

Onset of improvement in urinary symptoms reportedly has occurred about 7–15 days following injection; duration of benefit appears dose related.202 206 298 318

Consider reinjection when clinical effect of the previous bladder injection has diminished, but no sooner than 12 weeks after previous injection.1 Median time until patients qualified for second treatment in clinical trials was 42–48 weeks.1 447 454

Anal Sphincter Disorders
IM

Chronic anal fissure: Initially, 5–20 units.131 217 296 298 315 Healing rates may be higher with higher doses.131 315

May repeat injections using initial or higher dose in patients who fail to heal or have relapses.132

Pain reduction reported within 2 days; reduced sphincter tone maintained for ≥4 weeks.217

Achalasia
IM

80–100 units injected into the lower esophageal sphincter (LES) during endoscopy, generally as 4 injections of 20 units each (20 units/mL) into various quadrants of LES.184 187 189 190 191 192 316

Chronic Migraine Prophylaxis
IM

155 units per treatment session, given as multiple injections divided among 7 head and neck muscles.1 327 (See Table 3.)

5 Units (0.1 mL) of onabotulinumtoxinA per IM injection site.

Dose distributed bilaterally.

Table 3: Dosing of OnabotulinumtoxinA (Botox) for Chronic Migraine

Head/Neck Area

Recommended Dose (No. of Injection Sites)

Frontalis

20 units (4 sites)

Corrugator

10 units (2 sites)

Procerus

5 units (1 site)

Occipitalis

30 units (6 sites)

Temporalis

40 units (8 sites)

Trapezius

30 units (6 sites)

Cervical paraspinal muscle group

20 units (4 sites)

Total Dose per Treatment Session:

155 units (31 sites)

Maximum headache relief may not occur until several weeks after injections.327 328 Manufacturer-recommended retreatment schedule is every 12 weeks.1

Some clinicians suggest evaluating patients 4–6 weeks after injection and generally repeating injections after 3–4 months; duration of response varies.327 328

Upper Limb Spasticity
IM

Manufacturer-recommended doses and muscles to be injected shown in Table 4.1

Table 4: Dosing of OnabotulinumtoxinA for Upper Limb Spasticity

Muscle

Recommended Dose (No. of Injection Sites)

Biceps brachii

100–200 units (4 sites)

Flexor carpi radialis

12.5–50 units (1 site)

Flexor carpi ulnaris

12.5–50 units (1 site)

Flexor digitorum profundus

30–50 units (1 site)

Flexor digitorum sublimis

30–50 units (1 site)

Individualize doses in initial and sequential treatment sessions based on the size, number, and location of muscles involved; severity of spasticity; presence of local muscle weakness; patient response to previous treatment; and history of adverse events with onabotulinumtoxinA.1

Use of EMG to guide injections recommended.1

Use lowest recommended starting dose, generally ≤50 units per site.1 Doses of 75–360 units divided among selected muscles at a given treatment session used in clinical trials.1

May repeat treatment when effect of previous injection has diminished, but generally no sooner than 12 weeks after previous injection.1 Degree and pattern of muscle spasticity at time of reinjection may require alterations in dose and muscles to be injected.1

Spasticity Associated with Cerebral Palsy
IM

Optimal treatment regimen, including optimal dose, dilution, and number of injection sites, has not been determined.229 296

Base dose on the size of muscles to be injected, number of muscles to be injected concurrently, and patient's body weight; other considerations include general health of the patient, target muscle strength, antagonist muscle strength, potential number of neuromuscular junctions in target muscle, degree of joint function and/or deformity, patient age, concern for excessive muscular weakness, anticipated duration of therapy, and previous response to therapy.229 296 315

Based on clinical experience, 1–6 units/kg per muscle has been recommended.229 232 269 270 271 298 315

Maximum dose per treatment session: 3–6 units/kg for large muscles, 1–2 units/kg for small muscles; maximum dose of 50 units per injection site.229 232 269 270 271 298 315

Maximum recommended total dose administered during a single treatment session should not exceed 12 units/kg or 400 units, whichever is less.315 Alternatively, maximum dose of 6 units/kg per treatment session suggested by some clinicians.298

Largest total dose injected at one treatment session reportedly 29 units/kg, divided among several large muscles of the lower extremities.229 272

Maximum dose of 10–12 units/kg per treatment session has been recommended when only 1 or 2 muscles are injected.229 271

Onset of muscle weakness following injection generally occurs within 2–3 days and reaches a peak after about 3–4 weeks; reassess patients 6 weeks after initial treatment session.219 315 Muscle weakness generally wears off after 3 months; functional improvement may last considerably longer.230 234 280 315

Cervical Dystonia
IM

Titrate dose in initial and subsequent treatment sessions to patient’s previous response to the drug, history of adverse reactions, severity of dystonia based on head and neck position, localization of pain, muscular hypertrophy, mass of target muscles, and their proximity to critical toxin-sensitive anatomic structures (e.g., larynx, pharynx).1 56 296 298

Initial dose for toxin-naive patients should be relatively small; adjust subsequent doses based on patient response and tolerance.1 10 11 65 298

Manufacturer states that generally ≤50 units should be administered per injection site.1

May reduce risk of dysphagia by using multiple rather than a single injection site and by limiting total dose in sternocleidomastoid muscles to ≤100 units.1 65 240 (See Dysphagia and Breathing Difficulties under Cautions.)

Mean dose following adjustment according to initial response and tolerance in a clinical trial was 236 units (25th to 75th percentile range: 198–300 units) divided among affected muscles.1

Alternatively, some clinicians have suggested a dose of 25–75 units per affected muscle.37 65

Onset of clinical improvement generally observed within 2 weeks of treatment and maximum benefit occurs approximately 6 weeks after treatment; most patients return to their pretreatment status after 3 months.1

Spasmodic Dysphonia (Laryngeal Dystonia)
Adductor Muscle Dysphonia
IM

Some clinicians have used small doses (e.g., 0.031–4 units) injected into both vocal cords to produce mild bilateral paralysis,308 while others have injected larger doses (5–30 units) into one vocalis complex to produce unilateral paralysis.9 35 37 Dosage can be adjusted based on the severity of glottal spasms and the response to previous injections.35

Improvement in voice fluency generally occurs within 24–72 hours and lasts for up to 3–6 months.3 90 116 308

Abductor Muscle Dysphonia
IM

Total doses of 1.25–5 units have been injected into the posterior cricothyroid muscle.37 116 117 308

Alternatively, some experts use total doses averaging <1 unit (range: 0.1–10 units) per vocal cord.296 298

Some clinicians recommend injection of only one side of the abductor muscle during any given treatment session117 308 with an additional dose on the same side 2 weeks later if abduction is still present, or injection of the contralateral side if the initial injection produced paralysis of the abductor but did not result in adequate voice improvement.117 308

Oromandibular Dystonia
IM

Wide range of doses has been used.37 65 119 120 309

Low doses may be used initially to produce gradual muscle weakening, with dose titration on repeat injections according to response.119 309

Jaw-closing oromandibular dystonias: 25–50 units into each masseter muscle suggested; if satisfactory results are not obtained, 5–40 units also may be injected into each temporalis muscle.37 65 120 296 298 309

Primary Axillary Hyperhidrosis
Intradermal

Total dose of 50 units per axilla injected with a 30-gauge needle.1 Administer dose in aliquots of 0.1–0.2 mL in multiple (10–15), evenly spaced sites (to minimize the area of no effect) approximately 1–2 cm apart.1 138 143 296 298

Total doses of 50–60 units (e.g., 2.5–5 units/cm2 of skin area) injected among 10–20 sites in the hyperhidrotic area of each axilla also have been used.44 60 138 143

Unlike in other indications (e.g., cosmetic treatment of facial lines), the dose in hyperhidrosis is best determined by the surface area of involved skin rather than by muscle mass.138 143

Total doses as low as 30 units in each axilla have been used.44

Maximum total dose of 100 units per axilla in larger individuals recommended by some clinicians;138 143 doses of up to 200 units per axilla have been used in a limited number of patients to achieve a prolonged response (e.g., up to 19 months).159 170 296 298 314

Anhidrosis generally occurs within 24 hours, reaches a peak at 1 week, and lasts 4–12 months;143 157 296 duration of response appears to be dose related.159 May repeat injections when the clinical effect of previous dose has diminished.1

Blepharospasm and Associated Facial Nerve Disorders
Blepharospasm
IM

Initially, 1.25–2.5 units at each site injected with a sterile, 27- or 30-gauge needle without EMG guidance into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid.1 65

This dose represents an injection volume of 0.05–0.1 mL at each injection site using a solution containing 25 units/mL.1 65

Dose during subsequent treatment sessions may be increased by up to twofold if initial response is insufficient (e.g., the duration of effect is <2 months);1 however, little additional benefit from doses >5 units per site.1

Tolerance may occur, especially if injections for blepharospasm are administered at <3-month intervals.1

Alternatively, some clinicians recommend a dose of 15–20 units per eye divided among injection sites with a total cumulative dosage <100 units during any 30-day treatment period.296

Manufacturer states that the total cumulative dosage should not exceed 200 units during any 30-day treatment period;1 some clinicians report routine use of considerably lower cumulative dosages (e.g., <100 units).296

Initial effect generally occurs within 3 days of injection (range: 2–7 days),137 and maximal benefit occurs 1–2 weeks after treatment.1 The duration of effect is approximately 3 months and is rarely permanent.1

Hemifacial Spasm
IM

Initial dose: 12-25 units administered into the inferior and superior orbicularis oculi, buccolabial, and/or platysma muscles.3 9 20 29 33 34 35 37 65 100 106

Duration of response of hemifacial spasm may be somewhat longer compared with that in blepharospasm.3 20 24 90 98 99

Strabismus
IM

Several minutes prior to injections, instill several drops of a topical ophthalmic anesthetic (e.g., 0.5% proparacaine hydrochloride) and an ocular decongestant (e.g., 2.5% phenylephrine hydrochloride) in the affected eye(s).1 296

Strabismus involving vertical extraocular muscles or horizontal strabismus of <20 prism diopters: 1.25–2.5 units initially injected into any one muscle.1

Horizontal strabismus of 20–50 prism diopters: 2.5–5 units initially into any one muscle; some clinicians suggest dividing this dose between the muscles of both affected eyes.1 296

Persistent sixth-nerve palsy lasting ≥1 month: 1.25–2.5 units initially injected into the medial rectus muscle.1

Use lower dose in each dose range for treatment of small deviations and larger doses only for large deviations.1

The volume injected for the treatment of strabismus should be 0.05–0.15 mL per muscle.1

Paralysis of injected muscles generally begins 1–2 days after injection and increases in intensity during the first week after injection.1 Paralysis generally lasts 2–6 weeks and resolves gradually over a similar time period.1

Overcorrections exceeding 6 months in duration have been reported rarely.1

Reexamine patients 7–14 days after each injection to evaluate response and to determine need for additional or larger doses.1 296

Subsequent injections will be required in approximately 50% of patients because of inadequate initial response, mechanical factors (e.g., large deviations or restrictions), and/or lack of binocular motor fusion to stabilize the alignment.1

If subsequent injections are required, administer a dose comparable to the initial dose in patients who experience adequate paralysis of the target muscle.1 For patients experiencing incomplete paralysis of the target muscle after the initial injection, increase dose up to twofold compared with the previously administered dose.1 296

Do not administer subsequent injections until the effects of the previous dose have dissipated as evidenced by substantial return of function in the injected and adjacent muscles.1 296

Maximum dose as a single injection into any one muscle is 25 units.1

Cosmesis of Glabellar Facial (“Frown”) Lines
IM

Since the location, size, and use of the involved facial muscles vary markedly among individuals, dosage adjustment may be based on the effect of a given dose on facial line cosmesis determined by gross observation of the individual’s ability to activate the targeted superficial muscles 2–4 weeks after an injection.5 296

Manufacturer recommends total dose of 20 units per treatment session administered by injecting 4 units (0.1 mL of a solution containing 40 units/mL) into each of 5 sites: 2 injections in each corrugator muscle and one in the procerus muscle.5 64

A variety of other doses has been suggested.140 143 Initially, some clinicians suggest intentionally underdosing until the individual’s response to the drug is ascertained.149

Initial doses of 12.5–20 units per session or 2.5–5 units in each corrugator muscle and 2.5 units in the procerus muscle have been used.140 143

Some clinicians state that larger doses may be required in men because of greater forehead muscle mass or in women who have more horizontal brows, deeper frown lines, or larger and stronger forehead muscles.143

Initial injections generally induce chemical denervation of targeted muscles 24–48 hours after injection; 5 143 paralytic effect may continue to increase in intensity for as long as 1 week after injection,5 143 and sometimes may not become evident until up to 14 days following injection.143

Treatment sessions should be ≥3 months apart and lowest effective dose should be used.5 64 (See Immunogenicity under Cautions.)

Cosmetic effects generally last approximately 3–4 months,5 296 although durations of up to 6 months have been reported.64 143

Some clinicians repeat injections 2 weeks after initial treatment of hyperfunctional facial lines (e.g., glabellar region, forehead, lateral canthal wrinkles) if the individual is not pleased with the cosmetic results140 144 and suggest that the limitation on the injection interval is not crucial with the small doses (generally <100 units) used for most cosmetic indications.143 However, manufacturer states that safety and efficacy of dosing at intervals <3 months not clinically evaluated.5

Simultaneous treatment of lateral canthal and glabellar facial lines: Manufacturer recommends 24 units for lateral canthal lines and 20 units for glabellar lines (total dose of 44 units) per treatment session.5

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

Manufacturer-recommended dose: 24 units per treatment session, given as 4 units into each of 3 sites on each side (12 units per side).5

Some clinicians have used 6–18 units (e.g., 2.5–3 units per injection) for each side; higher doses necessary in some individuals.66 68 140 143 157 296 298 311

Alternatively, 8–10 units administered as 5 units in 2 sites on each side or as 8 units in 1 site on each side has been suggested.296

Simultaneous treatment of lateral canthal and glabellar facial lines: Manufacturer recommends 24 units for lateral canthal lines and 20 units for glabellar lines (total dose of 44 units) per treatment session.5

Cosmesis of Horizontal Forehead Lines
IM

Some clinicians recommend total doses of 5–35 units for the forehead area, administered as multiple injections of 2.5 or 5 units each about 1.5–2 cm apart in an evenly distributed grid pattern followed by firm massage laterally.68 140 143 157 296 298

Alternatively, administer 6 injections of 3 units each about 1.5–2 cm apart across the forehead.140 143

Alternatively, higher total doses of 25–60 units have been suggested.68 296

A second treatment session may be needed for optimal results if several rows of deep hyperfunctional forehead lines are present.140 296

Effects generally apparent within 3 days after injection; up to 14 days may be required for results to become evident.68 143

Maximal effects observed in 1–2 weeks and generally last 3–6 months; 68 prolonged responses reported in some patients, allowing yearly reinjection intervals.151

Prescribing Limits

Pediatric Patients

Blepharospasm
Pediatric Patients ≥12 Years of Age
IM

Total cumulative dosage should not exceed 200 units during any 30-day treatment period.1

Doses >5 units per site provide little added benefit.1 Tolerance to therapy increased if injections are administered at <3-month intervals.1

Strabismus
Pediatric Patients ≥12 Years of Age
IM

Maximum dose 25 units as a single injection into any one muscle.1

Spasticity Associated with Cerebral Palsy
IM

Suggested maximum recommended total dose administered during a single treatment session should not exceed 12 units/kg or 400 units, whichever is less.315

Alternatively, maximum dose of 6 units/kg per treatment session suggested by some clinicians.298

Largest total dose injected at one treatment session reportedly was 29 units/kg, divided among several large muscles of the lower extremities.229 272

Maximum dose of 10–12 units/kg per treatment session has been recommended when only 1 or 2 muscles are injected.229 271

Adults

Per manufacturer, maximum cumulative dose for one or more uses should not exceed 360 units in a 3-month period.1 5

Overactive Bladder
IM

Maximum recommended dose is 100 units per treatment.1

Detrusor Overactivity Associated with a Neurologic Condition
IM

Do not exceed 200 units per treatment.1

Upper Limb Spasticity
IM

In general, do not exceed 50 units per injection site.1

Spasticity Associated with Cerebral Palsy
IM

Suggested maximum recommended total dose administered during a single treatment session should not exceed 12 units/kg or 400 units, whichever is less.315

Alternatively, maximum dose of 6 units/kg per treatment session suggested by some clinicians.298

Largest total dose injected at one treatment session reportedly was 29 units/kg, divided among several large muscles of the lower extremities.229 272

Maximum dose of 10–12 units/kg per treatment session has been recommended when only 1 or 2 muscles are injected.229 271

Cervical Dystonia
IM

Decrease risk of dysphagia by using multiple injection sites rather than a single site and by limiting the total dose injected into the sternocleidomastoid muscles to ≤100 units.1 57 65 240 (See Dysphagia and Breathing Difficulties under Cautions.)

Some clinicians suggest total dose per treatment session should not exceed 200 units; however, doses as high as 300–400 units per treatment session reported.65 296 298

Primary Axillary Hyperhidrosis
IM

Maximum total dose: 100 units per axilla in larger individuals recommended by some clinicians.138 143 Doses of up to 200 units per axilla have been used.159 170 296 298 314

Blepharospasm
IM

Total cumulative dosage should not exceed 200 units during any 30-day treatment period.1

Doses exceeding 5 units per site provide little added benefit.1 Tolerance to therapy increased if injections are administered at <3-month intervals.1

Strabismus
IM

Maximum single injection dose: 25 units into any one muscle.1

Cosmesis of Glabellar Facial Lines
IM

When injections in the midpupillary line are made in individuals with large brow-depressor complexes, inject 1 cm above the bony superior orbital margin; dose should not exceed 5 units.141 142

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1 5 296 298

Cautions for Botox

Contraindications

  • Hypersensitivity to any botulinum toxin preparation or any ingredient in their formulations.1 5

  • Infection at the proposed injection site(s).1 5 259 296

  • Intradetrusor injection in patients with overactive bladder or detrusor overactivity associated with a neurologic condition who have a urinary tract infection.1

  • Intradetrusor injection in patients with urinary retention or postvoid residual volume >200 mL who are not routinely performing clean intermittent self-catheterization.1

Warnings/Precautions

Warnings

Distant Spread of Toxin Effects

Potential for systemic spread of toxin effects beyond local sites of injection; manifested as unintended muscular weakness in noncontiguous anatomic structures and other potentially life-threatening adverse effects.1 5 9 10 11 18 31 32 33 34 35 37 65 142 371 372 373 379 380 381 382 383 (See Boxed Warning.)

Monitor patients for possible systemic effects (e.g., dysphagia, dysphonia, respiratory compromise, generalized weakness) following administration.371

Weakness of adjacent muscles commonly reported with botulinum toxin administration.1 5 9 10 11 31 32 33 34 35 37 65 142 Such weakness reported within first week of treatment; generally transient but may persist for several months.5 35

Adverse effects consistent with mechanism of botulinum toxin action (e.g., asthenia/unexpected loss of strength or generalized muscle weakness, blurred vision, breathing difficulties/respiratory impairment, diplopia, dysarthria, dysphagia, dysphonia, hoarseness, ptosis, urinary incontinence) reported1 5 26 32 33 38 52 59 60 65 70 142 371 372 373 377 378 379 380 381 382 403 in both children and adults receiving botulinum toxin for a variety of conditions in a wide range of dosages.1 5 371 372 373 381 382 403

In some cases, swallowing and breathing difficulties have required hospitalization, mechanical ventilation, or feeding tubes and/or resulted in death.1 381 (See Dysphagia and Breathing Difficulties under Cautions.)

Risk of toxin spread probably highest in children treated for spasticity (currently not an FDA-labeled use for onabotulinumtoxinA).1 381 383 (See Pediatric Use under Cautions.)

To date, manufacturer states that no definitive serious adverse effects related to distant spread of toxin reported in patients receiving onabotulinumtoxinA for dermatologic use (Botox Cosmetic) at FDA-labeled doses of 20 units (for glabellar facial lines), 24 units (for lateral canthal lines), 44 units (for both lateral canthal and glabellar lines), or 100 units (for severe primary axillary hyperhidrosis).1 5

No definitive serious adverse effects related to distant spread of toxin reported with use of onabotulinumtoxinA (Botox) for blepharospasm or strabismus at recommended dose (≤30 units) or chronic migraine at FDA-labeled doses.1 5

Severe generalized muscle weakness reported rarely in patients receiving onabotulinumtoxinA injections into the detrusor muscle of the bladder for treatment of detrusor overactivity associated with a neurologic condition.1 260

Serious adverse events, including fatalities, reported in patients receiving onabotulinumtoxinA injections directly into salivary glands, the orolingualpharyngeal region, esophagus, or stomach.1 5

Sensitivity Reactions

Serious and/or immediate hypersensitivity reactions (e.g., anaphylaxis, urticaria, soft tissue edema, dyspnea) reported rarely.1 5 At least one fatal case of anaphylaxis reported; causal relationship not determined since lidocaine was used as diluent.1 5

If anaphylaxis or other severe allergic reaction occurs, discontinue onabotulinumtoxinA immediately and institute appropriate therapy (e.g., epinephrine) as indicated.1 5

Other Warnings and Precautions

Lack of Interchangeability Among Botulinum Toxin Preparations

Potency (“units”) of various botulinum toxin preparations are determined using specific assay methods, and are not interchangeable from one botulinum toxin preparation to another.1 381 Units of biologic activity for different serotypes or formulations of botulinum toxin cannot be compared with or converted to units of other botulinum toxins.1 5 381

Injection In or Near Vulnerable Anatomic Structures

Exercise care when injecting near vulnerable adjacent structures, in patients who have inflammation at the proposed site(s) of injection, and in those with excessive weakness and/or atrophy of the target muscle(s).1 5 33 37 298

Serious adverse events, including death, reported in patients receiving injections of the drug directly into salivary glands, the orolingual/pharyngeal region, esophagus, and stomach; some patients had preexisting dysphagia or substantial debility.1

Manufacturer states that safety and efficacy for uses pertaining to these injection sites have not been established.1

Exercise caution when injecting onabotulinumtoxinA near the lung, particularly the apices.1

Cardiovascular Effects

Use caution in patients with preexisting cardiovascular disease.1 5 Arrhythmia and MI, sometimes fatal, reported; some patients had cardiovascular risk factors.1 5

Preexisting Neuromuscular Disorders

Increased risk of serious adverse systemic effects (e.g., severe dysphagia, muscle weakness, respiratory compromise) with recommended doses in patients with neuromuscular disorders (e.g., peripheral motor neuropathic diseases [e.g., amyotrophic lateral sclerosis, motor neuropathy] or neuromuscular junction disorders [e.g., myasthenia gravis, Lambert-Eaton syndrome]); exercise caution in such patients.1 5 18 29 37 57 140 141 219 259 371 375 376 May be related to use of higher dosages in such patients.376

Rarely, extreme sensitivity to systemic effects of usual doses reported in patients with known or unrecognized neuromuscular disorders; some patients experienced several months of severe dysphagia and required a gastrostomy or nasogastric tube.1 5 9 57 69

Serious systemic effects related to distant spread of botulinum toxin reported more often and with greater severity in children with cerebral palsy.1 5 371 372 373 (See Pediatric Use under Cautions.) Some clinicians consider excessive muscle weakness in agonist or antagonist muscles a relative contraindication to treatment in patients with cerebral palsy.228

Dysphagia and Breathing Difficulties

Dysphagia is most common serious adverse effect reported in patients with cervical dystonia;1 5 11 14 35 53 57 65 69 also reported in patients receiving a type A botulinum toxin for other conditions (e.g., torticollis, muscle spasticity associated with cerebral palsy).1 5 371 375 376 Results from diffusion of the toxin to tissues (e.g., posterior pharyngeal muscles) outside the injected muscles.1 5 29 33 57 60 65 371

Rarely, fatal aspiration pneumonia or other serious debilities may develop subsequently.1 5 9 53 64 68 376

Occurs most frequently following injection of one or both sternocleidomastoid or scalenus muscles;1 5 9 18 35 37 57 65 risk increased in patients with cervical dystonia and smaller neck muscle mass (e.g., female) receiving bilateral injections and/or relatively high doses into the sternocleidomastoid muscle.1 5 9 35 57 86 Also increased risk in cervical dystonia patients with subclinical dysphagia.1 296 Injections into the levator scapulae associated with an increased risk of dysphagia and upper respiratory infection.1 5

Use lowest effective dose in high-risk muscles.1 5 65 296

Most cases are mild or moderate in severity,1 9 10 but some cases have required placement of gastric feeding tubes.1 5 9 371 410 Immediate medical attention may be required if patients develop problems with swallowing, speech, or respiratory disorders.1 5

Reduce risk by decreasing dose or volume of injection (e.g., using multiple small injections) or by injecting ≥2 cm above belly of contralateral sternocleidomastoid muscle.1 5 53 296 298

Pulmonary Effects

Closely monitor patients with upper limb spasticity or detrusor overactivity associated with a neurologic condition who have compromised respiratory status.1 Increased incidence of reduced forced vital capacity (FVC) reported in such patients.1

Use in Overactive Bladder

Increased incidence of urinary tract infection (UTI) in patients treated for overactive bladder.1 Clinical trials excluded patients with >2 UTIs in previous 6 months and those taking antibiotics routinely for recurrent UTIs.1

Use onabotulinumtoxinA for the management of overactive bladder in such patients and in patients with multiple recurrent UTIs during treatment only when benefit is likely to outweigh potential risk.1

Due to risk of urinary retention, use onabotulinumtoxinA only in patients willing and able to initiate catheterization posttreatment for urinary retention if required.1 (See Contraindications.)

In patients not catheterizing, assess postvoid residual urine volume within 2 weeks after treatment and periodically as appropriate for up to 12 weeks, particularly in patients with multiple sclerosis or diabetes mellitus.1 444 Depending on patient's symptoms, initiate catheterization if postvoid residual urine volume exceeds 200 mL; continue catheterization until postvoid residual urine volume <200 mL.1 Instruct patients to contact clinician if voiding becomes difficult since catheterization may be required.1

Use in Detrusor Overactivity Associated with a Neurologic Condition

Autonomic dysreflexia due to intradetrusor injection could occur in patients treated for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy.1

Due to risk of urinary retention, use onabotulinumtoxinA only in patients willing and able to initiate catheterization posttreatment for urinary retention if required.1 (See Contraindications.)

In patients not catheterizing, assess postvoid residual urine volume within 2 weeks after treatment and periodically as appropriate for up to 12 weeks, particularly in patients with multiple sclerosis or diabetes mellitus.1 444 Depending on patient's symptoms, initiate catheterization if postvoid residual urine volume exceeds 200 mL; continue catheterization until postvoid residual urine volume <200 mL.1 Instruct patients to contact clinician if voiding becomes difficult since catheterization may be required.1

Use in Upper Limb Spasticity

Increased incidence of bronchitis and upper respiratory infection reported in patients treated for upper limb spasticity.1

Use in Spasmodic Dysphonia (Laryngeal Dystonia)

Some clinicians suggest limiting use to clinicians experienced in treatment of diseases of the larynx;29 56 consider management under the care of a team composed of a neurologist, otolaryngologist, and speech pathologist.33 35 65

With laryngeal injections, some experts recommend ready availability of equipment to establish an airway.56 65

Injection into laryngeal area just prior to surgery not recommended because weakness of vocalis muscles may create postoperative airway vulnerability.117 296

Use in Oromandibular Dystonias

Some clinicians suggest considering a treatment team composed of a neurologist, otolaryngologist, and speech pathologist and a clinician experienced in regional EMG techniques.33 56

Use in Hyperhidrosis

Evaluate for potential causes of secondary hyperhidrosis (e.g., hyperthyroidism) to avoid possibility of symptomatic treatment without diagnosis and/or treatment of the underlying disease.1 237

Manufacturer states that safety and efficacy for hyperhidrosis in areas other than the axillae not established;1 237 hand muscle weakness or blepharoptosis may occur in patients treated for palmar or facial hyperhidrosis, respectively.1

Use in Blepharospasm

Corneal exposure, persistent epithelial defect, and corneal ulceration reported in patients receiving injections in the orbicularis muscle, especially those with facial nerve disorders and reduced blink response.1 296

Carefully evaluate for corneal sensation, especially in those who had prior surgical intervention.1 5 To decrease the risk of ectropion, avoid injection of lower lid area.1 5

Aggressively manage any epithelial defect that occurs with protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or by other clinically appropriate methods.1 5

Use in Strabismus

Retrobulbar hemorrhage due to needle penetration of the orbit and resultant compromised retinal circulation reported.1

Because of possibility of needle penetrations of the ocular globe, an ophthalmoscope and appropriate instruments should be readily available to decompress the orbit in the event of retrobulbar hemorrhage.1

Adverse effects such as spatial disorientation, double vision, and/or past pointing, if they occur, may be reduced by covering the affected eye.1 5

Cosmetic Use

Safety and efficacy not established in individuals with an inflammatory skin problem at the injection site,5 marked facial asymmetry,141 ptosis,5 excessive dermatochalasis,141 deep dermal scarring,141 thick sebaceous skin,141 or manually irreducible glabellar lines;5 use with caution in such individuals.5 141

Risk of Viral Disease Transmission

Formulation contains albumin derived from human blood.1 Remote risk of transmission of Creutzfeldt-Jakob disease (CJD) via albumin component; however, no cases identified to date.1 5

Injection-related Effects

Injection-related injury is possible, resulting in localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding or bruising.1 Needle-related pain and/or anxiety may result in vasovagal reactions (e.g., syncope, hypotension); may require treatment.1

Immunogenicity

Highly immunogenic (bacterial origin); possible formation of neutralizing antibodies resulting in reduced response to treatment.1 3 5 9 31 32 37 60 64 65 79 86 137 138 229 280 Antibodies to the toxin do not appear to induce hypersensitivity responses.60 143

Tolerance manifests as the absence of muscular paralysis, weakness, and/or atrophy after injection.14 29 31 32 42 86

Patients who develop tolerance to botulinum toxin type A may respond to botulinum toxin type B or other botulinum toxin serotypes (e.g., botulinum toxin type F);3 32 35 42 60 64 65 79 137 348 however, long-term response to other serotypes in such patients not fully elucidated.14 32 33

Administer lowest effective dose at the longest feasible treatment interval to minimize risk of antibody formation and tolerance.1 5 32 37 65 79 346 351 Manufacturer recommends ≥3-month interval between treatment sessions.5 32

Risk of neutralizing antibodies and tolerance may be increased by increased frequency of injection sessions, increased duration of therapy, higher injected doses (e.g., >300 units), inadvertent injection into the systemic circulation, and/or use of “booster” doses (i.e., additional injections of the drug 2 weeks after initial treatment into different muscles or at increased doses).1 5 9 14 29 32 37 42 65 79 137 138 143 296 298 346 348 349

Not known if patients with neutralizing antibodies to botulinum toxin type A are at increased risk of developing tolerance to botulinum toxin type B.345 351

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; abortion or fetal malformations observed in rabbits.1 5 296 298 If used during pregnancy or patient becomes pregnant while taking drug, apprise of potential hazard to fetus.1 5 296 298

At least one woman treated during pregnancy reportedly gave birth prematurely; causal relationship considered unlikely.140

Reporting Adverse Effects or Overdosage

In event of overdose or misinjection (i.e., wrong muscle), contact local or state health department to obtain botulism antitoxin through CDC Drug Service.1 5 If local or state health department not available within 30 minutes, contact CDC Emergency Operations Center directly at 770-488-7100.1 5 Antitoxin will not reverse botulinum toxin-induced muscle weakness already evident at the time of antitoxin administration but may stabilize the deficits.1 5

Information about antitoxin available at l.1 5

Specific Populations

Pregnancy

Category C.1

Do not use for cosmesis during pregnancy.5 140 141 259

Lactation

Not known whether distributed into human milk.1 5 219 Use with caution.1 5 219

Pediatric Use

Safety and efficacy not established in children <12 years of age with blepharospasm or strabismus.1

Safety and efficacy not established in children <16 years of age with cervical dystonia.1

Safety and efficacy not established in children <18 years of age for the management of upper limb spasticity, overactive bladder, detrusor overactivity associated with a neurologic condition, or axillary hyperhidrosis, or for prophylaxis of chronic migraine headache.1

Reportedly has been effective and well tolerated when used for management of strabismus in pediatric patients ≥2 months of age.107 111 112 113 115 296

Reportedly has been used generally without unusual adverse effects for the management of cerebral palsy in pediatric patients ≥18 months of age.229 231 232 233 270 271 272 280 285 315 321

Not recommended for cosmetic use in children <18 years of age.5 298

Some clinicians state that use is contraindicated in children <18 months of age.315

Serious systemic toxicity resembling botulism (e.g., dysphagia, respiratory failure) reported during postmarketing experience in children <16 years of age.371 Such effects observed with botulinum toxin type A doses of 6.25–32 units/kg.371 Severe cases involving death or hospitalization or requiring use of gastric feeding tubes and/or mechanical ventilation have occurred, principally in children with cerebral palsy-associated limb spasticity.371 372 373 No deaths or serious complications requiring intubation or ventilatory support reported among such cases of botulism in adults.371

Close monitoring in children receiving a botulinum toxin for possible effects on axonal growth suggested by some clinicians.296 298

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults;1 5 296 298 select dosage with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.1 5 296 298

Less effective in clinical trials for cosmesis of glabellar-line appearance in adults >65 years of age than in younger individuals, possibly because of loss of dermal elasticity with increasing age.5 144

Some clinicians suggest combined use with injectable dermal fillers (e.g., collagen) may improve cosmesis in geriatric individuals.296

Safety and efficacy data in patients ≥75 years of age insufficient for any comparison to results in younger adults.1 5 296

Common Adverse Effects

Formulations of Botox and Botox Cosmetic are identical; therefore, adverse effects observed with one of these preparations also may occur with use of the other preparation.1 5

Management of overactive bladder: Urinary tract infection,1 dysuria,1 urinary retention,1 bacteriuria,1 residual urine volume.1

Management of detrusor overactivity associated with a neurologic condition: Urinary tract infection,1 urinary retention,1 hematuria.1

Prophylaxis of chronic migraine: Neck pain,1 headache,1 migraine,1 eyelid ptosis,1 musculoskeletal stiffness,1 muscular weakness,1 bronchitis,1 myalgia,1 musculoskeletal pain,1 injection-site pain,1 facial paresis,1 muscle spasms,1 hypertension.1

Management of upper limb spasticity: Pain in extremity,1 muscular weakness,1 nausea,1 fatigue,1 bronchitis.1

Management of cervical dystonia: Dysphagia1 9 11 18 33 35 37 57 65 69 (e.g., swallowing difficulty, choking sensation), upper respiratory infection,1 neck pain,1 headache.1

Management of primary axillary hyperhidrosis: Injection site pain1 and hemorrhage,1 non-axillary sweating,1 infection, 1 pharyngitis,1 flu syndrome,1 headache,1 fever,1 neck or back pain,1 pruritus,1 anxiety.1

Management of blepharospasm: Ptosis,1 6 7 9 22 24 29 33 34 37 53 60 181 keratitis6 22 29 (including filamentary keratitis),181 dry eye,22 24 60 blurred vision,1 7 9 22 34 diplopia,1 7 9 22 24 33 53 181 entropion,1 9 conjunctivitis,29 increased tearing.1 9 34 60

Management of strabismus: Ptosis,1 9 33 34 37 60 vertical deviation.1 9 33 34 37 60

Cosmesis of glabellar lines: Blepharoptosis (eyelid ptosis),5 64 140 144 150 296 facial pain,5 muscular weakness,5 142 facial paresis.5

Cosmesis of lateral canthal lines: Eyelid edema.5

Injection-site reactions: Pain,5 infection,5 inflammation,5 tenderness,5 swelling,5 erythema,5 bleeding,5 bruising.5

Interactions for Botox

Specific Drugs

Drug

Interaction

Comments

Anticholinergic agents

Potentiation of systemic anticholinergic effects if administered after onabotulinumtoxinA1 5

Anticholinesterases

Potential for prolonged paralytic effect of toxin1 5

Use concomitantly with caution1 5 33 59 79 140 219 296 298

Anti-infective agents interfering with neuromuscular transmission (aminoglycosides, lincosamides, polymyxins)

Potential for prolonged paralytic effect of toxin1 5

Use concomitantly with caution1 5 33 59 79 140 219 296 298

Botulinum toxin treatment, concurrent or sequential

Possible increased paralytic effect with concurrent or sequential use within several months of administration of onabotulinumtoxinA1 2 5

Data on concurrent or sequential use of botulinum toxins lacking1 2 5

Magnesium salts (magnesium sulfate)

Potential for prolonged paralytic effect of toxin1 5

Use concomitantly with caution1 5 33 59 79 140 219 296 298

Neuromuscular blocking agents/muscle relaxants (e.g., atracurium, succinylcholine)

Potential for prolonged paralytic effect of toxin1 5

Use concomitantly with caution1 5 33 59 79 140 219 296 298

Quinidine

Potential for prolonged paralytic effect of toxin1 5

Use concomitantly with caution1 5 33 59 79 140 219 296 298

Botox Pharmacokinetics

Absorption

Bioavailability

Not detected in peripheral circulation following IM injection at recommended doses and systemic effects (e.g., generalized muscle weakness)260 generally do not occur; however, single-fiber electromyography (e.g., increased jitter) indicate subclinical effects in muscles distant from the injection site.1 2 5 14 142

Subclinical effects may indicate toxin spread via circulation, retrograde or orthograde axonal transport, or some action of the toxin at a third, central, or unidentified site.5

Onset

Following injection into a muscle, weakness ensues in approximately 2–4 days and total paralysis of the injected muscle occurs within 10 days;3 31 actively contracting muscles may internalize toxin more rapidly.

Duration

Extent of paralysis and atrophy of injected muscle correlates directly with the amount of toxin injected (i.e., concentration and volume of toxin solution).31 37 79

Redevelopment of extrajunctional receptors and terminals limits the duration of activity to a few months;3 5 31 functional recovery develops in 3–6 months, but neurologic redevelopment may continue for as long as 3 years.37 79

Response in autonomic disorders involving excessive glandular secretion (e.g., hyperhidrosis) may persist longer than in conditions involving overactivity of striated or smooth muscle;143 296 298 additional study needed.298

For additional information regarding onset and duration of effect, see specific indication in Dosage under Dosage and Administration.

Stability

Storage

Parenteral

Powder for Injection (Botox and Botox Cosmetic)

2–8°C; do not use after expiration date marked on vial.1 5

Following reconstitution with 0.9% sodium chloride injection without preservatives, store at 2–8°C and use within 24 hours; do not freeze.1 5

Actions

  • Induces chemical denervation and flaccid paralysis by disruption of neurotransmission; inhibits release of acetylcholine at presynaptic cholinergic nerve terminals of the peripheral nervous system and at ganglionic nerve terminals of the autonomic nervous system.1 3 5 16 31 32 37 194

  • Following intradetrusor injection, affects efferent pathways of detrusor activity via inhibition of acetylcholine release.1

  • Proposed mechanism in chronic migraine prophylaxis is inhibition of peripheral sensitization, leading indirectly to reduced progression of central sensitization.435 437

  • Inhibits sweat production by blocking release of acetylcholine, which mediates sympathetic neurotransmission in the eccrine glands.1

  • Induces neuromuscular blockade via a zinc-dependent endopeptidase, which blocks vesicles containing acetylcholine from fusing with the terminal membrane of the motor neuron.16 31 37 70 71 79

  • Without acetylcholine release, the muscle is unable to contract31 37 70 79 and flaccid paralysis ensues.1 3 5 16 31 32 37 194

  • At therapeutic doses, muscular paralysis limited to injected muscle; however, weakness or paralysis of adjacent muscles may occur as a result of local diffusion.1 5 31

  • Selective chemodenervation is reversible; although muscular atrophy occurs, regeneration of extrajunctional receptors and terminals limits the duration of activity to a few months.3 5 31

  • Recovery of neuromuscular activity occurs through neurogenesis of axonal sprouts and motor end plates.32 37 79

  • Functional recovery develops in 3–6 months, but sprouting and remodeling may continue for as long as 3 years.37 79

  • Response in autonomic disorders involving excessive glandular secretion (e.g., hyperhidrosis) may be longer than in conditions involving overactivity of striated or smooth muscle;143 296 298 additional study needed to elucidate mechanism in glandular and non-muscle tissue.298

Advice to Patients

  • Inform patients with cervical dystonia of possibility of dysphagia (typically mild to moderate);1 9 14 57 69 rarely, severe dysphagia occurs, sometimes associated with aspiration, dyspnea, pneumonia, and need to reestablish an airway.1 5

  • Importance of informing patients of possible systemic effects (e.g., weakness, shortness of breath, respiratory complications, swallowing difficulties) following local injection.371

  • Advise patients and/or caregivers to seek immediate medical attention if unexpected muscle weakness, swallowing, speech, or respiratory disorders occur.1 5 371

  • Advise previously sedentary patients to resume activity gradually following treatment.1 296 298

  • Advise women who become pregnant while receiving the drug of the potential risks to the fetus and that abortion and fetal malformations have been observed in animals given the drug during gestation.1 5 296 298

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., neuromuscular disorders).

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

FDA has determined that unlicensed botulinum toxin has been imported into the US without proper declaration of contents by sender; in some cases, unlicensed product has been shipped directly to physicians.364 Botulism has been reported in several individuals who received injections of unlicensed, highly concentrated botulinum toxin type A.370 377 378

To facilitate identification, vials of Botox and Botox Cosmetic have holographic film on the label that contains the name “Allergan” within horizontal lines of rainbow color.1 5 To see the hologram, rotate vial back and forth between fingers under a desk lamp or fluorescent light.1 5 (The holographic film is absent in the date/batch area of label.)1 5 If the lines of rainbow color or the name “Allergan” cannot be seen on product label, do not use product and contact Allergan for additional information at 800-890-4345 between 8:00 a.m. and 4:00 p.m. (Pacific Time).1 5

OnabotulinumtoxinA

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

50 units

Botox Cosmetic

Allergan

100 units

Botox

Allergan

Botox Cosmetic

Allergan

200 units

Botox

Allergan

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 05/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Botox 100UNIT Solution (ALLERGAN DERMATOLOGICS): 1/$609.97 or 3/$1,809.86

Botox 200UNIT Solution (ALLERGAN DERMATOLOGICS): 1/$1,230.01 or 3/$3,600.07

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions April 27, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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