OnabotulinumtoxinA (Monograph)

Brand names: Botox, Botox Cosmetic
Drug class: Botulinum toxins
Chemical name: Botulin A
CAS number: 93384-43-1

Medically reviewed by Drugs.com on Sep 21, 2023. Written by ASHP.

Introduction

Neurotoxin produced by Clostridium botulinum; disrupts neurotransmission by inhibiting release of acetylcholine from peripheral cholinergic and ganglionic nerve terminals.

Uses for OnabotulinumtoxinA

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. These preparations are not interchangeable; assay methods used to determine potency of these various toxins are specific to each individual manufacturer and/or formulation. 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.

Overactive Bladder

Treatment 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.

Reduces the frequency of urinary incontinence episodes and increases the volume voided per micturition.

Detrusor Overactivity Associated with a Neurologic Condition

Treatment 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.

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).

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.

Voiding Dysfunction Associated with Benign Prostatic Hyperplasia

Has been used for the management of voiding dysfunction associated with benign prostatic hyperplasia^{† [off-label]} (BPH).

Anal Sphincter Disorders

Has been used to treat uncomplicated cases of chronic anal fissure^{† [off-label]}, thought to be related to sustained high resting anal sphincter tone and associated anodermal ischemia. May be more effective and cause fewer adverse effects than topical nitroglycerin ointment.

Has been used for pain reduction following hemorrhoidectomy^{† [off-label]}.

Achalasia

Has been used successfully in a limited number of patients to relieve dysphagia, pain, and regurgitation associated with achalasia^{† [off-label]}.

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), those who have not responded to prior myotomy, those who have had esophageal perforation associated with pneumatic dilatation, and those with an epiphrenic diverticulum.

Chronic Migraine Prophylaxis

Prophylaxis of headaches in patients with chronic migraine (defined as headache lasting ≥4 hours per day on ≥15 days per month). The American Academy of Neurology (AAN) recommends onabotulinumtoxinA as a treatment option for patients with chronic migraine to increase the number of headache-free days.

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.

Manufacturer states that safety and efficacy for prophylaxis of episodic migraine^{† [off-label]} (≤14 headache days per month) not established.

Upper Limb Spasticity

Treatment 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), finger flexors (flexor digitorum profundus and flexor digitorum sublimis), and thumb flexors (adductor pollicis and flexor pollicis longus); safety and efficacy based on studies in adults who had experienced a stroke ≥6 weeks or 6 months previously.

Decreases spasticity, improves posture and range of motion, and relieves painful muscle spasms in adults with stroke-related spasticity; AAN recommends therapy with a botulinum toxin for the treatment of focal manifestations of spasticity involving upper limbs in adults.

Manufacturer states that safety and efficacy not established for the treatment of other upper limb muscle groups or for the treatment of upper or lower limb spasticity in pediatric patients^†, and not shown to improve upper extremity functional abilities or range of motion at a joint affected by a fixed contracture.

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

Lower Limb Spasticity

Treatment of lower limb spasticity to decrease the severity of increased muscle tone in ankle and toe flexors (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus, and flexor digitorum longus); safety and efficacy based on a study in adults with ankle spasticity who had experienced a stroke ≥3 months previously.

Decreases spasticity and improves muscle tone in adults with stroke-related spasticity; AAN recommends as a treatment option for focal manifestations of lower limb spasticity in adults.

Manufacturer states that safety and efficacy not established for the treatment of spasticity in other lower limb muscle groups or for the treatment of upper or lower limb spasticity in pediatric patients^†, and not shown to improve range of motion at a joint affected by a fixed contracture.

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

Spasticity Associated with Cerebral Palsy in Pediatric Patients

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

Some clinicians suggest conjunctive use of physical therapy and orthotics (e.g., casting).

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 in pediatric patients^†.

Designated an orphan drug by FDA for the treatment of dynamic muscle contracture in pediatric patients with cerebral palsy^†.

AAN states that botulinum toxin type A (e.g., onabotulinumtoxinA) should be considered an effective and generally well-tolerated treatment for localized/segmental spasticity in children and adolescents with cerebral palsy^†.

Cervical Dystonia

Management of cervical dystonia (spasmodic torticollis) to reduce the severity of associated abnormal head position and neck pain; designated an orphan drug by FDA for this use.

Botulinum toxins 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).

Spasmodic Dysphonia (Laryngeal Dystonia)

Considered treatment of choice for management of spasmodic dysphonia^† despite occasional complications and possible risk of reflex laryngeal stridor.

Spasmodic dysphonia involving the adductor muscles appears to be more common; 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.

Oromandibular Dystonias

Has been used successfully in the management of various oromandibular dystonias^† (e.g., Meige’s syndrome^†); considered a treatment of choice by some clinicians, although efficacy evidence from well-controlled studies is lacking.

Primary Axillary Hyperhidrosis

Management of severe primary axillary hyperhidrosis that is inadequately managed with topical agents.

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

Palmar Hyperhidrosis

Manufacturer states that safety and efficacy for the management of hyperhidrosis in body areas other than axillae not established. However, has been useful in some patients with focal palmar hyperhidrosis^†.

Blepharospasm and Associated Facial Nerve Disorders

Management of dystonia-associated blepharospasm, including benign essential blepharospasm and seventh cranial (facial) nerve disorders; considered a first-line therapy. AAN states that a botulinum toxin should be considered for the treatment of blepharospasm.

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

Also has shown clinical benefit in patients with hemifacial spasm^† (unilateral eyelid and facial movement disorder), which may occur in association with blepharospasm. 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).

Strabismus

Management of dystonia-associated strabismus; designated an orphan drug by FDA for this use in adults and children ≥12 years of age. An effective alternative or adjunct to surgery in selected patients with congenital or acquired strabismus.

Has been used in vertical strabismus in dysthyroid ophthalmopathy for which surgery is inappropriate.

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

Not effective in chronic paralytic strabismus^† except as an adjunct to surgical repair to reduce ocular antagonist muscle contracture.

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.

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

Cosmetic effects generally persist at least 4–6 months.

May not be appropriate when a wide range of facial expressions is required for professional or personal reasons.

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.

Cosmesis of Forehead Lines

Used for temporary improvement in the appearance of moderate to severe forehead lines caused by frontalis muscle activity.

Young individuals (usually females) with expressive horizontal forehead lines reportedly exhibit the best response.

Myofascial Pain Syndrome

Has been used in musculoskeletal pain disorders such as myofascial pain syndrome; may provide better and more prolonged relief than corticosteroids (e.g., methylprednisolone).

Tremor

Has been used for the management of various types of tremor^†, including essential hand tremor^†.

Related/similar drugs

Qulipta, Gemtesa, Ubrelvy, acetaminophen, ibuprofen, amitriptyline, naproxen

OnabotulinumtoxinA 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.

• 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.

• Some experts recommend limiting use of botulinum toxins to clinicians with specialized training.

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

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

• Optimal dosages for a number of conditions have not been fully elucidated.

• If a patient fails to respond, consider possibility of an inadequate drug dose, incorrectly reconstituted and/or improperly stored drug solution, and/or misinjection.

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

• 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.

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

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.

• 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.

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

• 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).

Administration

Administer by IM injection into affected muscles, intradermally , intracutaneously^†, sub-Q^†, or directly into affected glands^†.

IM Administration

Administer by IM injection into affected muscles.

Reconstitution

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

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.

To prevent possible toxin inactivation, allow stopper of vial to dry thoroughly after cleansing with alcohol before entering vial with a needle.

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

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

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. (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.

Use 0.9% sodium chloride injection without preservatives only.

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. Each syringe contains approximately 67 units of drug (for total dose of 200 units). Use immediately after reconstitution in syringe; dispose of any unused diluent.

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). Add 6 mL of same diluent to each syringe. Each syringe contains approximately 67 units of drug (for total dose of 200 units). Use immediately after reconstitution in syringe; dispose of any unused diluent.

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.

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

Record date and time of reconstitution on drug vial.

Dilution

The optimum dilution to produce maximal effect not established; 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.

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).

Lidocaine reportedly used as diluent to reduce pain on injection^†; 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.

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

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

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).

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.

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

Injection into the midbelly of larger muscles where the motor end plates are located may enhance benefit.

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. Also has been administered by transperineal injection guided by EMG or by transrectal ultrasound.

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

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

May use an intravesical instillation of diluted local anesthetic with or without sedation prior to injection of onabotulinumtoxinA. 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.

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

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. As final injection, inject approximately 1 mL of sterile 0.9% sodium chloride solution so remaining onabotulinumtoxinA in needle is delivered to bladder. After drug administration, observe patient for at least 30 minutes and until spontaneous void has occurred.

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. As final injection, inject approximately 1 mL of sterile 0.9% sodium chloride injection so remaining onabotulinumtoxinA in needle is delivered to bladder. After drug administration, drain 0.9% sodium chloride injection used for bladder wall visualization and observe patient for at least 30 minutes.

Injection Techniques/Precautions (Anal Sphincter Disorders)

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

Inject internal or external anal sphincter; optimal injection site not determined. 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.

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.

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

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. 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. 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.

Injection Techniques/Precautions (Upper or Lower 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.

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

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.

Total dose administered at each treatment session is given as several injections divided among affected muscles.

Identify affected muscles by careful clinical evaluation, including physical examination and palpation (e.g., for areas of hypertrophy, pain). 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.

EMG guidance also may be useful in delineating involved muscles for injection, particularly in obese patients or for muscles difficult to identify by palpation.

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; use hollow, Teflon-coated needle. Also has been given by indirect laryngeal endoscopy (without EMG guidance) in some (e.g., postsurgical) patients. While injections have been given into both vocal cords, some clinicians prefer unilateral injections to minimize adverse effects; optimal method controversial.

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

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).

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.

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.

Reduce risk of ptosis by avoiding injection near the levator palpebrae superioris.

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

Individualize treatment of hemifacial spasm^†, which sometimes occurs in conjunction with blepharospasm. 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.

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

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.

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.

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.

Minimize the risk of ptosis by avoiding injections near the levator palpebrae superioris, especially in individuals with larger brow-depressor complexes.

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

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.

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

To maintain brow in a neutral position, brow depressor muscles in the glabellar complex (corrugator supercilii and procerus) and the lateral fibers of the orbicularis oculi are usually treated simultaneously or a few days prior to treating the frontalis muscle.

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.

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 hours immediately following treatment.

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.

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

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).

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. 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. 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. Avoid making injections below the zygomaticus muscle to avoid ptosis of the upper lip.

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.

When treating forehead lines, assess the size of the patient's forehead and the distribution of frontalis muscle activity prior to identifying the injection sites. Consult the manufacturer’s literature for additional information regarding the location of these injection sites.

Some clinicians recommend varying volume and concentration of injections according to the area being treated (e.g., lateral canthal wrinkles, glabellar lines, platysma). 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. However, larger, less-concentrated volumes of solution reported to result in unacceptably short durations of improvement and larger areas of undesired paralysis.

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).

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

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.

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.

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

Firmly massage sites laterally following injection.

Intradermal Injection

Administer by intradermal injection for treatment of hyperhidrosis.

Primary Axillary Hyperhidrosis

Use standard staining techniques (e.g., Minor’s iodine starch test) to identify axillary hyperhidrotic area for injection.

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

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.

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

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

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

Intraglandular Injection†

Administer by injection directly into affected gland(s).

Voiding Dysfunction Associated with Benign Prostatic Hyperplasia†

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

Dosage

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

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. (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. Data on several different serotypes (e.g., botulinum toxin types A, B, C, F) and/or formulations of botulinum toxin have been reported; assay methods used to determine potency of these various toxins are specific to each individual manufacturer and/or formulation.

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

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.

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

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); however, little additional benefit from doses >5 units per site.

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

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.

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

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

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).

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

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.

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

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

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

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

Overcorrections exceeding 6 months in duration have been reported rarely.

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

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.

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

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.

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

Spasticity Associated with Cerebral Palsy†

IM

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

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.

Based on clinical experience, 1–6 units/kg per muscle has been recommended.

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.

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

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

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

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. Muscle weakness generally wears off after 3 months; functional improvement may last considerably longer.

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.

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

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.

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

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

Anal Sphincter Disorders†

IM

Chronic anal fissure: Initially, 5–20 units. Healing rates may be higher with higher doses.

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

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

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.

Chronic Migraine Prophylaxis

IM

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

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

Dose distributed bilaterally.

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

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

Upper Limb Spasticity

IM

Manufacturer-recommended doses and muscles to be injected shown in Table 4.

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.

Use of EMG to guide injections recommended.

Use lowest recommended starting dose, generally ≤50 units per site. Doses of 75–400 units divided among selected muscles at a given treatment session used in clinical trials.

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

Lower Limb Spasticity

IM

Manufacturer-recommended doses and muscles to be injected shown in Table 5. Manufacturer recommends 300–400 units divided among 5 muscles (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus, and flexor digitorum longus).

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.

Use of EMG to guide injections recommended.

Use lowest recommended starting dose, generally ≤50 units per site.

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

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).

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

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

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. (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.

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

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.

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, while others have injected larger doses (5–30 units) into one vocalis complex to produce unilateral paralysis. Dosage can be adjusted based on the severity of glottal spasms and the response to previous injections.

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

Abductor Muscle Dysphonia†

IM

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

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

Some clinicians recommend injection of only one side of the abductor muscle during any given treatment session 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.

Oromandibular Dystonia†

IM

Wide range of doses has been used.

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

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.

Primary Axillary Hyperhidrosis

Intradermal

Total dose of 50 units per axilla injected with a 30-gauge needle. 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.

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.

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.

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

Maximum total dose of 100 units per axilla in larger individuals recommended by some clinicians; 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).

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

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.

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

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); however, little additional benefit from doses >5 units per site.

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

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.

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

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

Hemifacial Spasm†

IM

Initial dose: 12-25 units administered into the inferior and superior orbicularis oculi, buccolabial, and/or platysma muscles.

Duration of response of hemifacial spasm may be somewhat longer compared with that in blepharospasm.

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).

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

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.

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

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

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

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

Overcorrections exceeding 6 months in duration have been reported rarely.

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

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.

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

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.

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

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.

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.

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

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.

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.

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

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

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

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 results and suggest that the limitation on the injection interval is not crucial with the small doses (generally <100 units) used for most cosmetic indications. However, manufacturer states that safety and efficacy of dosing at intervals <3 months not clinically evaluated.

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.

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).

Some clinicians have used 6–18 units (e.g., 2.5–3 units per injection) for each side; higher doses necessary in some individuals.

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.

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.

Cosmesis of Forehead Lines

IM

Treat forehead lines in conjunction with glabellar lines (see Cosmesis of Glabellar Facial [“Frown”] Lines under Dosage and Administration) to minimize potential for brow ptosis.

Manufacturer recommends total dose of 40 units (20 units for forehead lines and 20 units for glabellar lines). The 20-unit dose for the treatment of forehead lines is administered as 4 units into 5 sites of the frontalis muscle. (See Injection Techniques/Precautions [Facial Cosmesis] under Dosage and Administration.)

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.

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

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

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

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

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

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.

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

Strabismus

Pediatric Patients ≥12 Years of Age

IM

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

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.

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

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

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

Adults

Per manufacturer, maximum cumulative dose for one or more uses should not exceed 400 units in a 3-month period.

Overactive Bladder

IM

Maximum recommended dose is 100 units per treatment.

Detrusor Overactivity Associated with a Neurologic Condition

IM

Do not exceed 200 units per treatment.

Upper Limb Spasticity

IM

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

Lower Limb Spasticity

IM

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

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. (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.

Primary Axillary Hyperhidrosis

IM

Maximum total dose: 100 units per axilla in larger individuals recommended by some clinicians. Doses of up to 200 units per axilla have been used.

Blepharospasm

IM

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

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

Strabismus

IM

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

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.

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.

Cautions for OnabotulinumtoxinA

Contraindications

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

• Infection at the proposed injection site(s).

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

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

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. (See Boxed Warning.)

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

Weakness of adjacent muscles commonly reported with botulinum toxin administration. Such weakness reported within first week of treatment; generally transient but may persist for several months.

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) reported in both children and adults receiving botulinum toxin for a variety of conditions in a wide range of dosages.

In some cases, swallowing and breathing difficulties have required hospitalization, mechanical ventilation, or feeding tubes and/or resulted in death. (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). (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).

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.

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.

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

Sensitivity Reactions

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

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

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. Units of biologic activity for different serotypes or formulations of botulinum toxin cannot be compared with or converted to units of other botulinum toxins.

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).

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.

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

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

Cardiovascular Effects

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

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. May be related to use of higher dosages in such patients.

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.

Serious systemic effects related to distant spread of botulinum toxin reported more often and with greater severity in children with cerebral palsy. (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.

Dysphagia and Breathing Difficulties

Dysphagia is most common serious adverse effect reported in patients with cervical dystonia; also reported in patients receiving a type A botulinum toxin for other conditions (e.g., torticollis, muscle spasticity associated with cerebral palsy). Results from diffusion of the toxin to tissues (e.g., posterior pharyngeal muscles) outside the injected muscles.

Rarely, fatal aspiration pneumonia or other serious debilities may develop subsequently.

Occurs most frequently following injection of one or both sternocleidomastoid or scalenus muscles; 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. Also increased risk in cervical dystonia patients with subclinical dysphagia. Injections into the levator scapulae associated with an increased risk of dysphagia and upper respiratory infection.

Use lowest effective dose in high-risk muscles.

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

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.

Pulmonary Effects

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

Use in Overactive Bladder

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

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.

Due to risk of urinary retention, use onabotulinumtoxinA only in patients willing and able to initiate catheterization posttreatment for urinary retention if required. (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. Depending on patient's symptoms, initiate catheterization if postvoid residual urine volume exceeds 200 mL; continue catheterization until postvoid residual urine volume <200 mL. Instruct patients to contact clinician if voiding becomes difficult since catheterization may be required.

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.

Due to risk of urinary retention, use onabotulinumtoxinA only in patients willing and able to initiate catheterization posttreatment for urinary retention if required. (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. Depending on patient's symptoms, initiate catheterization if postvoid residual urine volume exceeds 200 mL; continue catheterization until postvoid residual urine volume <200 mL. Instruct patients to contact clinician if voiding becomes difficult since catheterization may be required.

Use in Upper Limb Spasticity

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

Use in Spasmodic Dysphonia (Laryngeal Dystonia)

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

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

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

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.

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.

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

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.

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

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.

Use in Strabismus

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

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.

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

Cosmetic Use

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

Risk of Viral Disease Transmission

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

Injection-related Effects

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

Immunogenicity

Highly immunogenic (bacterial origin); possible formation of neutralizing antibodies resulting in reduced response to treatment. Antibodies to the toxin do not appear to induce hypersensitivity responses.

Tolerance manifests as the absence of muscular paralysis, weakness, and/or atrophy after injection.

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); however, long-term response to other serotypes in such patients not fully elucidated.

Administer lowest effective dose at the longest feasible treatment interval to minimize risk of antibody formation and tolerance. Manufacturer recommends ≥3-month interval between treatment sessions.

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).

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

Fetal/Neonatal Morbidity and Mortality

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

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

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. If local or state health department not available within 30 minutes, contact CDC Emergency Operations Center directly at 770-488-7100. Antitoxin will not reverse botulinum toxin-induced muscle weakness already evident at the time of antitoxin administration but may stabilize the deficits.

Information about antitoxin available at l.

Specific Populations

Pregnancy

No adequate and well-controlled clinical studies with onabotulinumtoxinA in pregnant women. Abortion, decreased fetal body weight, and fetal malformations (e.g., skeletal ossification) observed in animals (e.g., mice, rats, rabbits) given the drug during gestation.

Most clinicians recommend not using for cosmesis during pregnancy.

Lactation

Not known whether distributed into human milk. Consider known benefits of breast-feeding along with mother's clinical need for onabotulinumtoxinA and any potential adverse effects of the drug or the underlying maternal condition on the infant.

Pediatric Use

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

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

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

Reportedly has been effective and well tolerated when used for management of strabismus in pediatric patients ≥2 months of age^†.

Reportedly has been used generally without unusual adverse effects for the management of cerebral palsy in pediatric patients ≥18 months of age^†.

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

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

Serious systemic toxicity resembling botulism (e.g., dysphagia, respiratory failure) reported during postmarketing experience in children <16 years of age. Such effects observed with botulinum toxin type A doses of 6.25–32 units/kg. 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. No deaths or serious complications requiring intubation or ventilatory support reported among such cases of botulism in adults.

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

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; 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.

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.

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

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

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.

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

Management of detrusor overactivity associated with a neurologic condition: Urinary tract infection, urinary retention, residual urine volume, bacteriuria, dysuria, hematuria.

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

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

Management of lower limb spasticity: Injection site pain, arthralgia, back pain, myalgia, upper respiratory tract infection.

Management of cervical dystonia: Dysphagia (e.g., swallowing difficulty, choking sensation), upper respiratory infection, neck pain, headache.

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

Management of blepharospasm: Ptosis, keratitis (including filamentary keratitis), dry eye, blurred vision, diplopia, entropion, conjunctivitis, increased tearing.

Management of strabismus: Ptosis, vertical deviation.

Cosmesis of glabellar lines: Blepharoptosis (eyelid ptosis), facial pain, muscular weakness, facial paresis.

Cosmesis of lateral canthal lines: Eyelid edema.

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

Drug Interactions

Specific Drugs

OnabotulinumtoxinA Pharmacokinetics

Absorption

Bioavailability

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

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.

Onset

Following injection into a muscle, weakness ensues in approximately 2–4 days and total paralysis of the injected muscle occurs within 10 days; 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).

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

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

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.

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

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.

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

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

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

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

• Without acetylcholine release, the muscle is unable to contract and flaccid paralysis ensues.

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

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

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

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

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

Advice to Patients

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

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

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

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

• 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.

• 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. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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Frequently asked questions

• What is botulinum toxin used to treat?

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