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OnabotulinumtoxinA

Pronunciation

(oh nuh BOT yoo lin num TOKS in aye)

Index Terms

  • Botulinum Toxin Type A
  • BTX-A

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Botox: 100 units (1 ea)

Solution Reconstituted, Injection [preservative free]:

Botox: 200 units (1 ea)

Solution Reconstituted, Intramuscular:

Botox Cosmetic: 100 units (1 ea) [contains albumin human]

Solution Reconstituted, Intramuscular [preservative free]:

Botox Cosmetic: 50 units (1 ea) [contains albumin human]

Brand Names: U.S.

  • Botox
  • Botox Cosmetic

Pharmacologic Category

  • Neuromuscular Blocker Agent, Toxin
  • Ophthalmic Agent, Toxin

Pharmacology

OnabotulinumtoxinA (previously known as botulinum toxin type A) is a neurotoxin produced by Clostridium botulinum, spore-forming anaerobic bacillus, which appears to affect only the presynaptic membrane of the neuromuscular junction in humans, where it prevents calcium-dependent release of acetylcholine and produces a state of denervation. Muscle inactivation persists until new fibrils grow from the nerve and form junction plates on new areas of the muscle-cell walls. Intradetrusor injection affects efferent pathways of detrusor activity by inhibiting release of acetylcholine. Intradermal injection results in temporary sweat gland denervation, reducing local sweating.

Absorption

Not expected to be present in peripheral blood at recommended doses following intramuscular (IM) injection

Onset of Action

Blepharospasm: ~3 to 4 days; Cervical dystonia: ~2 weeks; Detrusor overactivity associated with neurologic condition: ~2 weeks; Reduction of glabellar lines (Botox Cosmetic): 1 to 2 days, increasing in intensity during first week; Spasticity: Focal and cerebral palsy related: <2 weeks; Strabismus: ~1 to 2 days

Time to Peak

Blepharospasm: 1 to 2 weeks; Cervical dystonia: ~6 weeks; Spasticity (focal): 4 to 6 weeks; Strabismus: Within first week

Duration of Action

Blepharospasm: ~3 to 4 months; Cervical dystonia: ≤3 to 4 months; Detrusor overactivity associated with neurologic condition: ~42 to 48 weeks; Reduction of glabellar lines (Botox Cosmetic): ~3 to 4 months; Spasticity: ~3 to 3.5 months; Strabismus: ~2 to 6 weeks; Primary axillary hyperhidrosis: 201 days (mean)

Use: Labeled Indications

Axillary hyperhidrosis (Botox): Treatment of severe primary axillary hyperhidrosis in adults not adequately managed with topical agents.

Cervical dystonia (Botox): Treatment of cervical dystonia in patients ≥16 years to reduce the severity of abnormal head position and neck pain.

Chronic migraine (Botox): Prophylaxis of chronic migraine headaches (≥ 15 days/month with headache lasting ≥4 hours/day) in adults.

Glabellar lines (Botox Cosmetic): Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults.

Lateral canthal lines (Botox Cosmetic): Temporary improvement in the appearance of moderate to severe lateral canthal lines associated with orbicularis oculi activity in adults.

Lower limb spasticity (Botox): Treatment of lower limb spasticity in adults to decrease the severity of increased muscle tone in ankle and toe flexors (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus, and flexor digitorum longus).

Overactive bladder (Botox): Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in adults who have an inadequate response to or who are intolerant to an anticholinergic medication.

Strabismus and blepharospasm associated with dystonia (Botox): Treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders, in patients ≥12 years.

Upper limb spasticity (Botox): Treatment of upper limb spasticity in adults to decrease the severity of increased muscle tone in elbow flexors (biceps), 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).

Urinary incontinence due to detrusor overactivity (Botox): Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, spinal cord injury [SCI], multiple sclerosis [MS]) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.

Canadian labeling: Additional use (not in US labeling): Dynamic equinus foot deformity in pediatric cerebral palsy patients; treatment of forehead lines in adults

Use: Unlabeled

Treatment of oromandibular dystonia, spasmodic dysphonia (laryngeal dystonia) and other dystonias (ie, writer's cramp, focal task-specific dystonias); treatment of dynamic muscle contracture in pediatric cerebral palsy patients

Contraindications

Hypersensitivity to botulinum toxin, or any component of the formulation; infection at the proposed injection site(s).

Botox: Additional contraindications: Intradetrusor injection in patients with overactive bladder or detrusor overactivity with a neurologic condition who have a urinary tract infection; intradetrusor injection in patients with urinary retention and in patients with post-void residual (PVR) urine volume >200 mL who are not routinely performing clean intermittent self-catheterization

Dosing: Adult

Note: The lowest recommended dose should be used when initiating treatment (regardless of indication). In adults treated for more than one indication, the maximum cumulative dose should be ≤400 units/3 months for Botox or ≤360 units/3 months for Botox Cosmetic. Canadian labeling recommends a maximum cumulative dose of 6 units/kg (up to 360 units) over 3 months in adult patients receiving additional treatment for noncosmetic indications.

Bladder dysfunction: Intradetrusor: Note: Prophylactic antimicrobial therapy (excluding aminoglycosides) should be administered 1 to 3 days prior to, on the day of, and for 1 to 3 days following onabotulinumtoxinA administration to decrease risk of urinary tract infection (UTI). Discontinue antiplatelet therapy at least 3 days prior to administration.

Detrusor overactivity associated with neurologic condition: 30 injections of 1 mL (recommended concentration: ~6.7 units/mL) for a total dose of 200 units/30 mL (maximum: 200 units); for the final injection, ~1 mL of sterile NS should be injected to ensure that the remaining medication in the needle is delivered to the bladder; may consider re-treatment with diminishing effect but no sooner than 12 weeks from previous administration (median time until second treatment in studies: 42 to 48 weeks).

Overactive bladder: 20 injections of 0.5 mL (recommended concentration: 10 units/mL) for a total dose of 100 units/10 mL (maximum: 100 units); for the final injection, ~1 mL of sterile NS should be injected to ensure that the remaining medication in the needle is delivered to the bladder; may consider re-treatment with diminishing effect but no sooner than 12 weeks from the previous administration (median time until second treatment in studies: ~24 weeks)

Blepharospasm: IM:

Botox: Initial dose: 1.25 to 2.5 units injected into the medial and lateral pretarsal orbicularis oculi of the upper lid and lateral pretarsal orbicularis oculi of lower lid

Dose may be increased up to twice the previous dose if the response from the initial dose lasted ≤2 months; maximum dose per site: 5 units. Tolerance may occur if treatments are given more often than every 3 months, but the effect is not usually permanent. Cumulative dose:

US labeling: ≤200 units in 30-day period

Canadian labeling (not in US labeling): Botox: ≤200 units in 2-month period

Cervical dystonia: IM: For dosing guidance, the mean dose is 236 units (25th to 75th percentile range 198 to 300 units) divided among the affected muscles in patients previously treated with botulinum toxin (maximum: ≤50 units/site). Initial dose in previously untreated patients should be lower. Sequential dosing should be based on the patient's head and neck position, localization of pain, muscle hypertrophy, patient response, and previous adverse reactions. The total dose injected into the sternocleidomastoid muscles should be ≤100 units to decrease the occurrence of dysphagia.

Canadian labeling (not in US labeling): IM: Botox: Effective range of 200 to 360 units has been used in clinical practice; administer no more frequently than every 2 months

Chronic migraine: IM: Administer 5 units/0.1 mL per site. Recommended total dose is 155 units once every 12 weeks. Each 155 unit dose should be equally divided and administered bilaterally, into 31 total sites as described below (refer to prescribing information for specific diagrams of recommended injection sites):

Corrugator: 5 units to each side (2 sites)

Procerus: 5 units (1 site only)

Frontalis: 10 units to each side (divided into 2 sites/side)

Temporalis: 20 units to each side (divided into 4 sites/side)

Occipitalis: 15 units to each side (divided into 3 sites/side)

Cervical paraspinal: 10 units to each side (divided into 2 sites/side)

Trapezius: 15 units to each side (divided into 3 sites/side)

Spasticity: IM: Individualize dose based on patient size, extent, and location of muscle involvement, degree of spasticity, local muscle weakness, and response to prior treatment. May repeat therapy at ≥3 months with appropriate dosage based upon the clinical condition of patient at time of re-treatment. Single session doses of ≤1,200 units (off-label dose) have been reported; however, safety and efficacy of routine use of doses >500 units has not been evaluated (Francisco, 2004). Single site doses of ≤400 units (off-label dose) in a lower limb (off-label use) have been reported (Nalysnyk, 2013).

Lower limb spasticity: The lowest recommended starting dose should be used and ≤50 units/site should be administered. Note: Dose listed is total dose administered as divided separate intramuscular injection(s):

Flexor digitorum longus: 50 units (divided into 2 sites)

Flexor hallucis longus: 50 units (divided into 2 sites)

Gastrocnemius lateral head: 75 units (divided into 3 sites)

Gastrocnemius medial head: 75 units (divided into 3 sites)

Soleus: 75 units (divided into 3 sites)

Tibialis posterior: 75 units (divided into 3 sites)

Upper limb spasticity. The lowest recommended starting dose should be used and ≤50 units/site should be administered. Note: Dose listed is total dose administered as individual or separate intramuscular injection(s):

Adductor pollicis: 20 units (1 site)

Biceps brachii: 100 to 200 units (divided into 4 sites)

Flexor digitorum profundus: 30 to 50 units (1 site)

Flexor digitorum sublimes: 30 to 50 units (1 site)

Flexor carpi radialis: 12.5 to 50 units (1 site)

Flexor carpi ulnaris: 12.5 to 50 units (1 site)

Flexor pollicis longus: 20 units (1 site)

Suggested guidelines for the treatment of stroke-related upper limb spasticity: Canadian labeling: Note: Dose listed is total dose administered as individual or separate intramuscular injection(s):

Adductor pollicis: 20 units (1 to 2 sites)

Biceps brachii: 100 to 200 units (up to 4 sites)

Flexor digitorum profundus: 15 to 50 units (1 to 2 sites)

Flexor digitorum sublimes: 15 to 50 units (1 to 2 sites)

Flexor carpi radialis: 15 to 60 units (1 to 2 sites)

Flexor carpi ulnaris: 10 to 50 units (1 to 2 sites)

Flexor pollicis longus: 20 units (1 to 2 sites)

Strabismus: IM: Note: Several minutes prior to injection, administration of local anesthetic and ocular decongestant drops are recommended.

Initial dose:

Vertical muscles and for horizontal strabismus <20 prism diopters: 1.25 to 2.5 units in any one muscle

Horizontal strabismus of 20 to 50 prism diopters: 2.5 to 5 units in any one muscle

Persistent VI nerve palsy ≥1 month: 1.25 to 2.5 units in the medial rectus muscle

Re-examine patients 7 to 14 days after each injection to assess the effect of that dose. Subsequent doses for patients experiencing incomplete paralysis of the target may be increased up to twice the previous administered dose. The maximum recommended dose as a single injection for any one muscle is 25 units. Do not administer subsequent injections until the effects of the previous dose are gone.

Primary axillary hyperhidrosis: Intradermal: 50 units/axilla. Injection area should be defined by standard staining techniques. Injections should be evenly distributed into multiple sites (10 to 15), administered in 0.1 to 0.2 mL aliquots, ~1 to 2 cm apart. May repeat when clinical effect diminishes.

Cosmetic uses:

Reduction of glabellar lines: Adults: IM: An effective dose is determined by gross observation of the patient's ability to activate the superficial muscles injected. The location, size, and use of muscles may vary markedly among individuals. Inject 0.1 mL (4 units) dose into each of five sites, two in each corrugator muscle and one in the procerus muscle for a total dose 0.5 mL (20 units) administered no more frequently than every 3 to 4 months. Note: Treatment of adults >65 years is approved in the Canadian labeling.

Reduction of lateral canthus lines:

US labeling: Adults: IM: Inject 0.1 mL (4 units) into 3 injection sites per side (6 total injection points) in the lateral orbicularis oculi muscle for a total dose of 0.6 mL (24 units) administered no more frequently than every 3 months.

Canadian labeling: Adults: IM: Inject 2 to 6 units into each of 1 to 3 injection sites, lateral to the lateral orbital rim.

Reduction of forehead lines (Canadian labeling; not in US labeling): IM: Inject 2 to 6 units into each of four sites in the frontalis muscle every 1 to 2 cm along either side of forehead crease and 2 to 3 cm above eyebrows for total dose of 24 units.

Dosing: Geriatric

Initiate therapy at lowest recommended dose. Refer to adult dosing.

Dosing: Pediatric

Note: The lowest recommended dose should be used when initiating treatment (regardless of indication). Canadian labeling (not in US labeling) recommends a maximum cumulative dose of 6 units/kg (up to 200 units) over 3 months in pediatric patients receiving treatment for more than 1 indication.

Blepharospasm/strabismus: Children ≥12 years: Refer to adult dosing.

Cervical dystonia: Children ≥16 years: Refer to adult dosing.

Spasticity (cerebral palsy related [dynamic equinus foot deformity]): Botox: Canadian labeling (not approved in US labeling): Children ≥2 years: IM: 4 units/kg (total dose) divided into two injections into medial and lateral heads of the gastrocnemius of affected leg; if clinically indicated, may repeat every 2 months (maximum dose: 200 units); in diplegia, the recommended dose is 6 units/kg (total dose) divided between affected limbs

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Reconstitute with sterile, preservative free NS: Slowly inject diluent into the vial and gently mix; discard vial if a vacuum does not pull diluent into the vial. Note: Dilution information (excludes recommendations for preparing the solution for use in detrusor overactivity associated with a neurologic condition [described under separate heading]):

Dilution information for preparing the solution for use in detrusor overactivity associated with a neurologic condition are described separately below:

Botox 100-unit vial: Reconstitute vials with 1 mL of diluent to obtain concentration of 10 units per 0.1 mL; 2 mL of diluent to obtain concentration of 5 units per 0.1 mL; 4 mL of diluent to obtain concentration of 2.5 units per 0.1 mL; 8 mL of diluent to obtain concentration of 1.25 units per 0.1 mL; 10 mL of diluent to obtain concentration of 1 unit per 0.1 mL.

Botox 200-unit vial: Reconstitute vials with 1 mL of diluent to obtain concentration of 20 units per 0.1 mL; 2 mL of diluent to obtain concentration of 10 units per 0.1 mL; 4 mL of diluent to obtain concentration of 5 units per 0.1 mL; 8 mL of diluent to obtain concentration of 2.5 units per 0.1 mL; 10 mL of diluent to obtain concentration of 2 units per 0.1 mL.

Botox Cosmetic: Reconstitute 50-unit vial with 1.25 mL of diluent or 100-unit vial with 2.5 mL of diluent to obtain concentration of 4 units per 0.1 mL (20 units per 0.5 mL for glabellar lines and 24 units per 0.6 mL for lateral canthal lines). Reconstitute vial using an appropriate sized needle and syringe by inserting needle into vial at a 45° angle and allowing vacuum to pull diluent into vial (do not use if vacuum has been lost); mix gently. Note: Botox Cosmetic 200-unit vial [CAN; not available in US] may be reconstituted with 5 mL of diluent to obtain concentration of 4 units per 0.1 mL.

Detrusor overactivity associated with a neurologic condition: Dilution recommendations:

100-unit vial: Reconstitute two 100 unit vials, each with 6 mL of preservative free NS; mix gently. Withdraw 4 mL from each vial into each of two 10 mL syringes; withdraw remaining 2 mL from each vial into the third 10 mL syringe for a total of 4 mL in each of the three 10 mL syringes. To complete dilution, add 6 mL of preservative free NS into each of the three 10 mL syringes and mix gently; each of the 10 mL syringes will contain 10 mL (~6.7 units/mL) for a total of 200 units.

200-unit vial: Reconstitute with 6 mL of preservative free NS; mix gently. Withdraw 2 mL from the vial into each of three 10 mL syringes. To complete dilution, add 8 mL of preservative free NS into each of the three 10 mL syringes and mix gently; each of the 10 mL syringes will contain 10 mL (~6.7 units/mL) for a total of 200 units.

Administration

Bladder dysfunction (including overactive bladder and detrusor overactivity associated with neurologic condition): Intradetrusor: Prophylactic antimicrobial therapy (excluding aminoglycosides) should be administered 1 to 3 days prior to, on the day of, and for 1 to 3 days following onabotulinumtoxinA administration. Discontinue antiplatelet therapy at least 3 days prior to administration. If a local anesthetic is instilled into the bladder prior to treatment, drain bladder and irrigate with normal saline prior to injection. Instill saline into bladder to optimize visualization but avoid overdistention. The injection needle should be primed with ~1 mL of reconstituted onabotulinumtoxinA prior to injection to remove any air. Administer onabotulinumtoxinA via flexible or rigid cystoscope by inserting needle with the recommended volume ~2 mm into the detrusor (avoid the trigone). Injections should be spaced ~1 cm apart. After completion of injections, drain saline from bladder and monitor patient for ≥30 minutes. In overactive bladder patients, a spontaneous void should also occur prior to patient leaving the clinic.

Blepharospasm: Use a 27- or 30-gauge needle without electromyography guidance. Avoid injecting near the levator palpebrae superioris (may decrease ptosis); avoid medial lower lid injections (may decrease diplopia). Apply pressure at the injection site to prevent ecchymosis in the soft eyelid tissues.

Cervical dystonia: Use 25-, 27-, or 30-gauge needle for superficial muscles and a longer 22-gauge needle for deeper musculature; electromyography may help localize the involved muscles.

Chronic migraines: Use a 0.5 inch, 30 gauge needle to administer 5 units/0.1 mL to each of the 31 sites.

Detrusor overactivity associated with neurologic condition: Prophylactic antimicrobial therapy (excluding aminoglycosides) should be administered 1 to 3 days prior to, on the day of, and for 1 to 3 days following onabotulinumtoxinA administration. If a local anesthetic is instilled into the bladder prior to treatment, drain bladder and irrigate with normal saline prior to injection. Instill saline into bladder to optimize visualization but avoid overdistention. Administer onabotulinumtoxinA via flexible or rigid cystoscope by inserting needle ~2 mm into the detrusor. A total of 30 injections (1 mL per injection) should be administered ~1 cm apart. After completion of injections, drain saline from bladder and monitor patient for ≥30 minutes.

Spasticity (cerebral palsy related; Canadian labeling [not in US labeling]): Use a 23- to 26-gauge needle for administration into the medial and lateral heads of the gastrocnemius muscle of the affected limb.

Spasticity (upper or lower limb): Use a 25-, 27-, or 30-gauge needle for superficial muscles and a longer 22-gauge needle for deeper musculature; electromyography or nerve stimulation may help localize the involved muscles.

Strabismus injections: Must use surgical exposure or electromyographic guidance; use the electrical activity recorded from the tip of the injections needle as a guide to placement within the target muscle. Local anesthetic and ocular decongestant should be given before injection. The volume of injection should be 0.05 to 0.15 mL per muscle. Many patients will require additional doses because of inadequate response to initial dose.

Primary axillary hyperhidrosis: Inject each dose intradermally to a depth of ~2 mm and at a 45° angle. Do not inject directly into areas marked in ink (to avoid permanent tattoo effect). Prior to administration, injection area should be defined by standard staining techniques such as Minor's Iodine-Starch Test.

Instructions for Minor's Iodine-Starch Test: Patient should shave underarms and refrain from using deodorants or antiperspirants for 24 hours prior to test. At 30 minutes prior to test, patient should be at rest, no exercise, and not consume hot beverages. Underarm area should be dried and immediately painted with iodine solution. After area dries, lightly sprinkle with starch powder. Gently blow off excess powder. A deep blue-black color will develop over the hyperhidrotic area in ~10 minutes.

Reduction of glabellar lines (Botox Cosmetic): Use a 30- to 33-gauge needle. Inject into each of 5 sites (2 injections in each corrugator muscle and 1 injection in the procerus muscle). Ensure injected volume/dose is accurate and where feasible keep to a minimum. Avoid injection near the levator palpebrae superioris. Lateral corrugator injections should be at least 1 cm above the bony supraorbital ridge. Do not inject toxin closer than 1 cm above the central eyebrow.

Reduction of lateral canthal lines (Botox Cosmetic): For intramuscular use only. Use a 30- to 33-gauge needle and give injections with the needle bevel tip up and oriented away from the eye. Inject into 3 sites per side (6 total injection points) in the lateral orbicularis oculi muscle. The first injection should be approximately 1.5 to 2.0 cm temporal to the lateral canthus and just temporal to the orbital rim. If the lines are above and below the lateral canthus, administer the next 2 injections above and below the first injection point. Inject at a similar distance from the orbital rim at a position approximately 30° from the first injection. If the lines in the lateral canthal region are primarily below the lateral canthus, inject the next 2 injections below the first injection at a similar distance from the orbital rim.

Storage

Store unopened vials under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 36 months or until the expiration date on the vial (Botox Cosmetic). After reconstitution, store in refrigerator at 2°C to 8°C (36°F to 46°F) and use within 24 hours (does not contain a preservative).

Botox 100-unit vial: The following stability information has also been reported: May be stored at room temperature for up to 5 days (Cohen, 2007).

Drug Interactions

AbobotulinumtoxinA: OnabotulinumtoxinA may enhance the adverse neuromuscular effect of AbobotulinumtoxinA. Monitor therapy

Aminoglycosides: May enhance the neuromuscular-blocking effect of OnabotulinumtoxinA. Monitor therapy

Anticholinergic Agents: May enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Neuromuscular-Blocking Agents: May enhance the neuromuscular-blocking effect of OnabotulinumtoxinA. Monitor therapy

RimabotulinumtoxinB: OnabotulinumtoxinA may enhance the neuromuscular-blocking effect of RimabotulinumtoxinB. Monitor therapy

Adverse Reactions

Adverse effects usually occur in 1 week and may last up to several months. Frequency not always defined.

>10%:

Bladder dysfunction:

Genitourinary: Urinary tract infection (18% to 49%), urinary retention (6% to 17%)

Cervical dystonia:

Central nervous system: Headache (11%)

Gastrointestinal: Dysphagia (19%)

Neuromuscular & skeletal: Neck pain (11%)

Respiratory: Upper respiratory tract infection (12%)

Other indications (blepharospasm, glabellar lines, lateral canthal lines, primary axillary hyperhidrosis, strabismus):

Ophthalmic: Blepharoptosis (blepharospasm: 21%; strabismus: 1% to 38%; glabellar lines: 3%), vertical deviation of eyes (strabismus 17%)

1% to 10%:

Bladder dysfunction:

Central nervous system: Myasthenia (4%), abnormal gait (3%), falling (3%)

Gastrointestinal: Constipation (4%)

Genitourinary: Dysuria (4% to 9%), bacteriuria (4%), hematuria (4%), increased post-void residual urine volume (not requiring catheterization: 3%)

Neuromuscular & skeletal: Muscle spasm (2%)

Cervical dystonia:

Central nervous system: Dizziness (2% to 10%), hypertonia (2% to 10%), numbness (2% to 10%), speech disturbance (2% to 10%), drowsiness

Gastrointestinal: Nausea (2% to 10%), xerostomia (2% to 10%)

Immunologic: Antibody development (1%)

Local: Injection site reaction: Soreness (2% to 10%)

Neuromuscular & skeletal: Back pain (2% to 10%), stiffness (2% to 10%), weakness (2% to 10%)

Ophthalmic: Blepharoptosis (2% to 10%), diplopia (2% to 10%)

Respiratory: Cough (2% to 10%), dyspnea (2% to 10%), flu-like symptoms (2% to 10%), rhinitis (2% to 10%)

Miscellaneous: Fever (2% to 10%)

Chronic migraines:

Cardiovascular: Hypertension (2%)

Central nervous system: Headache (5%), exacerbation of migraine headache (4%), facial paresis (2%)

Local: Pain at injection site (3%)

Neuromuscular & skeletal: Neck pain (9%), myasthenia (4%), stiffness (4%), musculoskeletal pain (3%), myalgia (3%), muscle spasm (2%)

Ophthalmic: Blepharoptosis (4%)

Respiratory: Bronchitis (3%)

Lower limb spasticity:

Local: Pain at injection site (2%)

Neuromuscular & skeletal: Arthralgia (3%), back pain (3%), myalgia (2%)

Respiratory: Upper respiratory tract infection (2%)

Upper limb spasticity:

Central nervous system: Fatigue (2% to 3%)

Gastrointestinal: Nausea (2% to 3%)

Neuromuscular & skeletal: Limb pain (5% to 9%), myasthenia (2% to 4%)

Respiratory: Bronchitis (2% to 3%)

Other indications (blepharospasm, glabellar lines, lateral canthal lines, primary axillary hyperhidrosis, reduction of glabellar lines, strabismus):

Central nervous system: Facial pain (1%), facial paresis (1%), anxiety, dizziness, headache, pain

Dermatologic: Diaphoresis (nonaxillary), pruritus, skin rash

Gastrointestinal: Nausea

Immunologic: Antibody development (2%)

Infection: Infection

Local: Injection site reaction: Hemorrhage, pain, soreness

Neuromuscular & skeletal: Weakness (1%), back pain, neck pain

Ophthalmic: Dry eye syndrome (6%), eyelid edema (1%), diplopia, ectropion, entropion, eye irritation (includes dry eye, lagophthalmos, photophobia), keratitis, lacrimation, superficial punctate keratitis

Respiratory: Flu-like symptoms, pharyngitis

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Any indication: Acute angle-closure glaucoma, alopecia, anaphylaxis, anorexia, antibody development (neutralizing), aspiration pneumonia, asthma, brachial plexopathy, cardiac arrhythmia, corneal perforation, corneal ulceration, denervation, erythema, erythema multiforme, exacerbation of myasthenia gravis, eye infection, focal facial paralysis, hypersensitivity reaction, hypoacusis, lagophthalmos, madarosis, myalgia, myocardial infarction, peripheral neuropathy, pneumonia, psoriasiform eruption, radiculopathy, reduced blinking, respiratory depression, respiratory failure, retrobulbar hemorrhage, seizure, serum sickness, syncope, urinary incontinence

ALERT: U.S. Boxed Warning

Spread of toxin effect:

Postmarketing reports indicate that the effects of all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening, and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable with those used to treat cervical dystonia and spasticity and at lower doses.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Serious and/or immediate hypersensitivity reactions (eg, anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea) have occurred. If a reaction occurs, discontinue and institute immediate treatment.

• Antibody formation: Higher doses or more frequent administration may result in neutralizing antibody formation and loss of efficacy.

• Autonomic dysreflexia: Has been observed with therapy in patients with detrusor overactivity associated with a neurologic condition; acts as stimuli to trigger an exaggerated sympathetic and parasympathetic response. Clinical presentation often includes headache, a marked increase in blood pressure, and diaphoresis; prompt treatment may be required in patients presenting with severe symptoms (eg, hypertensive crisis).

• Cardiovascular events: Arrhythmia and myocardial infarction (some fatal) have been reported following administration. Some of these patients had risk factors including preexisting cardiovascular disease. The exact relationship to onabotulinumtoxinA has not been established.

• Dysphagia: Common when used for cervical dystonia and may persist anywhere from 2 weeks up to 5 months after administration. In severe cases (some fatal), patients may require alternative feeding methods (eg, feeding tube). Risk factors include smaller neck muscle mass, bilateral injections into the sternocleidomastoid muscle, or injections into the levator scapulae. Risk of aspiration resulting from severe dysphagia is increased in patients when swallowing is already compromised. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia.

• Hematologic: Use with caution in patients with bleeding disorders and/or receiving anticoagulation therapy.

• Respiratory effects: Bronchitis and upper respiratory infection have been reported more frequently in patients treated for upper or lower limb spasticity.

• Systemic toxicity: [US Boxed Warning]: Distant spread of botulinum toxin beyond the site of injection has been reported; dysphagia and breathing difficulties have occurred and may be life threatening; other symptoms reported include blurred vision, diplopia, dysarthria, dysphonia, generalized muscle weakness, ptosis, and urinary incontinence which may develop within hours or weeks following injection. The risk is likely greatest in children treated for the unapproved use of spasticity, but symptoms can also occur in adults treated for spasticity and other conditions. Systemic effects have occurred following use in approved and unapproved uses, including doses comparable to or lower than doses used to treat cervical dystonia and upper limb spasticity. Immediate medical attention required if respiratory disorders, speech, or swallowing difficulties appear.

• Urinary retention: An increased incidence of urinary retention and need for catheterization has been observed in patients receiving therapy for bladder dysfunction (overactive bladder or detrusor overactivity associated with a neurologic condition); due to the risk of urinary retention, treatment should only be used in patients able and willing to initiate post-treatment catheterization, if required. Patients with diabetes had an increased incidence of urinary retention. Patients experiencing difficulty in voiding should be instructed to consult their healthcare provider.

• Urinary tract infection: Therapy in patients with overactive bladder increases the incidence of urinary tract infections (UTIs); clinical trials for overactive bladder excluded patients with >2 UTIs in the previous 6 months and those taking chronic antibiotics for prophylaxis of recurrent UTIs. Consider risks vs benefits when contemplating use in these patients or patients experiencing recurrent UTIs during treatment. Patients with diabetes had an increased incidence of UTI.

Disease-related concerns:

• Episodic migraines: Safety and efficacy have not been established in patients with 14 or fewer headaches per month.

• Neuromuscular disease: Use with caution in patients with neuromuscular diseases such as myasthenia gravis or Lambert- Eaton syndrome and neuropathic disorders (such as amyotrophic lateral sclerosis). Risk of adverse events including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia, and respiratory compromise may be increased.

• Ocular diseases: Reduced blinking from injection of the orbicularis muscle can lead to corneal exposure and ulceration when treating blepharospasm. Retrobulbar hemorrhages may occur from needle penetration into orbit when treating strabismus; spatial disorientation, double vision, or past-pointing may occur if one or more extraocular muscles are paralyzed. Covering the affected eye may help. Careful testing of corneal sensation, avoidance of lower lid injections, and treatment of epithelial defects are necessary. Use caution in patients with angle closure glaucoma.

• Respiratory disease: Use extreme caution in patients with preexisting respiratory disease; treatment with botulinum toxin may weaken accessory muscles that are necessary for these patients to maintain adequate ventilation. Serious breathing difficulties, including respiratory failure have been reported. Risk of aspiration resulting from severe dysphagia is increased in patients with decreased respiratory function.

Concurrent drug therapy issues:

• Neuromuscular transmission: Use with extreme caution in patients receiving other agents that may interfere with neuromuscular transmission (eg, aminoglycosides, neuromuscular-blocking agents)

Dosage form specific issues:

• Albumin: Product contains albumin and may carry a remote risk of virus transmission.

• Product interchangeability: Botulinum products (abobotulinumtoxinA, onabotulinumtoxinA, rimabotulinumtoxinB) are not interchangeable; potency units are specific to each preparation and cannot be compared or converted to any other botulinum product.

Other warnings/precautions:

• Bladder dysfunction: Appropriate use: Rule out acute urinary tract infection (UTI) prior to treatment; appropriate prophylactic antimicrobial therapy is required prior to, during, and following treatment. Discontinue antiplatelet therapy at least 3 days prior to administration.

• Chronic therapy: Long-term effects of chronic therapy unknown.

• Hazardous tasks: May impair ability to drive and/or operate machinery due to the intended effects of treatment; if loss of strength, muscle weakness, or impaired vision occur, patients should avoid driving or engaging in other hazardous activities.

• Injection site: Use with caution if there is inflammation or excessive weakness or atrophy at the proposed injection site(s); use is contraindicated if infection is present. Serious events (including fatalities) have been observed with direct injection into the esophagus, stomach, salivary glands and oro-lingual-pharyngeal region. Use caution when administering in close proximity to the lungs (especially the apices); pneumothorax has been reported following administration near the thorax.

• Primary axillary hyperhidrosis: Appropriate use: Evaluate for secondary causes prior to treatment (eg, hyperthyroidism). Safety and efficacy for treatment of hyperhidrosis in other areas of the body have not been established.

• Temporary reduction in glabellar lines: Appropriate use: Do not use more frequently than every 3 months (Canadian labeling states not to use more frequently than every 2 months). Patients with marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, or the inability to substantially lessen glabellar lines by physically spreading them apart were excluded from clinical trials. Use with caution in patients with surgical alterations to the facial anatomy. Reduced blinking from injection of the orbicularis muscle can lead to corneal exposure and ulceration. Spatial disorientation, double vision, or past pointing may occur if one or more extraocular muscles are paralyzed.

• Unapproved use: Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, including fatalities, have been reported in patients who have received injections for unapproved uses. In these cases, the reactions were not necessarily related to distant spread of toxin, but may have resulted from administration to the site of injection and/or adjacent structures; several patients had preexisting dysphagia or other significant disabilities.

• Upper or lower limb spasticity: Appropriate use: Safety and effectiveness of other upper or lower limb muscle groups have not been established. Treatment has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture.

Monitoring Parameters

Detrusor overactivity associated with neurologic condition: Evaluate postvoid residual (PVR) urine volume within 2 weeks post-treatment and periodically thereafter up to 12 weeks in patients not catheterizing. Initiate catheterization with PVR urine volume >200 mL and continue until PVR <200 mL.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site irritation, neck pain, headache, reduced blinking, dry eyes, or dry mouth. Have patient report immediately to prescriber signs of infection, difficulty breathing, dysphagia, difficulty speaking, vision changes, eye pain, drooping eyelids, severe eye irritation, loss of strength, severe muscle weakness, severe muscle pain, urinary incontinence, urinary retention, or seeing double (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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