IncobotulinumtoxinA

Dosage Forms

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

Solution Reconstituted, Intramuscular [preservative free]:

Xeomin: 50 units (1 ea); 100 units (1 ea); 200 units (1 ea) [latex free; contains albumin human]

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

Pharmacology

Mechanism of Action

IncobotulinumtoxinA is a neurotoxin produced from Clostridium botulinum that inhibits acetylcholine release from peripheral cholinergic nerve endings. Inhibition occurs sequentially via binding and internalization of the neurotoxin into presynaptic cholinergic nerve terminals, translocation to the nerve terminal cytosol, and enzymatic cleavage of SNAP25, a protein necessary for acetylcholine release. Inhibition of acetylcholine release at the neuromuscular junction 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.

Pharmacokinetics/Pharmacodynamics

Absorption

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

Onset of Action

Improvement: ~4 to 7 days

Duration of Action

~3 to 4 months

Use: Labeled Indications

US labeling:

Blepharospasm: Treatment of adults with blepharospasm.

Cervical dystonia: Treatment of adults with cervical dystonia.

Glabellar lines: Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.

Sialorrhea: Treatment of chronic sialorrhea in adults.

Upper limb spasticity: Treatment of upper limb spasticity in adult patients.

Canadian labeling:

Xeomin:

Cervical dystonia: Treatment of cervical dystonia (spasmodic torticollis) in adults.

Hypertonicity disorders: Treatment of hypertonicity disorders of the seventh nerve (eg, blepharospasm, hemifacial spasm) in adults.

Upper limb spasticity: Treatment of poststroke spasticity of upper limb(s) in adults.

Xeomin Cosmetic: Glabellar lines: Temporary improvement in the appearance of moderate to severe glabellar lines in adults.

Contraindications

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

Canadian labeling: Additional contraindications (not in US labeling): Generalized disorders of muscle activity (eg, myasthenia gravis, Lambert-Eaton syndrome)

Dosage and Administration

Dosing: Adult

Blepharospasm: IM:

US labeling:

Treatment naive: Initial: 25 units per eye (50 units per treatment session); the number and location of subsequent injections may be changed in response to adverse reactions or response to treatment; maximum dose: 50 units per eye (100 units per treatment session). Administer repeat injections no more frequently than every 3 months.

Treatment experienced: Dose, response to treatment, duration of effect, and adverse events should be considered when determining dose for patients previously treated with a botulinum toxin A.

Canadian labeling: Initial: 1.25 to 2.5 units/injection site (maximum initial dose: 25 units/eye for treatment-naïve patients; 35 units/eye for patients previously receiving unknown dose). Titrate dose and interval for maximum patient benefit. Total dose should not exceed 100 units per treatment session. Administer no more frequently than every 3 months.

Cervical dystonia: IM:

US labeling: Initial total dose: 120 units (in clinical trials, similar efficacy was noted with initial total doses of 120 and 240 units and between treatment experienced and treatment naïve patients). Dose and number of injection sites should be individualized based on prior treatment, response, duration of effect, adverse events, number/location of muscle(s) to be treated and disease severity. In clinical trials most patients received a total of 2 to 10 injections into treated muscles. Administer no more frequently than every 3 months. Maximum cumulative dose per treatment session: 400 units.

Canadian labeling: Usual total dose does not exceed 200 units (maximum: 300 units; maximum dose per injection site: 50 units); administer no more frequently than every 3 months

Reduction of glabellar lines: IM: Inject 4 units into each of the 5 sites (2 injections in each corrugator muscle and 1 injection in the procerus muscle) for a total dose of 20 units per treatment session. Administer no more frequently than every 3 months.

Sialorrhea: Intraglandular: Inject 100 units divided between the parotid and submandibular glands on both sides (ie, 4 injection sites per treatment session); divide dose with a ratio of 3:2 between parotid and submandibular glands. Treatment may be repeated no sooner than every 16 weeks based on clinical need.

Upper limb spasticity: IM:

US labeling: Initiate dosing at the low end of the dosing range and titrate as clinically indicated. Base dosage, frequency and number of injection sites on size, number and location of muscles to be treated, severity of spasticity, presence of local muscle weakness, patient's response to previous treatment and adverse event history. Administer no more frequently than every 3 months. Maximum cumulative dose per treatment session: 400 units.

Clenched fist: Flexor digitorum superficialis or flexor digitorum profundus: 25 to 100 units divided into 2 injection sites

Flexed wrist:

Flexor carpi radialis: 25 to 100 units divided into 1 to 2 injection sites

Flexor carpi ulnaris: 20 to 100 units divided into 1 to 2 injection sites

Flexed elbow:

Brachioradialis: 25 to 100 units divided into 1 to 3 injection sites

Biceps: 50 to 200 units divided into 1 to 4 injection sites

Brachialis: 25 to 100 units divided into 1 to 2 injection sites

Pronated forearm:

Pronator quadratus: 10 to 50 units in 1 injection

Pronator teres: 25 to 75 units divided into 1 to 2 injections

Thumb-in-palm:

Flexor pollicis longus: 10 to 50 units in 1 injection

Adductor pollicis: 5 to 30 units in 1 injection

Flexor pollicis brevis/opponens pollicis: 5 to 30 units in 1 injection

Canadian labeling: Initiate dosing at the low end of the dosing range and titrate as clinically indicated. Administer no more frequently than every 3 months. Total dose should not exceed 400 units in a treatment session.

Flexed wrist: Total initial dose 90 units

Flexor carpi radialis: Initial dose 50 units; subsequent dose range 25 to 100 units divided into 1 to 2 injection sites

Flexor carpi ulnaris: Initial dose 40 units; subsequent dose range 20 to 100 units divided into 1 to 2 injection sites

Clenched fist: Total initial dose 80 units

Flexor digitorum superficialis: Initial dose 40 units; subsequent dose range 40 to 100 units divided into 2 injection sites

Flexor digitorum profundus: Initial dose 40 units; subsequent dose range 40 to 100 units divided into 2 injection sites

Flexed elbow: Total initial dose 130 to 190 units

Brachioradialis: Initial dose 60 units; subsequent dose range 25 to 100 units divided into 1 to 3 injection sites

Biceps: Initial dose 80 units; subsequent dose range 75 to 200 units divided into 1 to 4 injection sites

Brachialis: Initial dose 50 units; subsequent dose range 25 to 100 units divided into 1 to 2 injection sites

Pronated forearm: Total initial dose 25 to 65 units

Pronator quadratus: Initial dose 25 units; subsequent dose range 10 to 50 units in 1 injection

Pronator teres: Initial dose 40 units; subsequent dose range 25 to 75 units divided into 1 to 2 injections

Thumb-in-palm: Total initial dose 10 to 40 units

Flexor pollicis longus: Initial dose 20 units; subsequent dose range 10 to 50 units in 1 injection

Adductor pollicis: Initial dose 10 units; subsequent dose range 5 to 30 units in 1 injection

Flexor pollicis brevis/opponens pollicis: Initial dose 10 units; subsequent dose range 5 to 30 units in 1 injection

Dosing: Geriatric

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

Reconstitution

Using a 20 to 27 gauge short bevel needle, reconstitute with sterile, preservative free 0.9% sodium chloride. Gently inject saline into vial and rotate carefully swirling and inverting/flipping vial to mix. Do not shake vigorously. Do not use if solution is cloudy or contains particulate matter.

50 unit vials: May be reconstituted with 0.25 mL of diluent to obtain concentration of 20 units per 0.1 mL; 0.5 mL of diluent to obtain concentration of 10 units per 0.1 mL; 1 mL of diluent to obtain concentration of 5 units per 0.1 mL; 1.25 mL of diluent to obtain concentration of 4 units per 0.1 mL; 2 mL of diluent to obtain concentration of 2.5 units per 0.1 mL; 2.5 mL of diluent to obtain concentration of 2 units per 0.1 mL; 4 mL of diluent to obtain concentration of 1.25 units per 0.1 mL; 5 mL of diluent to obtain concentration of 1 unit per 0.1 mL

100 unit vials: May be reconstituted with 0.5 mL of diluent to obtain concentration of 20 units per 0.1 mL; 1 mL of diluent to obtain concentration of 10 units per 0.1 mL; 1.25 mL of diluent to obtain concentration of 8 units per 0.1 mL; 2 mL of diluent to obtain concentration of 5 units per 0.1 mL; 2.5 mL of diluent to obtain concentration of 4 units per 0.1 mL; 4 mL of diluent to obtain concentration of 2.5 units per 0.1 mL; 5 mL of diluent to obtain concentration of 2 units per 0.1 mL

200 unit vials: May be reconstituted with 0.5 mL of diluent to obtain concentration of 40 units per 0.1 mL; 1 mL of diluent to obtain concentration of 20 units per 0.1 mL; 1.25 mL of diluent to obtain concentration of 16 units per 0.1 mL; 2 mL of diluent to obtain concentration of 10 units per 0.1 mL; 2.5 mL of diluent to obtain concentration of 8 units per 0.1 mL; 4 mL of diluent to obtain concentration of 5 units per 0.1 mL; 5 mL of diluent to obtain concentration of 4 units per 0.1 mL

Administration

IM: Note: Do not inject through pen marks (if proposed injection sites are marked with a pen); permanent tattooing effect may occur.

Blepharospasm: Use a 30-gauge (12.5 mm length) needle. Electromyography guidance is unnecessary. Avoid injecting near the levator palpebrae superioris (may decrease ptosis). Avoid medial lower lid injections (may decrease ectropion). Apply pressure at the injection site to prevent ecchymosis in the soft eyelid tissues.

Cervical dystonia and upper limb spasticity: Use a 26-gauge (37 mm length) needle for superficial muscles and a 22-gauge (75 mm length) needle for deeper musculature; electromyography or nerve stimulation may help localize the involved muscles. The Canadian labeling recommends avoiding administering bilateral injections or doses >100 units to the sternocleidomastoid muscle (increased risk of adverse events, particularly dysphagia).

Reduction of glabellar lines: Use a 30- to 33-gauge (13 mm length) needle. To reduce ptosis, corrugator injections should be ≥1 cm above the bony supraorbital ridge and injections near the levator palpebrae superioris should be avoided.

Intraglandular: Sialorrhea: Use a 27- to 30-gauge, 12.5 mm length needle. Locate salivary glands using ultrasound imaging or surface anatomical landmarks (refer to manufacturer's labeling).

Storage

Undiluted vials may be stored at room temperature 20°C to 25°C (68°F to 77°F), under refrigeration 2°C to 8°C (36°F to 46°F), or frozen -20°C to -10°C (-4°F to 14°F). After reconstitution, store in refrigerator at 2°C to 8°C (36°F to 46°F) and administer within 24 hours. Vial should only be used for one injection session and one patient.

Drug Interactions

Aminoglycosides: May enhance the neuromuscular-blocking effect of Botulinum Toxin-Containing Products. Monitor therapy

Anticholinergic Agents: Botulinum Toxin-Containing Products may enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Botulinum Toxin-Containing Products: May enhance the neuromuscular-blocking effect of other Botulinum Toxin-Containing Products. Monitor therapy

Muscle Relaxants (Centrally Acting): May enhance the adverse/toxic effect of Botulinum Toxin-Containing Products. Specifically, the risk for increased muscle weakness may be enhanced. Monitor therapy

Neuromuscular-Blocking Agents: Botulinum Toxin-Containing Products may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Adverse Reactions

Upper limb spasticity and cervical dystonia:

>10%:

Central nervous system: Myasthenia (cervical dystonia: 7% to 11%)

Gastrointestinal: Dysphagia (cervical dystonia: 13% to 18%)

Infection: Infection (cervical dystonia: 13% to 14%)

Neuromuscular & skeletal: Neck pain (cervical dystonia: 7% to 15%)

Respiratory: Respiratory system disorder (cervical dystonia: 10% to 13%)

1% to 10%:

Central nervous system: Seizure (upper limb spasticity: 3%)

Gastrointestinal: Xerostomia (upper limb spasticity: 2%)

Immunologic: Antibody development (neutralizing; cervical dystonia, upper limb spasticity: ≤2%)

Local: Pain at injection site (cervical dystonia: 9%)

Neuromuscular & skeletal: Musculoskeletal pain (cervical dystonia: 4% to 7%)

Respiratory: Nasopharyngitis (upper limb spasticity: 2%), upper respiratory tract infection (upper limb spasticity: 2%)

Blepharospasm, chronic sialorrhea, and glabellar lines:

>10%:

Gastrointestinal: Xerostomia (blepharospasm: 16%; chronic sialorrhea: 4%)

Ophthalmic: Blepharoptosis (blepharospasm: 19%; reduction of glabellar lines: <1%), dry eye syndrome (blepharospasm: 16%; chronic sialorrhea: 3%), visual disturbance (blepharospasm: 12%)

1% to 10%:

Cardiovascular: Hypertension (chronic sialorrhea: 4%)

Central nervous system: Headache (blepharospasm: 7%; reduction of glabellar lines: 5%), falling (chronic sialorrhea: 3%), voice disorder (chronic sialorrhea: 3%)

Gastrointestinal: Diarrhea (blepharospasm, chronic sialorrhea: 4% to 8%), tooth loss (chronic sialorrhea: 5%)

Neuromuscular & skeletal: Back pain (chronic sialorrhea: 3%)

Respiratory: Dyspnea (blepharospasm: 5%), nasopharyngitis (blepharospasm: 5%), respiratory tract infection (blepharospasm: 5%), bronchitis (chronic sialorrhea: 3%)

<1%, postmarketing and/or case reports: Any indication: Allergic dermatitis, anaphylaxis, antibody development (neutralizing; blepharospasm, chronic sialorrhea), asthenia, blepharospasm, blurred vision, corneal perforation, diplopia, dysarthria, dysphagia, dyspnea, ecchymoses, edema, erythema of skin, eye disease, eyelid edema, facial pain, facial paresis, flu-like symptoms, hematoma at injection site, herpes zoster infection, hypersensitivity reaction, inflammation at injection site, injection site reaction, local hypersensitivity reaction, muscle spasm, myalgia, nausea, pain at injection site, pruritus, reduced blinking (leading to corneal ulceration), respiratory failure, serum sickness, skin rash, swelling of eye, urinary incontinence, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Serious hypersensitivity (eg, serum sickness, urticaria, soft tissue edema, dyspnea) and anaphylactic reactions may occur; discontinue therapy immediately with signs/symptoms of hypersensitivity. Immediate medical treatment should be available.
• Antibody formation: Higher doses, more frequent administration and/or onset of disease at a younger age may result in neutralizing antibody formation and loss of efficacy.
• Cardiovascular events: Rarely, arrhythmia and myocardial infarction have been reported with use of another botulinum toxin product, sometimes in patients with preexisting cardiovascular disease.
• CNS depression: 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.
• Dysphagia: Common when used for cervical dystonia; may occur within hours to weeks and persist for several months after administration. In severe cases, patients may require alternative feeding methods. Risk factors include smaller neck muscle mass and bilateral injections into the sternocleidomastoid muscle. Incidence of dysphagia may be reduced by limiting dose administered into sternocleidomastoid muscle.
• Hematologic: Use with caution in patients with bleeding disorders and/or receiving anticoagulation therapy.
• 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. Systemic effects have occurred following use in approved and unapproved uses, including low doses. Use caution in patients with underlying conditions which may predispose them to these symptoms. Immediate medical attention required if respiratory, speech, or swallowing difficulties appear.

Disease-related concerns:

• Neuromuscular disease: Use with caution in patients with neuromuscular diseases such as myasthenia gravis or Lambert- Eaton syndrome (contraindicated in Canadian labeling) and neuropathic disorders (such as amyotrophic lateral sclerosis). Risk of adverse events including 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. Careful testing of corneal sensation, avoidance of lower lid injections to prevent ectropion, and treatment of epithelial defects are necessary. Therapeutic soft contact lenses, application of protective drops or ointment, or covering the affected eye may help. Gentle pressure at injection site may limit bruising of eyelid. Use caution in patients with angle-closure glaucoma.
• Respiratory disease: Use extreme caution in patients with pre-existing respiratory disease; treatment of cervical dystonia using botulinum toxin may weaken accessory muscles that are necessary for these patients to maintain adequate ventilation. Risk of aspiration resulting from severe dysphagia is increased in patients with decreased respiratory function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Albumin: Product contains albumin and may carry a remote risk of virus transmission and variant Creutzfeldt-Jakob disease (vCJD). There also is a theoretical risk for transmission of CJD.
• Product interchangeability: Botulinum products (incobotulinumtoxinA, 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:

• Chronic therapy: Long-term effects of chronic therapy unknown.
• Injection site: Use with caution if there is excessive weakness or atrophy at the proposed injection site(s); use is contraindicated if infection is present.

Pregnancy

Pregnancy Considerations

Adverse events were observed in some 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 pain, neck pain, dry mouth, reduced blinking, dry eyes, tooth pain, muscle pain, bone pain, stuffy nose, common cold symptoms, sore throat, or diarrhea. Have patient report immediately to prescriber blurred vision, double vision, change in voice, drooping eyelids, loss of strength and energy, loss of bladder control, difficulty breathing, difficulty swallowing, difficulty speaking, signs of infection, severe headache, severe dizziness, passing out, vision changes, seizures, eye pain, or eye irritation (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.