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

IncobotulinumtoxinA

Pronunciation

(in kuh BOT yoo lin num TOKS in aye)

Index Terms

  • Botulinum Toxin Type A

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) [contains albumin human]

Brand Names: U.S.

  • Xeomin

Pharmacologic Category

  • Neuromuscular Blocker Agent, Toxin
  • Ophthalmic Agent, Toxin

Pharmacology

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.

Absorption

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

Onset of Action

Improvement: ~4-7 days

Duration of Action

~3-4 months

Use: Labeled Indications

U.S. labeling: Treatment of blepharospasm in patients previously treated with onabotulinumtoxinA (Botox®); treatment of cervical dystonia in botulinum toxin-naïve and previously treated patients; temporary improvement in the appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity

Canadian labeling:

Xeomin®: Treatment of hypertonicity disorders of the seventh nerve (eg, blepharospasm, hemifacial spasm); treatment of poststroke spasticity of upper limb(s); treatment of cervical dystonia (spasmodic torticollis)

Xeomin Cosmetic™: Temporary improvement in the appearance of moderate-to-severe glabellar lines

Contraindications

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

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

Dosage

IM: Adults:

Blepharospasm:

U.S. labeling: Initial: Total dose should be the same as previously administered onabotulinumtoxinA dose. If prior onabotulinumtoxinA dose is not known: 1.25-2.5 units/injection site (maximum initial dose: 35 units/eye or 70 units/both eyes). Number and location of injection sites based on disease severity and previous dose/response to onabotulinumtoxinA (in clinical trials, a mean number of 6 injections per eye were administered). Cumulative dose should not exceed 35 units/eye or 70 units/both eyes administered no more frequently than every 3 months.

Canadian labeling: Initial: 1.25-2.5 units/injection site (maximum initial dose: 25 units/eye). 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. Cumulative dose should not exceed 35 units/eye or 70 units/both eyes administered no more frequently than every 3 months.

Cervical dystonia:

U.S. 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 2-10 injections into treated muscles. Administer no more frequently than every 3 months

Canadian labeling: Usual total dose: 200 units (maximum: 300 units; maximum dose per injection site: 50 units); administer no more frequently than every 3 months

Reduction of glabellar lines: 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.

Spasticity of upper limb (poststroke): Canadian labeling (not in U.S. labeling): Individualize dose based on patient size, extent, and location of muscle involvement, degree of spasticity, local muscle weakness, and response to prior treatment. In clinical trials, total doses up to 400 units were administered as separate injections typically divided among selected muscles; may repeat therapy at ≥3 months with appropriate dosage based upon the clinical condition of patient at time of retreatment.

Suggested guidelines for the treatment of stroke-related upper limb spasticity: Note: The lowest recommended starting dose should be used. Dosage and number of injection sites should be individualized. Multiple injections may minimize adverse effects. Dose listed is total dose administered to site:

Biceps: 80 units

Brachialis: 50 units

Brachioradialis: 60 units

Flexor carpi radialis: 50 units

Flexor carpi ulnaris: 40 units

Flexor digitorum profundus: 40 units

Flexor digitorum superficialis: 40 units

Adductor pollicis: 10 units

Flexor pollicis brevis: 10 units

Flexor pollicis longus: 20 units

Pronator quadratus 25 units

Pronator teres: 40 units

Elderly: Initiate therapy at lowest recommended dose and titrate upward cautiously.

Dosage adjustment in renal impairment: There are no dosage adjustments provided in manufacturer's labeling.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in manufacturer's labeling.

Reconstitution

Reconstitute with sterile, preservative free 0.9% sodium chloride. Gently inject saline into vial and rotate vial to mix. 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; 8 mL of diluent to obtain concentration of 1.25 units per 0.1 mL

Administration

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

Blepharospasm: Use a 26- to 30-gauge (37 mm length) needle for superficial muscles and a 22-gauge (75 mm length) needle for deeper musculature; electromyography guidance is unnecessary. 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 a 26- to 30-gauge (37 mm length) needle for superficial muscles and a 22-gauge (75 mm length) needle for deeper musculature; electromyography or nerve stimulation techniques may help localize the involved muscles. Number of injections per treatment depends on size of muscle to be treated and volume to be administered.

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.

Spasticity of upper limb: 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.

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.

Adverse Reactions

>10%:

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

Gastrointestinal: Dysphagia (cervical dystonia 13% to 18%), xerostomia (blepharospasm 16%)

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

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

1% to 10%:

Central nervous system: Headache (blepharospasm 7%; reduction of glabellar lines 5%

Gastrointestinal: Diarrhea (blepharospasm 8%)

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

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

Respiratory: Dyspnea (blepharospasm 5%), nasopharyngitis (blepharospasm 5%), respiratory tract infection (blepharospasm 5%)

<1% (Limited to important or life-threatening): Any indication: Abdominal distension, allergic dermatitis, anaphylaxis, antibody development, blepharospasm, circulatory shock, corneal perforation, diplopia, edema, erythema, eye pain, eyelid ecchymosis, eyelid edema, facial pain, facial paresis, flu-like symptoms, hematoma at injection site, herpes zoster, hypersensitivity reaction, inflammation at injection site, muscle spasm, nausea, peripheral edema, reduced blinking (leading to corneal ulceration), respiratory failure, serum sickness, skin rash, soft tissue edema, swelling of eye, urinary incontinence, voice disorder

ALERT: U.S. Boxed Warning

Distant spread of toxin effects:

Postmarketing reports indicate that the effects of incobotulinumtoxinA and 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, blurred vision, 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 adults, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Hypersensitivity 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.

• 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: [U.S. 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:

• 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 (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.

• 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 excessive weakness or atrophy at the proposed injection site(s); use is contraindicated if infection is present.

Pregnancy Risk Factor

C

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 irritation, headache, cervicalgia, xerostomia, reduced blinking, xerophthalmia, dyspepsia, or diarrhea. Have patient report immediately to prescriber signs of infection, dyspnea, dysphagia, difficulty speaking, severe myalgia, considerable asthenia, sudden vision changes, ophthalmalgia, eye irritation, urinary incontinence, diplopia, or ptosis (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 healthcare 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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