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  • CLASSES

    Muscle Relaxants, Other Neuromuscular Blockers

    BOXED WARNING

    Children, distant spread of toxin effects, infants, neonates

    Postmarketing data for incobotulinumtoxinA and other botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening; deaths related to the distant spread of toxin effects have been reported. Advise patients and caregivers to seek immediate medical help if speech, swallowing, or respiratory disorders occur. The risk of symptoms is probably greatest in neonates, infants, and children treated for spasticity but symptoms can occur in adult treated for spasticity and other conditions, and particularly in those patients who have underlying conditions that would predispose them to these symptoms. Symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral acetylcholine release inhibitor and neuromuscular blocking agent
    Used for treatment or improvement of adult patients with blepharospasm, cervical dystonia, upper limb spasticity, severe glabellar lines, or chronic sialorrhea
    Spread of toxin effect beyond site of local injection reported

    COMMON BRAND NAMES

    Xeomin

    HOW SUPPLIED

    Xeomin Intramuscular Inj Pwd F/Sol: 50U, 100U, 200U

    DOSAGE & INDICATIONS

    For the treatment of blepharospasm in patients who were previously treated with onabotulinumtoxinA.
    Intramuscular dosage
    Adults

    Use same initial dose as the patient's previous treatment with onabotulinumtoxinA; if the previous dose is unknown, then 1.25 to 2.5 units/injection site IM. Determine subsequent dosing and timing for repeat administration based on clinical response, but generally no sooner than every 12 weeks. Do not exceed 35 units/eye. Dosing has not been established in patients who have not been previously treated with onabotulinumtoxinA.

    For the treatment of cervical dystonia.
    Intramuscular dosage
    Adults

    120 units IM divided into affected muscles (e.g., sternocleidomastoid, levator scapulae, splenius capitis, scalenus, trapezius). Individualize dose and number of injection sites in each treated muscle based on number and location of the muscle(s) to be treated, degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin treatments. Determine timing for repeat administration based on clinical response, but generally no sooner than every 12 weeks.

    For the treatment of moderate to severe glabellar lines (facial wrinkles).
    Intramuscular dosage
    Adults

    4 units/injection IM with 2 injections in each corrugator muscle and 1 injection in the procerus muscle. Max total dose: 20 units. Do not administer more frequently than every 3 months.

    For the treatment of upper limb spasticity.
    Intramuscular dosage
    Adults

    Individualize dosage, frequency, and number of injection sites based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient’s response to previous treatment, or adverse event history with incobotulinumtoxinA. In patients not previously treated with botulinum toxins, begin initial dosing at the low end of the recommended dosing range and titrate as necessary. Do not exceed 400 units/treatment session. Do not administer more frequently than every 12 weeks; most patients were retreated between 12 and 14 weeks in clinical trials. Dosing by muscle: clenched fist: flexor digitorum superficialis or flexor digitorum profundus, 25 to 100 units IM with 2 injection sites/muscle; flexed wrist: flexor carpi radialis, 25 to 100 units IM with 1 to 2 injection sites/muscle, or flexor carpi ulnaris, 20 to 100 units IM with 1 to 2 injection sites/muscle; flexed elbow: brachioradialis, 25 to 100 units IM with 1 to 3 injection sites/muscle, or biceps, 50 to 200 units IM with 1 to 4 injection sites/muscle, or brachialis, 25 to 100 units IM with 1 to 2 injection sites/muscle; pronated forearm: pronator quadratus, 10 to 50 units IM with 1 injection site/muscle, or pronator teres, 25 to 75 units IM with 1 to 2 injection sites/muscle; thumb-in-palm: flexor pollicis longus, 10 to 50 units IM with 1 injection site/muscle, or adductor pollicis or flexor pollicis brevis/opponens pollicis, 5 to 30 units IM with 1 injection site/muscle. In clinical trials, up to 400 units in divided doses IM were injected to affected muscle groups at a minimum dosing interval of 12 weeks for up to 6 doses.

    For the treatment of chronic sialorrhea.
    Intraglandular dosage
    Adults

    30 units intraglandular for each parotid gland and 20 units intraglandular for each submandibular gland. Determine timing for repeat administration based on clinical response, and no sooner than every 16 weeks.

    MAXIMUM DOSAGE

    Adults

    35 units/eye IM for blepharospasm; 120 units/treatment session IM for cervical dystonia; 20 units/treatment session IM for glabellar facial wrinkles; 400 units/treatment session IM for upper limb spasticity; 100 units/treatment session intraglandular for chronic sialorrhea.

    Geriatric

    35 units/eye IM for blepharospasm; 120 units/treatment session IM for cervical dystonia; 20 units/treatment session IM for glabellar facial wrinkles; 400 units/treatment session IM for upper limb spasticity; 100 units/treatment session intraglandular for chronic sialorrhea.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Use each vial of reconstituted incobotulinumtoxinA for 1 session and 1 patient only.
    Practitioners should be familiar with musculature and any anatomical abnormalities (e.g., past surgical procedures) of affected areas.
    Do not inject through pen markings; a permanent tattooing effect may result.
     
    Reconstitution/Dilution:
    Reconstitute with sterile, preservative-free 0.9% Sodium Chloride Injection.
    Using aseptic technique, withdraw the proper amount of diluent in the appropriate size syringe, and slowly inject the diluent into the vial. Discard the incobotulinumtoxinA if a vacuum does not pull the diluent into the vial.
    Gently mix by rotating the vial; the solution should be clear, colorless, and free of particulate matter.
    Using a 50 unit vial, dilutions calculated for an injection volume of 0.1 mL are as follows:
    0.25 mL of diluent = 20 units/0.1 mL
    0.5 mL of diluent = 10 units/0.1 mL
    1 mL of diluent = 5 units/0.1 mL
    1.25 mL of diluent = 4 units/0.1 mL
    2 mL of diluent = 2.5 units/0.1 mL
    2.5 mL of diluent = 2 units/0.1 mL
    4 mL of diluent = 1.25 units/0.1 mL
    5 mL of diluent = 1 unit/0.1 mL
    Using a 100 unit vial, dilutions calculated for an injection volume of 0.1 mL are as follows:
    0.5 mL of diluent = 20 units/0.1 mL
    1 mL of diluent = 10 units/0.1 mL
    1.25 mL of diluent = 8 units/0.1 mL
    2 mL of diluent = 5 units/0.1 mL
    2.5 mL of diluent = 4 units/0.1 mL
    4 mL of diluent = 2.5 units/0.1 mL
    5 mL of diluent = 2 units/0.1 mL
    Using a 200 unit vial, dilutions calculated for an injection volume of 0.1 mL are as follows:
    0.5 mL of diluent = 40 units/0.1 mL
    1 mL of diluent = 20 units/0.1 mL
    1.25 mL of diluent = 16 units/0.1 mL
    2 mL of diluent = 10 units/0.1 mL
    2.5 mL of diluent = 8 units/0.1 mL
    4 mL of diluent = 5 units/0.1 mL
    5 mL of diluent = 4 units/0.1 mL
    Storage: Store reconstituted solution under refrigeration (2 to 8 degrees C) until ready for use. Administer within 24 hours of reconstitution.

    Intramuscular Administration

    Blepharospasm:
    Use a sterile 26-gauge (0.45 mm diameter), 37 mm length needle for superficial muscles; or a 22-gauge (0.7 mm diameter), 75 mm length needle for injections into deeper muscles.
    Avoid injection into the medial lower eyelid area to prevent ectropion.
    Ecchymosis occurs easily in the soft eyelid tissues and can be prevented by applying pressure at the injection site immediately after the injection.
     
    Cervical dystonia:
    Use a sterile 26-gauge (0.45 mm diameter), 37 mm length needle for superficial muscles; or a 22-gauge (0.7 mm diameter), 75 mm length needle for injections into deeper muscles.
    Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful.
    Inject carefully when the injection site is close to sensitive structures (e.g., carotid artery, lung apices, and esophagus).
     
    Glabellar facial wrinkles:
    Use a sterile 30- to 33-gauge (0.2 to 0.3 mm diameter), 13 mm length needle.
    Avoid injection near the levator palpebrae superioris to reduce the risk of ptosis, particularly in patients with larger brow depressor complexes.
    Administer at least 1 cm above the bony supraorbital ridge.

    Other Injectable Administration

    Intraglandular injection:
    The concentration after reconstitution used in clinical trials was 5 units/0.1 mL.
    Use a sterile 27- to 30-gauge (0.3 to 0.4 mm diameter), 12.5 mm length needle.
    Inject into the parotid and submandibular salivary glands on both sides.
    The salivary glands can be located using ultrasound imaging or surface anatomical landmarks.

    STORAGE

    Xeomin:
    - Discard unused portion. Do not store for later use.
    - Store reconstituted product in refrigerator (36 to 46 degrees F) and administer within 24 hours
    - Store unopened product at room temperature (68 to 77 degree F), in refrigerator (36 to 46 degrees F), or freezer (-4 to 14 degrees F) for up to 36 months

    CONTRAINDICATIONS / PRECAUTIONS

    Albumin hypersensitivity, sucrose hypersensitivity

    IncobotulinumtoxinA is contraindicated in individuals with known hypersensitivity to any ingredient in the formulation; do not use this medication in patients with a history of hypersensitivity to botulinum neurotoxin type A, a sucrose hypersensitivity, or an albumin hypersensitivity.

    Infection

    IncobotulinumtoxinA is contraindicated in the presence of infection at the proposed injection site(s). Use in patients with an infection at the injection site could lead to severe local or disseminated infection.

    Children, distant spread of toxin effects, infants, neonates

    Postmarketing data for incobotulinumtoxinA and other botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening; deaths related to the distant spread of toxin effects have been reported. Advise patients and caregivers to seek immediate medical help if speech, swallowing, or respiratory disorders occur. The risk of symptoms is probably greatest in neonates, infants, and children treated for spasticity but symptoms can occur in adult treated for spasticity and other conditions, and particularly in those patients who have underlying conditions that would predispose them to these symptoms. Symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.

    Dysphagia, respiratory insufficiency

    Treatment with incobotulinumtoxinA other botulinum toxins can result in swallowing or breathing difficulties. Patients with pre-existing dysphagia or respiratory insufficiency may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection. When distant effects occur, additional respiratory muscles may be involved. Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who have become dependent upon these accessory muscles. Serious breathing difficulties, including respiratory failure, have been reported in patients with cervical dystonia treated with botulinum toxins. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles have been reported to be at greater risk of dysphagia. Deaths as a complication of severe dysphagia have been reported. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Dysphagia may persist for several months. Limit the dose injected into the sternocleidomastoid muscle to decrease the occurrence of dysphagia.

    Amyotrophic lateral sclerosis (ALS), myasthenia gravis, neuromuscular disease

    Patients with neuromuscular disease with peripheral motor neuropathic disorders, amyotrophic lateral sclerosis (ALS), or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome), may be at increased risk for severe dysphagia and respiratory compromise from typical doses of incobotulinumtoxinA.

    Viral infection

    IncobotulinumtoxinA products contain albumin, a derivative of human blood. As with other products derived from or purified with human blood components, the remote possibility of contamination or infection with hepatitis, Creutzfeldt-Jakob disease (CJD), or other bacterial or viral infection exists in patients receiving incobotulinumtoxinA. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents. The manufacturing processes are designed to reduce the risk of transmitting infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present in this product. No cases of transmission of viral disease or CJD have ever been reported for albumin.

    Closed-angle glaucoma

    Use incobotulinumtoxinA with caution, in patients with or at risk for closed-angle glaucoma, as the toxin has anticholinergic effects.

    Pregnancy

    Use incobotulinumtoxinA during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate data on the developmental risk associated with the use of incobotulinumtoxinA in pregnant women. IncobotulinumtoxinA was embryotoxic in rats and increased abortions in rabbits when given intramuscularly at doses higher than the maximum recommended human dose (MRHD) for cervical dystonia (120 units), on a body weight basis. The no-effect doses for embryotoxicity in rats and increased abortion in rabbits were 6 units/kg (3 times the MRHD for cervical dystonia on a body weight basis) and 2.5 units/kg (similar to the MRHD for cervical dystonia on a body weight basis), respectively.

    Breast-feeding

    There are no data on the presence of incobotulinumtoxinA in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for incobotulinumtoxinA and any potential adverse effects on the breast-fed infant from incobotulinumtoxinA or the underlying maternal condition. No adverse effects were observed when an 8-month old infant was breast-fed during a severe clinical botulism illness in the mother. Type A botulism toxin was present in the serum and stool of the mother upon hospital admission (day 3 of illness). No botulinum toxin was detected in the infant's blood or stool, and no botulism organisms were detected in the infant's stool at hospital admission. A breast milk sample obtained at 4 hours after administration of 2 vials of trivalent botulism antitoxin to the mother did not contain any detectable botulinum toxin or botulism organisms. The infant continued to breast-feed throughout the maternal illness without any adverse effects.

    Requires an experienced clinician

    Use of incobotulinumtoxinA requires an experienced clinician as safe and effective use of this medication depends upon proper product storage, dose selection, medication reconstitution, and administration technique, in addition to, knowledge of the treated condition. Units of biological activity of incobotulinumtoxinA cannot be compared or converted to other botulinum toxin products. Physicians must understand the relevant neuromuscular and/or orbital anatomy of the area involved and know of any alterations to the anatomy due to prior surgical procedures. Use of standard electromyographic guidance or nerve stimulation techniques may be useful.

    Surgery

    As with other botulinum toxin products, administer incobotulinumtoxinA with caution to patients with a history of surgery in the treatment area as this may alter drug distribution within the injected muscles and thus alter the intended effect. Further, ask all patients if they have any planned surgical procedures upcoming. Advise patients to tell their other health care practitioners of this therapy prior to any surgeries.

    Driving or operating machinery

    Advise patients to avoid engaging in potentially hazardous activities including driving or operating machinery if a loss of strength, muscle weakness, blurred vision, or drooping eyelids develops during incobotulinumtoxinA therapy.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 12.0-12.0
    seizures / Delayed / 3.0-3.0
    anaphylactoid reactions / Rapid / Incidence not known
    serum sickness / Delayed / Incidence not known
    ectropion / Early / Incidence not known
    corneal erosion / Delayed / Incidence not known
    distant spread of toxin effects / Early / Incidence not known

    Moderate

    dysphagia / Delayed / 13.0-18.0
    blurred vision / Early / 12.0-12.0
    dyspnea / Early / 5.0-5.0
    hypertension / Early / 4.0-4.0
    dysphonia / Delayed / 3.0-3.0
    photophobia / Early / 1.4-1.4
    antibody formation / Delayed / 1.1-1.1
    paresis / Delayed / 0-1.0
    hematoma / Early / 0.6-1.0
    blepharospasm / Early / 0.2-0.2
    edema / Delayed / Incidence not known
    erythema / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known

    Mild

    infection / Delayed / 0-20.0
    ptosis / Delayed / 0.2-19.0
    xerophthalmia / Early / 3.0-16.0
    xerostomia / Early / 2.0-16.0
    weakness / Early / 7.0-11.0
    injection site reaction / Rapid / 0-9.0
    diarrhea / Early / 4.0-8.0
    headache / Early / 5.4-7.1
    musculoskeletal pain / Early / 4.0-7.0
    back pain / Delayed / 3.0-5.0
    arthralgia / Delayed / 3.0-3.0
    pharyngitis / Delayed / 2.0-2.0
    myalgia / Early / 2.0-2.0
    asthenia / Delayed / 2.0-2.0
    blepharedema / Early / 0.4-0.9
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    diplopia / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    influenza / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    nausea / Early / Incidence not known

    DRUG INTERACTIONS

    Amikacin: (Moderate) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. Monitor aminoglycoside concentrations, and monitor for evidence of neurotoxicity including systemic neuromuscular blockade.
    Anticholinergics: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Aspirin, ASA; Carisoprodol: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Atracurium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Atropine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Atropine; Difenoxin: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Atropine; Diphenoxylate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Atropine; Edrophonium: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Baclofen: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Belladonna; Opium: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Benztropine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Capreomycin: (Moderate) The effects of Botulinum Toxins could be potentiated by drugs that interfere with neuromuscular transmission, such as capreomycin.
    Capsaicin; Metaxalone: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Carisoprodol: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Chlordiazepoxide; Clidinium: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Chloroquine: (Major) One study reported that chloroquine antagonized the actions of botulinum toxins (e.g., abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB). The study suggested that chloroquine may prevent internalization by inhibiting toxin binding at the cell membrane or inhibit lysosomal processing of the toxin in the cell interior.
    Chlorzoxazone: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Cisatracurium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Cyclobenzaprine: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Dantrolene: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Dicyclomine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Doxacurium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Flavoxate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Gentamicin: (Moderate) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. Monitor aminoglycoside concentrations, and monitor for evidence of neurotoxicity including systemic neuromuscular blockade.
    Glycopyrrolate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Glycopyrrolate; Formoterol: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Homatropine; Hydrocodone: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Hydroxychloroquine: (Major) One study reported that chloroquine antagonized the actions of botulinum toxins. The study suggested that chloroquine may prevent internalization by inhibiting toxin binding at the cell membrane or inhibit lysosomal processing of the toxin in the cell interior. Hydroxychloroquine, a related quinoline agent, may also interfere with the actions of botulinum toxins.
    Hyoscyamine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Indacaterol; Glycopyrrolate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Kanamycin: (Moderate) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission.
    Mepenzolate: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Metaxalone: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Methscopolamine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Mivacurium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Neomycin: (Minor) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. However, neomycin oral and topical products are not well absorbed systemically; interactions are not expected.
    Neuromuscular blockers: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Orphenadrine: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Oxybutynin: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Pancuronium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Paromomycin: (Minor) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. However, paromomycin is not well absorbed following oral administration; interactions are not expected.
    Polymyxins: (Moderate) The effects of botulinum toxin type A or botulinum toxin type B can be potentiated by drugs that interfere with neuromuscular transmission, such as colistimethate sodium. If these drugs are used in combination, monitor patients for increased adverse effects. Neuromuscular blockade may be associated with colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    Propantheline: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Rapacuronium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Rocuronium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Scopolamine: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Skeletal Muscle Relaxants: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Solifenacin: (Moderate) Systemic anticholinergic effects (e.g., blurred vision) may be potentiated if antimuscarinics are administered after administration of botulinum toxins.
    Streptomycin: (Moderate) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. Monitor aminoglycoside concentrations, and monitor for evidence of neurotoxicity including systemic neuromuscular blockade.
    Succinylcholine: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Tapentadol: (Moderate) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants including botulinum toxins. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.
    Tobramycin: (Moderate) The effects of botulinum toxin can be potentiated by systemic aminoglycosides or other drugs that interfere with neuromuscular transmission. Monitor aminoglycoside concentrations, and monitor for evidence of neurotoxicity including systemic neuromuscular blockade.
    Trihexyphenidyl: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
    Trospium: (Moderate) Systemic anticholinergic effects (e.g., blurred vision) may be potentiated if antimuscarinics are administered after administration of botulinum toxins.
    Tubocurarine: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.
    Vecuronium: (Major) The effects of botulinum toxins can be potentiated by neuromuscular blockers, or other drugs that interfere with neuromuscular transmission. Monitor for symptoms of unintended or prolonged neuromuscular blockade, including respiratory rate and muscle movements.

    PREGNANCY AND LACTATION

    Pregnancy

    Use incobotulinumtoxinA during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate data on the developmental risk associated with the use of incobotulinumtoxinA in pregnant women. IncobotulinumtoxinA was embryotoxic in rats and increased abortions in rabbits when given intramuscularly at doses higher than the maximum recommended human dose (MRHD) for cervical dystonia (120 units), on a body weight basis. The no-effect doses for embryotoxicity in rats and increased abortion in rabbits were 6 units/kg (3 times the MRHD for cervical dystonia on a body weight basis) and 2.5 units/kg (similar to the MRHD for cervical dystonia on a body weight basis), respectively.

    There are no data on the presence of incobotulinumtoxinA in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for incobotulinumtoxinA and any potential adverse effects on the breast-fed infant from incobotulinumtoxinA or the underlying maternal condition. No adverse effects were observed when an 8-month old infant was breast-fed during a severe clinical botulism illness in the mother. Type A botulism toxin was present in the serum and stool of the mother upon hospital admission (day 3 of illness). No botulinum toxin was detected in the infant's blood or stool, and no botulism organisms were detected in the infant's stool at hospital admission. A breast milk sample obtained at 4 hours after administration of 2 vials of trivalent botulism antitoxin to the mother did not contain any detectable botulinum toxin or botulism organisms. The infant continued to breast-feed throughout the maternal illness without any adverse effects.

    MECHANISM OF ACTION

    IncobotulinumtoxinA blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junctions by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. The neurotoxin first binds to the cholinergic nerve terminals, enters the nerve terminals, then the light-chain portion of the neurotoxin molecule translocates into the cytosol of the nerve terminal where it cleaves the SNAP25 protein, which is integral to the successful docking and release of acetylcholine from vesicles within nerve endings. In both muscles and glands, impulse transmission is re-established when new nerve endings are formed.

    PHARMACOKINETICS

    IncobotulinumtoxinA is administered by intramuscular and intraglandular injection. Animal (rodent) studies have shown the degree and duration of muscle paralysis to be dose-dependent. A median first onset of effect within 7 days and duration of action of up to 3 months is typical; however, individual patients may experience a shorter or longer duration of effect.

    Intramuscular Route

    After IM administration of recommended doses, it is not possible to detect incobotulinumtoxinA in the peripheral blood using current technology. In a comparator study of incobotulinumtoxinA and onabotulinumtoxinA, the paralytic effect was measured by changes in compound muscle action potential (CMAP) after the IM injection of 4 units of either drug into the extensor digitorum brevis muscle of the foot in 14 healthy male adults. Regardless of the agent used, a 30% reduction in CMAP occurred in more than 50% of subjects on day 1. By day 7, all subjects had a 30% CMAP reduction after incobotulinumtoxinA receipt. The maximal effect on CMAP occurred between 7 to 14 days after administration (median CMAP approximately 40% of baseline); the median CMAP with both treatment methods was approximately 60% of baseline at the trial end on day 90.
     
    In a phase 3 clinical trial of incobotulinumtoxinA for the treatment of blepharospasm, the median time to onset of effect was 4 days, the median time to waning of effect was 11 weeks, and the median duration of treatment effect was 110 days as reported by study patients.
     
    In a phase 3 clinical trial of incobotulinumtoxinA therapy for the treatment of cervical dystonia, the median time to onset of treatment effect was 7 days, the median time to waning of effect was 10 weeks, and the median duration of treatment effect was 110 days as reported by study patients.
     
    From pooled data of 2 phase 3 studies of incobotulinumtoxinA for the treatment of glabellar lines, the median time to onset of treatment effect was 2 to 3 days. After day 30, there was a gradual decline in the improvement of frown line severity; however, mean improvement compared to baseline was still present at day 120.
     
    In a phase 3 study of incobotulinumtoxinA in patients with poststroke upper limb spasticity, the median time to onset of treatment effect was 4 days, and the median time to waning of effect was 10 weeks as reported by study patients.

    Other Route(s)

    Intraglandular Route
    After intrasalivary gland administration of recommended doses, it is not possible to detect incobotulinumtoxinA in the peripheral blood using current technology.