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  • CLASSES

    Muscle Relaxants, Other Neuromuscular Blockers

    BOXED WARNING

    Botulism, cerebral palsy

    A boxed warning in the labeling of incobotulinumtoxinA includes post-marketing reports of the distant spread of botulinum toxic effects that have resulted in symptoms suggestive of systemic botulism (including asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, swallowing problems, dysphonia, dysarthria, urinary incontinence and breathing difficulties) after the use of botulinum toxins types A and B. These effects have been seen in patients who received a botulinum toxin for a variety of conditions and a wide range of doses, including doses at and lower than those used to treat cervical dystonia; however, the majority of cases have occurred in pediatric patients treated for cerebral palsy-associated limb spasticity. Fatalities have been reported. These adverse effects have occurred as early as hours and as late as several weeks after treatment. Patients and caregivers should be able to identify the signs and symptoms of systemic effects after receiving an injection of a botulinum toxin, and they should seek immediate medical attention if they have worsening or unexpected difficulty swallowing or talking, trouble breathing, or muscle weakness.

    DEA CLASS

    Rx

    DESCRIPTION

    Intramuscular neurotoxin
    Used to reduce local muscle activity in patients with blepharospasm, cervical dystonia, and upper limb spasticity; used cosmetically for glabellar facial wrinkles.
    Less stringent storage requirements and longer shelf-life than other botulinum toxin products

    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 (Botox).
    Intramuscular dosage
    Adults

    The initial recommended dose is the same dose as the patient's previous treatment with onabotulinumtoxinA (Botox); if the previous dose is unknown, then the initial recommended dose is 1.25 to 2.5 units/injection. Do not exceed 35 units/eye. Each treatment is expected to last approximately 12 weeks, after which the procedure can be repeated; do not dose more frequently than every 12 weeks. At repeat treatment sessions, the dose may be adjusted based on the response of the individual patient, up to a maximum of 35 units/eye. IncobotulinumtoxinA dosing has not been established in patients who are botulinum toxin naive and, specifically, have not been previously treated with onabotulinumtoxinA.

    For the treatment of cervical dystonia to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naive and botulinum toxin-experienced patients.
    Intramuscular dosage
    Adults

    An initial total dose of 120 units IM divided and injected into affected muscles (e.g., sternocleidomastoid, levator scapulae, splenius capitis, scalenus, trapezius) is recommended. Tailor dosing in the initial and follow-up treatment sessions to the individual patient based on head and neck position, localization of pain, muscle hypertrophy, patient response to previous botulinum toxin treatments, and adverse event history. Base the frequency of repeat doses on the patient's clinical response; however, dosing more frequent than every 12 weeks is generally not recommended.

    For the treatment of moderate to severe glabellar lines (facial wrinkles).
    NOTE: IncobotulinumtoxinA has been studied in a limited number of geriatric patients (age >= 65 years) with glabellar facial wrinkles (4% of study patients). Efficacy was observed in 20% (3/15) of incobotulinumtoxinA treated patients 65 years and over, with no increase in the incidence of adverse events.
    Intramuscular dosage
    Adults

    20 Units total dose divided equally (4 Units/injection) and injected IM at 5 sites, 2 injections in each corrugator muscle and 1 injection in the procerus muscle; do not re-treat more frequently than every 3 months.

    For the treatment of upper limb spasticity.
    Intramuscular dosage
    Adults

    Individualize dosage, frequency, and number of injection sites to the individual 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. The frequency of injections should be no sooner than every 12 weeks. In patients not previously treated with botulinum toxins, initial dosing should begin at the low end of the recommended dosing range and titrated as necessary. In clinical trials, most patients were retreated between 12 and 14 weeks. The total dosage in any treatment session did not exceed 400 Units. Dose guidance for specific muscle groups is as follows: CLENCHED FIST: FLEXOR DIGITORUM SUPERFICIALIS or FLEXOR DIGITORUM PROFUNDUS: 25 to 100 units IM injected in 2 muscles. FLEXED WRIST: FLEXOR CARPI RADIALIS: 25 to 100 units IM injected in 1 to 2 muscles. FLEXOR CARPI ULNARIS: 20 to 100 units IM injected in 1 to 2 muscles. FLEXED ELBOW: BRACHIORADIALIS: 25 to 100 units IM injected into 1 to 3 muscles. BICEPS: 50 to 200 units IM injected into 1 to 4 muscles. BRACHIALIS: 25 to 100 units IM injected into 1 to 2 muscles. PRONATED FOREARM: PRONATOR QUADRATUS: 10 to 50 units IM injected into 1 muscle. PRONATOR TERES: 25 to 75 units IM injected into 1 to 2 muscles. THUMB-IN-PALM: FLEXOR POLLICIS LONGUS: 10 to 50 units IM injected into 1 muscle. ADDUCTOR POLLICIS: 5 to 30 units IM injected into 1 muscle. FLEXOR POLLICIS BREVIS/OPPONENS POLLICIS: 5 to 30 units IM injected into 1 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.

    MAXIMUM DOSAGE

    Adults

    400 units IM per treatment session is recommended for upper limb spasticity; 120 units IM per treatment session is recommended for cervical dystonia; 35 units IM per eye is recommended for blepharospasm; 20 units IM per treatment session is recommended for glabellar facial wrinkles.

    Geriatric

    400 units IM per treatment session is recommended for upper limb spasticity; 120 units IM per treatment session is recommended for cervical dystonia; 35 units IM per eye is recommended for blepharospasm; 20 units IM per treatment session is recommended for glabellar facial wrinkles.

    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.

    Intramuscular Administration

    IncobotulinumtoxinA is administered by local intramuscular injection.
     
    Reconstitution/Dilution:
    Reconstitute with sterile, preservative-free 0.9% sodium chloride. Using aseptic technique draw up the proper amount of diluent (see dilutions below) 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 injection 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
    2 mL of diluent = 2.5 units/0.1 mL
    4 mL of diluent = 1.25 units/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
    2 mL of diluent = 5 units/0.1 mL
    4 mL of diluent = 2.5 units/0.1 mL
    8 mL of diluent = 1.25 units/0.1 mL
    Store reconstituted solution under refrigeration (2 to 8 degrees C) until ready for use. Administer within 24 hours of reconstitution.
     
    Intramuscular injection:
    Use each vial of reconstituted incobotulinumtoxinA for one session and one 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.
    Blepharospasm: Use a sterile 26-gauge (0.45 mm diameter), 37 mm length needle for superficial muscles; or a 22-gauge (0.70 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 (0.70 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. Injections should be made very 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—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.

    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

    The administration of 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 an increase in the severity of the infection or dissemination of the infection.

    Botulism, cerebral palsy

    A boxed warning in the labeling of incobotulinumtoxinA includes post-marketing reports of the distant spread of botulinum toxic effects that have resulted in symptoms suggestive of systemic botulism (including asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, swallowing problems, dysphonia, dysarthria, urinary incontinence and breathing difficulties) after the use of botulinum toxins types A and B. These effects have been seen in patients who received a botulinum toxin for a variety of conditions and a wide range of doses, including doses at and lower than those used to treat cervical dystonia; however, the majority of cases have occurred in pediatric patients treated for cerebral palsy-associated limb spasticity. Fatalities have been reported. These adverse effects have occurred as early as hours and as late as several weeks after treatment. Patients and caregivers should be able to identify the signs and symptoms of systemic effects after receiving an injection of a botulinum toxin, and they should seek immediate medical attention if they have worsening or unexpected difficulty swallowing or talking, trouble breathing, or muscle weakness.

    Dysphagia, respiratory insufficiency

    IncobotulinumtoxinA-induced weakening of injected muscles may result in the development of impaired swallowing and/or respiration in patients with cervical dystonia, particularly in those with pre-existing dysphagia or respiratory insufficiency. Patients who are dependent on neck muscles to serve as accessory muscles of ventilation may be at increased risk of respiratory compromise after treatment a botulinum toxin product. Dysphagia, if it occurs, is typically mild to moderate; however, rare consequences of severe dysphagia include aspiration, dyspnea, pneumonia, and the need to reestablish an airway. Death as a complication of severe dysphagia has been reported after treatment with botulinum toxin. Such adverse events can occur within hours to weeks and may persist for several months. Patients at the greatest risk are those with smaller neck muscle mass and those who require bilateral injections into the sternocleidomastoid muscle when treating cervical dystonia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Advise patients and caregivers to seek immediate medical assistance if problems with speech, swallowing, or respiration develop.

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

    Use incobotulinumtoxinA cautiously in patients with myopathy associated with neuromuscular disease [e.g., amyotrophic lateral sclerosis (ALS), motor neuropathy, myasthenia gravis or Lambert-Eaton syndrome]. These patients may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of incobotulinumtoxinA. Increased monitoring is prudent in such patients.

    Viral infection

    IncobotulinumtoxinB 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 who receive incobotulinumtoxinB. 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. Further, 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. Botulinum toxin should be given only if a benefit is expected. All infections thought by a physician to have been possibly transmitted by this medication should be reported to the manufacturer. Prior to therapy initiation discuss the risks and benefits of this product with the patient and/or the health care surrogate of the patient.

    Closed-angle glaucoma

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

    Children, infants

    The safety and efficacy of incobotulinumtoxinA in infants, children, and adolescents has not been established. Post-marketing cases of the distant spread of botulinum toxic effects resulting in symptoms suggestive of systemic botulism have been reported; pediatric patients appear to be at the highest risk for systemic effects.

    Pregnancy

    IncobotulinumtoxinA is classified in FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. In animal studies, doses above the maximum recommended human dose (MRHD) for cervical dystonia (120 units) on a body weight basis resulted in embryotoxicity in rats and increased abortion in rabbits. The manufacturer recommends use during pregnancy only if the benefit to the mother justifies the potential risk to the fetus.

    Breast-feeding

    Data are limited regarding use of incobotulinumtoxinA during breast-feeding, and its excretion in human milk is unknown. According to the manufacturer, the drug should be used with caution in breast-feeding mothers; however, because measurable concentrations are not expected to be present in systemic circulation, excretion into breast milk is considered unlikely. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    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 develop during incobutulinumtoxinA therapy. Such symptoms may result from local effects of the toxin in the injected muscles; if however, the symptoms result from distant spread of the toxin product, this may indicate a potentially fatal condition. Advise patients and caregivers to seek medical help if general weakness or problems with breathing, swallowing, or talking are noted. Symptoms have occurred within hours to weeks following treatment.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 0-12.0
    serum sickness / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    ectropion / Early / Incidence not known
    corneal erosion / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known

    Moderate

    dysphagia / Delayed / 0-18.0
    blurred vision / Early / 0-12.0
    dyspnea / Early / 0-5.0
    photophobia / Early / 1.4-1.4
    antibody formation / Delayed / 1.1-1.1
    paresis / Delayed / 0-1.0
    hematoma / Early / 0-1.0
    blepharospasm / Early / 0-0.2
    edema / Delayed / Incidence not known
    erythema / Early / Incidence not known
    hypoventilation / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    urinary incontinence / Early / Incidence not known
    dysarthria / Delayed / Incidence not known

    Mild

    infection / Delayed / 0-20.0
    ptosis / Delayed / 0-19.0
    xerophthalmia / Early / 0-16.0
    xerostomia / Early / 0-16.0
    weakness / Early / 0-11.0
    injection site reaction / Rapid / 0-9.0
    diarrhea / Early / 0-8.0
    headache / Early / 0-7.1
    musculoskeletal pain / Early / 0-7.0
    pharyngitis / Delayed / 0-5.0
    back pain / Delayed / 0-5.0
    arthralgia / Delayed / 0-3.0
    myalgia / Early / 0-2.0
    asthenia / Delayed / 0-2.0
    blepharedema / Early / 0-1.0
    rash (unspecified) / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / 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.
    Darifenacin: (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).
    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.
    Fesoterodine: (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).
    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

    IncobotulinumtoxinA is classified in FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. In animal studies, doses above the maximum recommended human dose (MRHD) for cervical dystonia (120 units) on a body weight basis resulted in embryotoxicity in rats and increased abortion in rabbits. The manufacturer recommends use during pregnancy only if the benefit to the mother justifies the potential risk to the fetus.

    Data are limited regarding use of incobotulinumtoxinA during breast-feeding, and its excretion in human milk is unknown. According to the manufacturer, the drug should be used with caution in breast-feeding mothers; however, because measurable concentrations are not expected to be present in systemic circulation, excretion into breast milk is considered unlikely. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    IncobotulinumtoxinA blocks neuromuscular conduction by inhibiting the release of acetylcholine from peripheral motor 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 SNAP-25 protein, which is integral to the successful docking and release of acetylcholine from vesicles within nerve endings. After intramuscular injection of a therapeutic dose, incobotulinumtoxinA produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. Impulse transmission re-establishment occurs when new nerve ending are formed.

    PHARMACOKINETICS

    IncobotulinumtoxinA is administered by local intramuscular injection. Animal (rodent) studies have shown the degree and duration of muscle paralysis to be dose-dependent. The recommended quantities of neurotoxin administered at each treatment session are not expected to result in systemic, overt distant clinical effects, i.e. muscle weakness, in patients without other neuromuscular dysfunction.

    Intramuscular Route

    After IM administration of recommended doses, it is not possible to detect incobotulinumtoxinA in the peripheral blood using current technology. A median first onset of effect within 7 days and a duration of action of up to 3 months is typical; however, individual patients may experience a shorter or longer duration of effect. 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. After receiving onabotulinumtoxinA, 5 subjects had a 30% reduction in CMAP on Day 2 and 1 subject had a 30% reduction in CMAP on Day 7 and 9 each. 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.