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    Anti-wrinkle Agents, Rx
    Injectable Agents for Hyperhidrosis
    Muscle Relaxants, Other Neuromuscular Blockers

    BOXED WARNING

    Children, distant spread of toxin effects

    Postmarketing safety data suggest injection of botulinum toxins may, in some cases, result in the distant spread of toxin effects resulting in systemic symptoms (e.g., asthenia, generalized muscle weakness, diplopia, ptosis, trouble swallowing, dysphonia, dysarthria, urinary incontinence, breathing difficulties). Advise patients or caregivers to seek immediate medical care if swallowing, speech, or respiratory disorders occur. These symptoms have been reported hours to weeks after injection. There have been reports of death related to the spread of toxin effects. Risk is probably greatest in children treated for spasticity, but symptoms can also occur in adults treated for other indications, especially in those who have underlying conditions predisposing them to these effects. Symptoms have been reported in patients receiving doses comparable to or lower than doses used to treat cervical dystonia and spasticity.[29334] [41123]

    DEA CLASS

    Rx

    DESCRIPTION

    Formerly known as botulinum toxin type A; IM toxin that reduces local muscle activity
    Used for cervical dystonia, blepharospasm, strabismus, upper and lower limb spasticity, facial wrinkles, migraine prophylaxis, excessive sweating, overactive bladder, and neurogenic detrusor overactivity
    Distant spread of botulinum toxic effects from the site of injection has resulted in symptoms suggestive of systemic botulism (including respiratory compromise and death) after the use of botulinum toxins types A and B

    COMMON BRAND NAMES

    Botox, Botox Cosmetic

    HOW SUPPLIED

    Botox Intradermal Inj Pwd F/Sol: 100U, 200U
    Botox/Botox Cosmetic Intramuscular Inj Pwd F/Sol: 50U, 100U, 200U

    DOSAGE & INDICATIONS

    For the treatment of blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders.
    Intramuscular dosage
    Adults, Adolescents, and Children >= 12 years

    The initial recommended dose is 1.25—2.5 units (0.05—0.1 mL) injected at each site. Generally, the initial effect of the injections is seen within 3 days and reaches a peak 1—2 weeks posttreatment. Each treatment lasts approximately 3 months, after which the procedure can be repeated. At repeat treatment sessions, the dose may be increased up to 2-fold if the response from the initial treatment is considered insufficient, which is usually defined as an effect that does not last longer than 2 months. Little benefit appears to be obtained from injecting more than 5 units per site. Some tolerance may be observed when the toxin is administered any more frequently than every 3 months, and it is rare to have the effect be permanent. The cumulative dose in a 30-day period should not exceed 200 units.

    For the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia.
    Intramuscular dosage
    Adults and Adolescents >= 16 years

    Phase III studies for cervical dystonia involved patients who had extended histories of receiving and tolerating onabotulinumtoxinA injections, with prior individualized dosage adjustments. The mean dose in phase III studies was 236 units IM (range: 198—300 units) divided among the affected muscles. Dosing in initial and sequential treatment sessions should be tailored to the individual patient based on head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history. Patients without prior use of botulinum toxin should be started with a lower initial dose, with subsequent dosing adjusted based on individual response. Limiting the total dose injected into the sternocleidomastoid muscles to 100 units or less may decrease the occurrence of dysphagia.

    For the treatment of strabismus.
    NOTE: Injection should be carried out only with electromyographic guidance. The toxin must be suitably diluted, and the volume injected should be between 0.05—0.15 mL per muscle, dependent on the extent of strabismus. Use the lower doses for small deviations and the larger doses only for large deviations. Initial doses typically create paralysis of injected muscles beginning 1—2 days after injection and increasing in intensity during the first week. The paralysis lasts for 2—6 weeks and gradually resolves over a similar time period. Overcorrections lasting longer than 6 months rarely occur. About 50% of patients will require subsequent doses because of inadequate paralytic response to the initial dose, because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilize the alignment.
    For vertical muscles, and for horizontal strabismus of less than 20 prism diopters.
    Intramuscular dosage
    Adults, Adolescents, and Children >= 12 years

    1.25—2.5 units in any 1 muscle.

    For horizontal strabismus of 20 prism diopters to 50 prism diopters.
    Intramuscular dosage
    Adults, Adolescents, and Children >= 12 years

    2.5—5 units in any 1 muscle.

    For persistent VI nerve palsy of 1 month or longer duration.
    Intramuscular dosage
    Adults, Adolescents, and Children >= 12 years

    1.25—2.5 units in the medial rectus muscle.

    For subsequent dosing for residual or recurrent strabismus.
    Intramuscular dosage
    Adults, Adolescents, and Children >= 12 years

    Patients should be reexamined 7—14 days after each injection to assess the effect of that dose. Patients experiencing adequate paralysis of the target muscle who require subsequent injections should receive a dose comparable to the initial dose. For patients experiencing incomplete paralysis of the target muscle, subsequent doses may be increased up to 2-fold compared to the previously administered dose. Subsequent injections should not be given until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles. The maximum recommended dose as a single injection for any 1 muscle is 25 units.

    For temporary improvement in the appearance of facial wrinkles.
    For temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugators and/or procerus muscle activity.
    Intramuscular dosage
    Adults

    The approved dose is 20 units total dose divided equally (4 units/injection) and injected intramuscularly at 5 sites, 2 injections in each corrugator muscle and 1 injection in the procerus muscle; the duration of effect is expected to last 3 to 4 months; more frequent use is not recommended. For simultaneous treatment with glabellar lines, the dose is 24 units for lateral canthal lines and 20 units for glabellar lines, with a total dose of 44 units. The response rate was lower in subjects aged 65 years and older compared with younger subjects in clinical studies. Higher doses have been used in clinical practice; women typically receive 25 units of onabotulinumtoxinA per session in a 5-step process consisting of 2 injections on each side: 1 injection each to paralyze the corrugator superciliaris muscle and the orbicularis muscle and a fifth injection of 5 units made into the middle of the procerus muscle. Men require 2 additional injections of 5 units on each side into the orbicularis, just above the eyebrow in the mid pupillary line making the total dose 35 units. Successful therapy is indicated by muscle weakening 24 to 48 hours after injection and peaking at up to 7 days. Retreatment depends upon how deep and pronounced the glabellar furrow is. Patients without deep furrows typically should return for reinjection when they notice return of brow wrinkling. For those with deep glabellar furrow, reinjection every 3 to 4 months is recommended to allow the furrow to drop out, which generally requires 12 months. Once the forehead is smooth, these patients should return only when they notice a return of muscle movement.

    For temporary improvement in the appearance of other wrinkles such as melolabial folds† and other hyperkinetic facial lines†.
    Subcutaneous dosage†
    Adults

    OnabotulinumtoxinA is used as a muscle weakener in treating wrinkles in areas other than the glabella. These wrinkles are the result of physiologically important facial muscles and complete paralysis may create unacceptable functional deficits. Typically, 1 to 2 units per site is injected subcutaneously.

    For temporary improvement in the appearance of moderate to severe lateral canthal lines associated with orbicularis oculi activity (crow's feet).
    Intramuscular dosage
    Adults

    Inject 4 units into 3 sites per side (6 total injection points) in the lateral orbicularis oculi muscle for a total of 24 units, or 12 units per side. The first injection should be approximately 1.5 to 2 cm temporal to the lateral canthus and just temporal to the orbital rim. For simultaneous treatment with glabellar lines, the dose is 24 units for lateral canthal lines and 20 units for glabellar lines, with a total dose of 44 units. The safety and efficacy of dosing more frequently than every 3 months has not been evaluated. The response rate was lower in subjects aged 65 years and older compared with younger subjects in clinical studies.

    For the treatment of moderate to severe forehead lines associated with frontalis muscle activity.
    Intramuscular dosage
    Adults

    Inject 4 units into 5 sites in the frontalis muscle, for a total of 20 units. Place the 5 injections at the intersection of the horizontal treatment. Treat forehead lines in conjunction with glabellar lines to minimize the potential for brow ptosis. The total recommended dose for forehead lines (20 units) in conjunction with glabellar lines (20 units) is 40 units. For simultaneous treatment with lateral canthal lines, the total dose is 64 units, comprised of 20 units for forehead lines, 20 units for glabellar lines, and 24 units for lateral canthal lines.

    For the treatment of spasticity.
    For upper limb spasticity.
    Intramuscular dosage
    Adults

    75 to 400 units IM divided among the affected muscles was used during clinical trials. Max cumulative dose per 3-month period: 400 units. Tailor dosing to the individual based on size, number and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient response to previous treatment, and history of adverse events. Use the lowest recommended starting dose; no more than 50 units/site should generally be administered. Specific recommendations per muscle group are as follows: BICEPS BRACHII: 60 to 200 units IM divided in 2 to 4 sites; BRACHIALIS: 30 to 50 units IM divided in 1 to 2 sites; BRACHIORADIALIS: 45 to 75 units IM divided in 1 to 2 sites; FLEXOR CAPRI RADIALIS and ULNARIS: 12.5 to 50 units IM in 1 site; FLEXOR DIGITORUM PROFUNDUS and SUBLIMIS: 30 to 50 units IM in 1 site; FLEXOR POLLICIS BREVIS/OPPONENS POLLICIS: 5 to 25 units IM in 1 site; FLEXOR POLLICIS LONGUS and ADDUCTOR POLLICIS: 20 units IM in 1 site; LUMBRICALS/INTEROSSEI: 5 to 10 units IM in 1 site; PRONATOR QUADRATUS: 10 to 50 units IM in 1 site; PRONATOR TERES: 15 to 25 units IM in 1 site. Repeat treatment when the effect of the previous injection has diminished; however, generally, no sooner than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may require alterations in the dose and the muscles to be injected.[29334] Clinical practice guidelines consider onabotulinumtoxinA to be effective for the treatment of upper limb spasticity and is probably superior to tizanidine for reducing upper extremity tone. In a placebo-controlled trial, onabotulinumtoxinA was superior to tizanidine for improving wrist and finger flexor tone.[61468]

    Children and Adolescents 2 to 17 years

    3 to 6 units/kg IM divided among the affected muscles. Max per treatment session: 6 units/kg or 200 units, whichever is less. Max cumulative dose per 3-month period: 10 units/kg or 340 units, whichever is less. Tailor dosing to the individual based on size, number and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient response to previous treatment, and history of adverse events. Use the lowest recommended starting dose; no more than 50 units/site should generally be administered. Specific recommendations per muscle group are as follows: BICEPS BRACHII: 1.5 to 3 units/kg IM divided in 4 sites; BRACHIALIS, FLEXOR CARPI RADIALIS, or FLEXOR CARPI ULNARIS: 1 to 2 units/kg IM divided in 2 sites; BRACHIORADIALIS, FLEXOR DIGITORUM PROFUNDUS, or FLEXOR DIGITORUM SUBLIMIS: 0.5 to 1 unit/kg IM divided in 2 sites. Repeat treatment when the effect of the previous injection has diminished; however, generally, no sooner than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may require alterations in the dose and the muscles to be injected.[29334]

    For the chronic management of focal spasticity† in pediatric patients with cerebral palsy and concurrent equinus gait (tiptoeing).
    Intramuscular dosage
    Children and Adolescents 2 to 17 years

    4 units/kg IM (Max: 200 units per treatment) every 3 months was used in a study of 207 pediatric patients with cerebral palsy exhibiting equinus foot deformity; 155 patients recieved at least 1 year of treatment. The total calculated dose was diluted to a volume of 4 mL for hemiplegic patients and 8 mL for diplegic patients in order to keep the total volume injected constant. At 6 weeks, 46% of patients (n = 185) had improvement in their gait pattern and ankle position. After 2 years, the improvements were maintained in nearly 50% of patients.[26756] Based on previous studies by the lead author, an injection of 2 mL was injected per muscle site (2 mL in the medial and 2 mL in the lateral gastrocnemius of each involved leg).[26757] [26758]

    For lower limb spasticity.
    Intramuscular dosage
    Adults

    300 to 400 units IM divided among 5 muscles. Max cumulative dose per 3-month period: 400 units. Tailor dosing to the individual based on size, number and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient response to previous treatment, and history of adverse events. Use the lowest recommended starting dose; no more than 50 units/site should generally be administered. Specific recommendations per muscle group are as follows: GASTROCNEMIUS MEDIAL HEAD and LATERAL HEAD, SOLEUS, and TIBIALIS POSTERIOR: 75 units IM divided in 3 sites; FLEXOR HALLUCIS LONGUS and DIGITORUM LONGUS: 50 units IM divided in 2 sites. Repeat treatment when the effect of the previous injection has diminished; however, generally, no sooner than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may require alterations in the dose and the muscles to be injected.[29334] OnabotulinumtoxinA has demonstrated significant reductions in lower extremity muscle tone but inconsistent results with functional outcomes, suggesting that functional gains are highly patient-specific. Clinical practice guidelines consider onabotulinumtoxinA to be effective for the treatment of lower extremity spasticity.[61468]

    Children and Adolescents 2 to 17 years

    4 to 8 units/kg IM divided among the affected muscles. Max per treatment session: 8 units/kg or 300 units, whichever is less. Max cumulative dose per 3-month period: 10 units/kg or 340 units, whichever is less. Tailor dosing to the individual based on size, number and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient response to previous treatment, and history of adverse events. Use the lowest recommended starting dose; no more than 50 units/site should generally be administered. Specific recommendations per muscle group are as follows: GASTROCNEMIUS MEDIAL and LATERAL HEAD, SOLEUS, and TIBIALIS POSTERIOR: 1 to 2 units/kg IM divided in 2 sites. Repeat treatment when the effect of the previous injection has diminished; however, generally, no sooner than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may require alterations in the dose and the muscles to be injected.[29334]

    For the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating).
    NOTE: Safety and efficacy for the treatment of hyperhidrosis in other body areas have not ben established. Use for palmar hyperhidrosis may lead to weakness of hand muscles and use for facial hyperhidrosis may lead to blepharoptosis.
    NOTE: Evaluate patients for potential causes of secondary hyperhidrosis (e.g. hyperthyroidism) prior to initiating therapy.
    Intradermal dosage
    Adults

    50 units (diluted to 25 units/mL) injected intradermally to each axilla; distribute dose in 0.1—0.2 mL aliquots at multiple (10—15) sites approximately 1—2 cm apart. Re-treat when clinical effect of previous injection diminishes. Prior to dose administration, define hyperhidrotic area to be injected using standard staining techniques, e.g., Minor's Iodine-Starch Test.

    For chronic migraine prophylaxis.
    Intramuscular dosage
    Adults

    155 units IM as 5 units/injection divided across 7 specific head and neck muscle areas and 31 injection sites. The recommended doses per muscle area are as follow: frontalis: 20 units divided in 4 sites; corrugator: 10 units divided in 2 sites; procerus: 5 units in 1 site; occipitalis: 30 units divided in 6 sites; temporalis: 40 units divided in 8 sites; trapezius: 30 units divided in 6 sites; cervical paraspinal muscle group: 20 units divided in 4 sites. Administer bilaterally to each muscle/muscle group except to the procerus muscle, which is injected once at the midline. Repeat every 12 weeks.[29334] Guidelines classify onbotulinumtoxinA as having established efficacy for chronic migraine prophylaxis.[57981] [64551] [61468]

    For the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., as occurs with neurogenic bladder in spinal cord injury, multiple sclerosis) in patients with an inadequate response or intolerance to an anticholinergic medication.
    Intramuscular dosage
    Adults

    200 units IM per treatment injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. Insert the needle approximately 2 mm into the detrusor, and space 30 injections of 1 mL (approximately 67 units/mL) each about 1 cm apart. Inject approximately 1 mL of sterile normal saline for the final injection to assure the full dose is delivered to the bladder. Consider re-injection when the clinical effect diminishes (median time to retreatment: 42 to 48 weeks), but no sooner than 12 weeks.

    Children and Adolescents 5 to 17 years weighing 34 kg or more

    200 units IM per treatment injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. Insert the needle approximately 2 mm into the detrusor, and space 20 injections of 0.5 mL (10 units/0.5 mL) each about 1 cm apart. Inject approximately 1 mL of sterile normal saline for the final injection to assure the full dose is delivered to the bladder. Consider re-injection when the clinical effect diminishes (median time to retreatment: 30 weeks), but no sooner than 12 weeks.

    Children and Adolescents 5 to 17 years weighing less than 34 kg

    6 units/kg IM per treatment injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. Insert the needle approximately 2 mm into the detrusor, and space 20 injections of 0.5 mL each about 1 cm apart. Inject approximately 1 mL of sterile normal saline for the final injection to assure the full dose is delivered to the bladder. Consider re-injection when the clinical effect diminishes (median time to retreatment: 30 weeks), but no sooner than 12 weeks.

    For the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency in adults intolerant to or with inadequate response from anticholinergic medications.
    Intramuscular dosage
    Adults

    The recommended and maximum dose is 100 units IM per treatment injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The injection needle should be filled (primed) with approximately 1 mL of reconstituted drug prior to the start of the injection to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each should be spaced about 1 cm apart. For the final injection, approximately 1 mL of sterile normal saline should be injected so the full dose is administered. The bladder should be instilled with enough saline to achieve adequate visualization for the injection, but avoid overdistention. Following the injections, the saline used for visualization should be drained. The patient should be observed for at least 30 minutes after the injection and until a spontaneous void has occurred. Per individual site practice, intravesical installation of diluted local anesthetic, with or without sedation, may be administered prior to the injection. Retreatment for diminished effectiveness should be considered no sooner than 12 weeks from the previous bladder injection. Intradetrusor injection is contraindicated in patients with urinary tract infection (UTI), and patients with urinary retention or postvoid residuals (PVR) greater than 200 mL who are not routinely performing clean intermittent self-catheterizations (CIC). Per guidelines, intradetrusor onabotulinumtoxina is a third-line treatment for patients refractory to first- and second-line OAB treatments who are able and willing to return for frequent post-void residual evaluation and able and willing to perform self-catheterization if necessary.

    For the treatment of achalasia†.
    Endoscopic injection dosage
    Adults

    A usual dose is 20 to 25 units per injection, diluted in 0.5 to 1 mL of preservative-free saline, injected 1 cm above the squamocolumnar junction into 4 or more quadrants of the lower esophageal sphincter (LES); total dosage not to exceed 100 units/treatment. A sclerotherapy needle is used to achieve placement during upper-gastrointestinal endoscopy. A systematic review has shown initial (1-month) response to therapy is 78.7%, however long-term (12-month) success rate is 40.6%. Repeat injections were needed in 46.6% of patients and 30% of patients required additional treatments for symptom relief. Doses higher than 100 units/treatment have not been shown to be more effective. Authors of a small (n = 30) study concluded that if the initial response to the first injection is symptomatic, then sustained response is likely, whereas no initial response suggests poor response to additional injections. They also indicated that a residual LES tone of less than 18 mm Hg after botulinum injection is a predictor of a good response. Guidelines recommend against the use of botulinum toxin injection as definitive therapy for achalasia; it may be reserved for patients who are not candidates for other definitive therapies.

    For the treatment of sialorrhea† (excessive drooling).
    For sialorrhea† associated with Parkinson's disease†.
    Glandular dosage
    Adults

    In one randomized, placebo-controlled trial, a single treatment of 50 units was injected into each parotid gland without ultrasound guidance. Compared to baseline measurements, there was significant improvement at 1 month in the objective measure of saliva production as well as subjective outcome measures including the visual analogue score of drooling frequency (VAS-D), the assessment of patient embarrassment within the familial (VAS-FD) and social (VAS-SD) context, and the drooling subscore of the Unified Parkinson’s Disease Rating Scale (UPDRS), but not the UPDRS dysphagia subscore. Assessment of global satisfaction also favored the active treatment group (88% vs. 31%). Duration of treatment effect beyond 1 month and efficacy of repeated treatments were not examined. In a separate study including 2 patients with Parkinson's disease, parotid gland doses ranged from 15—40 units (mean: 28 units/gland) into 2 injection sites. The dose administered in the submandibular glands ranged from 10—15 units/gland (mean: 12 units/gland) using ultrasound guidance. The total dose for each patient was calculated based on the rate of salivation before treatment and the patient’s body weight, and ranged from 50—100 units (mean: 77 units). Nine patients (90%) reported a lessening in hypersalivation after treatment. In one dose-finding study including 12 patients with Parkinson's disease, low intraparotid doses (i.e., 18.75—37.5 units) had a less robust effect, with only the 75-unit total dose achieving the primary end point of a significant reduction in sialorrhea (approximately 50%). Injections were repeated 3 months later. There was a stable reduction of drooling for 1 month after the injection with a partial relapse about 3 months after treatment. Ultrasound-guided injections appear to be associated with superior results compared to administration without ultrasound guidance as measured by quantitative saliva assessments.

    For sialorrhea† associated with amyotrophic lateral sclerosis (ALS)†.
    Glandular dosage
    Adults

    In one small study, parotid gland doses ranged from 15—40 units (mean: 28 units/gland) into 2 injection sites with ultrasound guidance. The dose administered in the submandibular glands ranged from 10—15 units/gland. The total dose per patient ranged from 50—100 units. Of 4 ALS patients, only 1 did not experience improvement after receiving the maximum study dose. In a separate placebo-controlled dose-finding study including 12 patients with ALS, low intraparotid doses (i.e., 18.75—37.5 units) had a less robust effect, with only the 75-unit dose achieving the primary end point of a significant reduction in sialorrhea (approximately 50%). Injections were repeated 3 months later. There was a stable reduction of drooling for 1 month after the injection with a partial relapse about 3 months after treatment.

    For sialorrhea† associated with cerebral palsy† .
    Glandular dosage
    Children >= 21 months of age and Adolescents

    In one controlled trial of children aged 6—16 years, a total of 2 units/kg up to a maximum of 70 units total dose was distributed into the parotid and submandibular glands as follows: 1.4 units/kg divided between the 2 parotid glands, and 0.6 units/kg divided between the 2 submandibular glands with ultrasound guidance. The dose used was weight based and ranged from 31.4—70 units (mean: 50.9 units) per child. Each child received 6 injections: 1 into the center of each submandibular gland and 2 into each parotid gland. Drooling frequency and severity showed statistically significant reductions at 4 weeks and 12 weeks. In a separate trial (n = 24), children aged 21 months to 7 years received treatment with 50 units of botulinum toxin A or placebo into each parotid gland (total 100 units) without ultrasound guidance. A second injection of either 70 units of botulinum toxin A or placebo into each parotid gland (total 140 units) was given 4 months later. There was a significant reduction in the frequency and severity of drooling in the active treatment group compared to placebo. Only 2 patients experienced a transient increase in drooling after treatment with the drug.

    For the treatment of Tourette's syndrome† or chronic tic disorders†.
    Intramuscular dosage
    Adults

    Treatment must be individualized and is based on the target muscles injected. In 4 open-label studies of patients 8 to 84 years of age, doses ranged from 2.5 to 300 units IM per treatment session. The effects last 12 to 16 weeks, after which treatment needs to be repeated. Experts recommend use in only very specific situations, such as severely disabling vocal tics (e.g., coprolalia) or very distressing motor tics of the upper face or neck. The American Academy of Neurology (AAN) practice guideline states that onabotulinumtoxinA is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders when used for localized and bothersome simple motor tics or severely disabling or aggressive vocal tics. Premonitory urges may also be improved.

    Children and Adolescents 8 years and older

    Treatment must be individualized and is based on the target muscles injected. In 4 open-label studies of patients 8 to 84 years of age, doses ranged from 2.5 to 300 units IM per treatment session. The effects last 12 to 16 weeks, after which treatment needs to be repeated. Experts recommend use in only very specific situations, such as severely disabling vocal tics (e.g., coprolalia) or very distressing motor tics of the upper face or neck. The American Academy of Neurology (AAN) practice guideline states that onabotulinumtoxinA is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders when used for localized and bothersome simple motor tics or severely disabling or aggressive vocal tics. Premonitory urges may also be improved.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    400 units per 3 month period.

    Geriatric

    400 units per 3 month period.

    Adolescents

    10 units/kg (Max: 340 units) per 3 month period.

    Children

    2 to 12 years: 10 units/kg (Max: 340 units) per 3 month period.
    1 year: 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

    No dosage adjustment needed.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

     
    NOTE: The potency units are not interchangeable with other preparations of botulinum toxin products. Therefore, units of biological activity of onabotulinumtoxinA cannot be compared or converted into units of any other botulinum toxin products assessed with any other specific assay method.[29334]

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    OnabotulinumtoxinA is administered by local intradermal or intramuscular injection and, for specific applications, by specialized local injection techniques adjacent to the appropriate muscle groups.
     
    Reconstitution/Dilution
    Reconstitute with preservative-free 0.9% Sodium Chloride Injection.
    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 vial if a vacuum does not pull the diluent into the vial.
    Gently mix by rotating the vial.
    Storage: Administer within 24 hours of reconstitution. Store unused reconstituted solution in a refrigerator (2 to 8 degrees C) until the time of use. Vials are single-dose only; discard unused portion.[29334]
     
    50 unit onabotulinumtoxinA vial dilution: Add diluent as shown below for desired final concentration.[41123]
    1.25 mL of diluent = 4 units/0.1 mL
     
    100 unit onabotulinumtoxinA vial dilution: Add diluent as shown below for desired final concentration.[29334] [41123]
    1 mL of diluent = 10 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
    8 mL of diluent = 1.25 units/0.1 mL
    10 mL of diluent = 1 unit/0.1 mL
     
    200 unit onabotulinumtoxinA vial dilution: Add diluent as shown below for desired final concentration.[29334]
    1 mL of diluent = 20 units/0.1 mL
    2 mL of diluent = 10 units/0.1 mL
    4 mL of diluent = 5 units/0.1 mL
    8 mL of diluent = 2.5 units/0.1 mL
    10 mL of diluent = 2 units/0.1 mL

    Intramuscular Administration

    Blepharospasm
    Use a sterile 27- to 30-gauge needle without electromyographic guidance.
    Inject into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid.
    Avoiding injection near the levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia.
    Ecchymosis occurs easily in the soft eyelid tissues and can be prevented by applying pressure at the injection site immediately after the injection.[29334]
     
    Cervical dystonia
    A 25-, 27-, or 30-gauge needle may be used for superficial muscles, and a longer 22-gauge needle may be used for deeper musculature.
    Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques is recommended.[29334]
     
    Chronic migraine prophylaxis
    A 30-gauge 0.5 inch needle may be used for IM injections; use a 1 inch needle for thick neck muscles if needed.
    Dilute to a final concentration of 5 units per 0.1 mL.
    Divide the dose to be administered across 7 specific head/neck muscle areas; administer an equal number of injections to each the right and left side of the head and neck with the exception of the procerus muscle, which is injected once at the midline. See product full prescribing information for specific recommendations for sites to be injected and the exact dose to be injected at each site.[29334]
     
    Glabellar facial wrinkles
    Use the 50 or 100 unit vial diluted to a final concentration of 4 units per 0.1 mL.
    Administer injections with patients in the seated position.
    To treat glabellar furrows, the patient is first asked to frown in order to isolate the corrugator superciliaris muscle. Once the patient is relaxed, the toxin is injected into the corrugator muscle by passing the needle inferoposteriorly from just above the brow. The needle tip lines up vertically with the inner canthus. About one-half of the needle length will be in the skin and subcutaneous tissue if it is correctly positioned. At this point, 5 units of the toxin are injected directly into the muscle. With care taken to keep it in the same puncture site, the needle is then almost completely withdrawn and repositioned perpendicular to the skin. After advancing the needle once again to about half its length, 5 units of toxin is injected to treat the most superomedial part of the orbicularis without compromising normal orbicularis function. The 2 injections are then repeated on the contralateral side with needle reinserted directly midline between the eyebrows just below the brow line. A fifth injection of 5 units is made into the middle of the procerus muscle. In men, 2 additional injections of 5 units on each side into the orbicularis are made just above the eyebrow in the midpupillary line.
    At the end of therapy, patients should remain vertical and refrain from touching the treated areas for 3 to 4 hours to avoid spread of toxin to adjacent muscle groups.
    It is important that injections be symmetric so that no unnatural balance is created after therapy. Also, it is important to avoid injection into the eyebrow lateral to the inner canthus because this will increase the likelihood of ptosis.[26405] [26406] [26407] [26408] [26409]
     
    Forehead facial lines
    Use the 50 unit or 100 unit vial diluted to a final concentration of 4 units per 0.1 mL.
    Treat forehead lines in conjunction with glabellar lines to minimize the potential for brow ptosis.
    Draw at least 1 mL (for forehead lines treated in conjunction with glabellar lines) of reconstituted toxin into the sterile syringe (preferably tuberculin). Remove the needle used to reconstitute the product and attach a 30- to 33-gauge needle.
    Locate the horizontal treatment rows by light palpitation of the forehead at rest and maximum eyebrow elevation.
    Superior margin of frontalis activity: approximately 1 cm above the most superior forehead crease.
    Lower treatment row: midway between the superior margin of frontalis activity and the eyebrow, at least 2 cm above the eyebrow.
    Upper treatment row: midway between the superior margin of frontalis activity and lower treatment row.
    Place 5 injections (4 units each) at the intersection of the horizontal treatment rows.
    On the lower treatment row at the midline of the face, and 0.5 to 1.5 cm medial to the palpated temporal fusion line (temporal crest); repeat for the other side.
    On the upper treatment row, midway between the lateral and medial sites on the lower treatment row; repeat for the other side.[41123]
     
    Lateral canthal lines
    Use the 50 unit or 100 unit vial diluted to a final concentration of 4 units per 0.1 mL.
    Inject with the needle bevel tip up and oriented away from the eye.
    Inject into (4 units) 3 sites per side in the lateral orbicularis oculi muscle for a total of 24 units.
    The first injection should be approximately 1.5 to 2 cm temporal to the lateral canthus and just temporal to the orbital rim.[41123]
     
    Strabismus
    OnabotulinumtoxinA is intended for injection into extraocular muscles utilizing the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle.
    Injection without surgical exposure or electromyographic guidance should not be attempted. Physicians should be familiar with electromyographic technique.[29334]
     
    Upper limb spasticity
    A 25-, 27-, or 30-gauge needle may be used for superficial muscles, and a longer 22-gauge needle may be used for deeper musculature.
    Localization of the involved muscles with electromyographic guidance, nerve stimulation, or ultrasound is recommended.[29334]
     
    Bladder detrusor overactivity associated with a neurologic condition
    Discontinue anti-platelet medications at least 3 days prior to treatment. Manage patients on anticoagulant therapy appropriately to decrease the risk of bleeding.
    Administer prophylactic antibiotics (excluding aminoglycosides) 1 to 3 days prior to treatment, on treatment day, and 1 to 3 days after treatment. Alternatively, in patients receiving general anesthesia (or conscious sedation), 1 dose of IV prophylactic antibiotics (excluding aminoglycosides) may be administered on the day of treatment.
    Consider diluted instillation of local anesthetic, use of a sedative, or general anesthesia prior to injection. If local anesthetic instillation is performed, drain and irrigate the bladder with sterile saline before injection.[29334]
    Preparation
    For adult patients, 1 of 2 reconstitution methods may be used depending on the vial strength:
    Reconstitution of 200 unit vial: Reconstitute one 200 unit vial with 6 mL of preservative-free 0.9% Sodium Chloride Injection and mix the vial gently. Draw 2 mL from the vial into each of three 10 mL syringes. Complete reconstitution by adding 8 mL of preservative-free 0.9% Sodium Chloride Injection into each of the 10 mL syringes and mix gently. Each syringe will then contain 10 mL (approximately 67 units), for a total of 200 units of reconstituted onabotulinumtoxinA.
    Reconstitution of 100 unit vials: Reconstitute two 100 unit vials, each with 6 mL of preservative-free 0.9% Sodium Chloride Injection and mix the vials gently. Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe. Complete reconstitution by adding 6 mL of preservative-free 0.9% Sodium Chloride Injection into each of the 10 mL syringes, and mix gently. Each syringe will then contain 10 mL (approximately 67 units), for a total of 200 units of reconstituted onabotulinumtoxinA.
    For pediatric patients, 1 of 2 reconstitution methods may be used depending on the vial strength:
    Reconstitution of 200 unit vials: Add 10 mL of preservative-free 0.9% Sodium Chloride Injection and mix the vial gently.
    Reconstitution of 100 unit vials: Add 5 mL of preservative-free 0.9% Sodium Chloride Injection to each vial and mix gently.
    For pediatric patients weighing 34 kg or more, draw 10 mL (200 units) from the vial(s) into one 10 mL dosing syringe.
    For pediatric patients weighing less than 34 kg, further dilute the reconstituted solution with preservative-free Sodium Chloride Injection (diluent) in a 10 mL dosing syringe, based on patient weight:
    32 to 33 kg: 9.6 mL of reconstituted solution and 0.4 mL diluent (192 units/10 mL syringe)
    30 to 31 kg: 9 mL of reconstituted solution and 1 mL diluent (180 units/10 mL syringe)
    28 to 29 kg: 8.4 mL of reconstituted solution and 1.6 mL diluent (168 units/10 mL syringe)
    26 to 27 kg: 7.8 mL of reconstituted solution and 2.2 mL diluent (156 units/10 mL syringe)
    24 to 25 kg: 7.2 mL of reconstituted solution and 2.8 mL diluent (144 units/10 mL syringe)
    22 to 23 kg: 6.6 mL of reconstituted solution and 3.4 mL diluent (132 units/10 mL syringe)
    20 to 21 kg: 6 mL of reconstituted solution and 4 mL diluent (120 units/10 mL syringe)
    18 to 19 kg: 5.4 mL of reconstituted solution and 4.6 mL diluent (108 units/10 mL syringe)
    16 to 17 kg: 4.8 mL of reconstituted solution and 5.2 mL diluent (96 units/10 mL syringe)
    14 to 15 kg: 4.2 mL of reconstituted solution and 5.8 mL diluent (84 units/10 mL syringe)
    12 to 13 kg: 3.6 mL of reconstituted solution and 6.4 mL diluent (72 units/10 mL syringe)
    Storage: Use preparation immediately after reconstitution and dispose of any unused saline.[29334]
    Administration
    Inject the reconstituted preparation into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. Instill the bladder with enough saline to achieve adequate visualization for the injections; over-distension should be avoided.
    Prime the injection needle with about 1 mL of reconstituted onabotulinumtoxinA prior to injection to remove any air.
    Insert the needle about 2 mm into the detrusor.
    For adult patients, space 30 injections of 1 mL about 1 cm apart.
    For pediatric patients, space 20 injections of 0.5 mL about 1 cm apart.
    Refer to product full prescribing information for visual aide of injection pattern.
    For the final injection, inject about 1 mL of preservative-free 0.9% Sodium Chloride Injection to assure the full dose is administered.
    Drain the saline used for bladder wall visualization.
    Observe the patient for 30 minutes post-injection.[29334]
     
    Overactive bladder
    Use the 100 unit vial reconstituted with 10 mL of preservative-free 0.9% Sodium Chloride for Injection. Use preparation immediately after reconstitution and dispose of any unused saline.
    Reconstituted preparation should be injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections; over-distension should be avoided.
    Fill (prime) the injection needle with approximately 1 mL reconstituted onabotulinumtoxinA prior to injection to remove any air. Insert needle approximately 2 mm into the detrusor. Twenty (20) injections of 0.5 mL each (total volume of 10 mL) should be spaced about 1 cm apart. For the final injection, approximately 1 mL of sterile preservative-free 0.9% Sodium Chloride for Injection should be injected so full dose is administered.
    An intravesical instillation of diluted local anesthetic, with or without sedation, may be used prior to injection. If used, the bladder should be drained and irrigated with sterile saline before injection.
    Discontinue anti-platelet medications at least 3 days prior to injection in any patients receiving such treatment.
    Administer prophylactic antibiotics (excluding aminoglycosides) 1 to 3 days prior to treatment, on treatment day, and 1 to 3 days after treatment.
    May refer to product full prescribing information for visual aide of injection pattern.[29334]

    Subcutaneous Administration

    Facial wrinkles other than glabellar facial wrinkles (e.g., horizontal forehead lines, melolabial folds, and other hyperkinetic facial lines)
    NOTE: OnabotulinumtoxinA is not FDA-approved for these indications.
    Unlike treatment of glabellar facial wrinkles, which are treated via IM injection (see separate Administration instructions), other facial wrinkles are treated with subcutaneous administration of onabotulinumtoxinA. The toxin is used to weaken, not paralyze, related muscles as these wrinkles are the result of physiologically important facial muscles, and complete paralysis may create unacceptable functional deficits.[26405] [26406] [26407] [26408] [26409]

    Other Injectable Administration

    Intradermal Administration
    Primary axillary hyperhidrosis
    Administer onabotulinumtoxinA intradermally for this indication.
    Prior to administration, identify the hyperhydrotic area using standard staining techniques (e.g., Minor's Iodine-Starch Test).
    Dilute to a final onabotulinumtoxinA concentration of 2.5 units/0.1 mL.
    Using a 30-gauge needle, administer 10 to 15 injections intradermally in 0.1 mL to 0.2 mL aliquots within each axilla. Evenly distribute the injections, spacing them approximately 1 to 2 cm apart.
    Administer each injection to a depth of approximately 2 mm and at a 45 degree angle to the skin surface, with the bevel side up to minimize leakage and to ensure the injections remain intradermal.
    If injection sites are marked in ink, do not inject directly through the ink mark to avoid a permanent tattoo effect.[29334]

    STORAGE

    Botox:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store product in refrigerator (36 to 46 degrees F) for up to 36 months from date of manufacture
    - Store reconstituted product in refrigerator (36 to 46 degrees F) and administer within 24 hours
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    Botox Cosmetic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - 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 unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Previously sedentary patients who will resume activities after administration of onabotulinumtoxinA should do so gradually.

    Intravenous administration, requires an experienced clinician

    Use of onabotulinumtoxinA requires an experienced clinician as safe and effective use of onabotulinumtoxinA depends upon proper product storage, dose selection, product reconstitution, and administration technique, in addition to, knowledge of the treated condition. Units of biological activity of onabotulinumtoxinA 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. An understanding of standard electromyographic techniques is also required for the treatment of strabismus and may be useful for the treatment of cervical dystonia. Serious, sometimes fatal, adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, have been reported in patients receiving onabotulinumtoxinA for unapproved uses. Reactions were not necessarily related to distant spread of toxin but may have resulted from the administration of the drug to the site of injection and/or adjacent structures. Several of the cases involved patients with pre-existing difficulty with swallowing or other significant disabilities; however, specific risk factors associated with an increased risk for adverse reactions with the unapproved use onabotulinumtoxinA have not been identified.[29334] The health care professional should have immediate availability of epinephrine (1 mg/mL) injection and other agents used in the treatment of severe anaphylaxis in the event of a serious allergic reaction to onabotulinumtoxinA. Avoid intravenous administration of onabotulinumtoxinA as this can cause distant spread of toxin effects, resulting in serious adverse events, including excessive paralysis, breathing and swallowing difficulties, consistent with botulinum toxicity. In the event of overdose, antitoxin raised against botulinum toxin is available from the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, contact the local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100.

    Children, distant spread of toxin effects

    Postmarketing safety data suggest injection of botulinum toxins may, in some cases, result in the distant spread of toxin effects resulting in systemic symptoms (e.g., asthenia, generalized muscle weakness, diplopia, ptosis, trouble swallowing, dysphonia, dysarthria, urinary incontinence, breathing difficulties). Advise patients or caregivers to seek immediate medical care if swallowing, speech, or respiratory disorders occur. These symptoms have been reported hours to weeks after injection. There have been reports of death related to the spread of toxin effects. Risk is probably greatest in children treated for spasticity, but symptoms can also occur in adults treated for other indications, especially in those who have underlying conditions predisposing them to these effects. Symptoms have been reported in patients receiving doses comparable to or lower than doses used to treat cervical dystonia and spasticity.[29334] [41123]

    Infection, urinary tract infection (UTI)

    OnabotulinumtoxinA is contraindicated in the presence of infection at ANY proposed injection site(s). For example, intradetrusor injection is contraindicated in patients with urinary tract infection (UTI). It is also contraindicated in individuals with known hypersensitivity to any ingredient in the formulation.

    Hyperthyroidism, thyroid disease

    Patients should be evaluated for potential causes of secondary hyperhidrosis (e.g., thyroid disease like hyperthyroidism) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease. The safe and effective use of onabotulinumtoxinA for hyperhidrosis in other body areas have not been established. Weakness of hand muscles may occur in patients who receive the drug for palmar hyperhidrosis. Blepharoptosis may occur in patients who receive it for facial hyperhidrosis.

    Albumin hypersensitivity, viral infection

    Commercial preparations of onabotulinumtoxinA contain albumin and should be used cautiously in patients with albumin hypersensitivity. Albumin is also a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral infection. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin or albumin contained in other licensed products. 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 viral infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present in this product. Botulism 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.

    Dysphagia

    Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia, which is typically mild to moderate, but could be severe after receipt of onabotulinumtoxinA. Additionally, when treating for cervical dystonia, patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia. Rare consequences of severe dysphagia include aspiration, dyspnea, pneumonia, and the need to reestablish an airway. In some patients, symptoms of dysphagia or dyspnea may be the result of distal toxin spread after administration. Serious, sometimes fatal, adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, have been reported in patients receiving onabotulinumtoxinA for unapproved uses and may be related to the site or technique of administration for the unapproved use; in several of the cases involved patients with pre-existing dysphagia or other significant disabilities.

    Pregnancy

    There are no human data on the developmental risk associated with the use of onabotulinumtoxinA during human pregnancy. When administered intramuscularly (8 and 16 units/kg) two times to pregnant mice or rats during organogenesis, reductions in fetal weight and decreased fetal skeletal ossification were observed. The no-effect dose for developmental toxicity is approximately equivalent to the human dose of 400 units. No adverse effects were observed when pregnant rats received a single intramuscular injection.

    Breast-feeding

    It is not known whether onabotulinumtoxinA is excreted in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for onabotulinumtoxinA and any potential adverse effects on the breastfed infant. OnabotulinumtoxinA is not detectable systemically after intramuscular use, thus excretion into breast milk is considered unlikely.

    Geriatric

    Generally, dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Clinical studies of onabotulinumtoxinA for each indication included insufficient numbers of subjects aged 65 and over, therefore it could not be determined whether they respond differently from younger adult subjects. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after the time of initiating treatment with a urinary incontinence medication. These medications have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability.

    Ocular disease, visual disturbance

    Clinicians should use onabotulinumtoxinA with caution in patients with ocular disease. The efficacy of onabotulinumtoxinA treatment in deviations over 50 prism diopters, in restrictive strabismus, in Duane's syndrome with lateral rectus weakness, and in secondary strabismus caused by prior surgical over-recession of the antagonist has not been established. The toxin is ineffective in chronic paralytic strabismus except when used in conjunction with surgical repair to reduce antagonist contracture. When using onabotulinumtoxinA to treat blepharospasm, reduced blinking of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. One case of corneal perforation in an aphakic eye requiring corneal grafting has occurred because of this effect. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. Protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means my be required. Retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit during administration of onabotulinumtoxinA for strabismus. It is recommended that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. An ophthalmoscope to diagnosis the condition should be available. Inducing paralysis in one or more extraocular muscles may produce a visual disturbance such as spatial disorientation, double vision, or past pointing. Covering the affected eye may alleviate these symptoms.

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

    Use onabotulinumtoxinA cautiously in patients with myopathy associated with neuromuscular disease (e.g., amyotrophic lateral sclerosis (ALS), motor neuropathy (autonomic neuropathy), myasthenia gravis or Lambert-Eaton syndrome). Patients with known or unrecognized neuromuscular disorders or neuromuscular junction disorders may be at increased risk of clinically significant systemic effects including generalized weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia, and respiratory compromise from typical doses of onabotulinumtoxinA.

    Cardiac disease

    OnabotulinumtoxinA should be used cautiously in patients with cardiac disease. There have been rare reports of adverse reactions involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established.

    Respiratory insufficiency

    Patients with respiratory insufficiency treated with onabotulinumtoxinA for upper limb spasticity should be monitored closely. In a double-blind, placebo-controlled, parallel group study in patients with stable reduced pulmonary function (defined as FEV1 40% to 80% of predicted value and FEV1/FVC 0.75 or less), the event rate in change of Forced Vital Capacity (FVC) 15% or more or 20% or more was generally greater in patients treated with onabotulinumtoxinA than in patients treated with placebo; it should be noted that differences from placebo were not statistically significant. In addition, in patients with reduced lung function treated for upper limb spasticity, upper respiratory tract infection was reported more frequently as an adverse reaction in patients treated with onabotulinumtoxinA vs. placebo. Caution is also advisable when administering onabotulinumtoxinA to patients with detrusor overactivity associated with a neurologic condition and restrictive lung disease of neuromuscular etiology (defined as FVC 50% to 80% of predicted value in patients with spinal cord injury between C5 and C8, or MS). Study data indicate that the event rate in change of FVC 15% or more or 20% or more was generally greater in patients receiving onabotulinumtoxinA than placebo.

    Driving or operating machinery

    Caution all patients to avoid driving or operating machinery if they experience a loss of strength, muscle weakness, blurred vision, or drooping eyelids as a result of onabotulinumtoxinA therapy.

    Surgery

    Administer onabotulinumtoxinA with caution in 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. Advise patients to tell their other health care practitioners of this therapy prior to any surgeries.

    Anticoagulant therapy

    Anti-platelet therapy should be discontinued at least 3 days prior to onabotulinumtoxinA treatment in patients with detrusor overactivity associated with a neurologic condition. Patients on anticoagulant therapy need to be managed appropriately to reduce the risk of bleeding.

    Urinary retention

    Intradetrusor injection of onabotulinumtoxinA is contraindicated in patients with urinary retention (post-void residuals (PVR) greater than 200 mL) who are not routinely performing clean intermittent self-catheterization (CIC). Following treatment, patients who are not catheterizing should have PVR assessed within 2 weeks of injection and periodically as needed for up to 12 weeks. Begin catheterization if PVR increase to more than 200 mL and continue until PVR is less than 200 mL. Treatment should be avoided in patients not able or unwilling to begin catheterization, if needed.

    ADVERSE REACTIONS

    Severe

    keratitis / Delayed / 0-6.0
    seizures / Delayed / 1.0-5.0
    ocular hemorrhage / Delayed / 0-0.3
    ocular hypertension / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    ectropion / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    distant spread of toxin effects / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known

    Moderate

    dysphagia / Delayed / 0-19.0
    hypertropia / Early / 0-17.0
    hypotropia / Early / 0-17.0
    urinary retention / Early / 0-17.0
    dysarthria / Delayed / 2.0-10.0
    dysuria / Early / 4.0-9.0
    dyspnea / Early / 0-4.5
    myasthenia / Delayed / 0-4.0
    hematuria / Delayed / 0-4.0
    constipation / Delayed / 0-4.0
    hypertension / Early / 0-2.0
    paresis / Delayed / 0-2.0
    erythema / Early / 0-2.0
    ocular infection / Delayed / 0-1.0
    lagophthalmos / Early / Incidence not known
    entropion / Early / Incidence not known
    photophobia / Early / Incidence not known
    dysphonia / Delayed / Incidence not known
    antibody formation / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known

    Mild

    infection / Delayed / 0-49.0
    ptosis / Delayed / 0-21.0
    pruritus / Rapid / 0-10.0
    fever / Early / 1.0-10.0
    cough / Delayed / 1.0-10.0
    rhinitis / Early / 1.0-10.0
    pharyngitis / Delayed / 1.0-10.0
    influenza / Delayed / 1.0-10.0
    back pain / Delayed / 2.0-10.0
    asthenia / Delayed / 2.0-10.0
    nausea / Early / 0-10.0
    xerostomia / Early / 2.0-10.0
    dizziness / Early / 0-10.0
    drowsiness / Early / 0-10.0
    anxiety / Delayed / 0-10.0
    injection site reaction / Rapid / 2.0-10.0
    ecchymosis / Delayed / 2.0-10.0
    hyperhidrosis / Delayed / 0-10.0
    xerophthalmia / Early / 0-6.0
    headache / Early / 0-5.0
    rhinorrhea / Early / 0-4.0
    musculoskeletal pain / Early / 0-4.0
    nasal congestion / Early / 0-3.0
    myalgia / Early / 0-3.0
    anorexia / Delayed / 0-2.0
    insomnia / Early / 0-2.0
    blepharedema / Early / 0-1.0
    vertigo / Early / 0-1.0
    diplopia / Early / Incidence not known
    lacrimation / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    fatigue / Early / Incidence not known
    malaise / Early / Incidence not known
    weakness / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    diarrhea / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    syncope / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    tinnitus / Delayed / 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; Caffeine; 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.
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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; 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).
    Bacitracin: (Minor) Use botulinum Toxin Type A , which has skeletal muscle relaxant properties, cautiously in patients receiving systemic bacitracin. If bacitracin is administered parenterally during surgery, there may be increased skeletal muscle relaxation, and postoperative use may reinstate neuromuscular blockade.
    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).
    Budesonide; 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).
    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).
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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).
    Diphenoxylate; 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).
    Doxacurium: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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).
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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.
    Phenobarbital; Hyoscyamine; Atropine; 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).
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    RimabotulinumtoxinB: (Major) The effect of administering botulinum toxin type A and type B neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.
    Rocuronium: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    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: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.
    Vecuronium: (Moderate) Use neuromuscular blockers and botulinum toxins concurrently with caution because the effect of the botulinum toxin may be potentiated. If coadministered, observe the patient closely.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no human data on the developmental risk associated with the use of onabotulinumtoxinA during human pregnancy. When administered intramuscularly (8 and 16 units/kg) two times to pregnant mice or rats during organogenesis, reductions in fetal weight and decreased fetal skeletal ossification were observed. The no-effect dose for developmental toxicity is approximately equivalent to the human dose of 400 units. No adverse effects were observed when pregnant rats received a single intramuscular injection.

    It is not known whether onabotulinumtoxinA is excreted in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for onabotulinumtoxinA and any potential adverse effects on the breastfed infant. OnabotulinumtoxinA is not detectable systemically after intramuscular use, thus excretion into breast milk is considered unlikely.

    MECHANISM OF ACTION

    OnabotulinumtoxinA blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering nerve terminals, and inhibiting the release of acetylcholine. Inhibition occurs as the neurotoxin cleaves a protein (SNAP-25) integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. After intramuscular injection of a therapeutic dose, onabotulinumtoxinA produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. Additionally, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. Evidence exists that suggests that reinnervation of the muscle may occur thereby slowly reversing muscle denervation produced by the neurotoxin.
     
    A reduction in sialorrhea may also occur by blocking the liberation of acetylcholine in autonomic nerve terminals in the parotid and submandibular glands. There is no evidence of axonal sprouting and consecutive innervation in autonomic nerve fibers in sialorrhea studies.
     
    For treatment of neurogenic bladder, after injection into the detrusor muscle the efferent pathways of detrusor activity are affected via inhibition of acetylcholine release; inhibition of afferent neurotransmitters and sensory pathways is also thought to occur. Therapy increases maximal bladder capacity, reduces maximum detrusor pressure, reduces incontinence episodes, and may reduce the need for anticholinergics in patients with neurogenic overactive bladder.

    PHARMACOKINETICS

    OnabotulinumtoxinA is administered by local intramuscular injection. 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. Onset and duration of action depend on the clinical use of the drug.

    Intramuscular Route

    The onset and duration of action of onabotulinumtoxinA depends on the clinical use of the drug.