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  • CLASSES

    Muscle Relaxants, Other Neuromuscular Blockers

    BOXED WARNING

    Cerebral palsy, children, distant spread of toxin effects, visual impairment

    There have been postmarketing reports of the distant spread of toxin 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. Symptoms of systemic botulism due to distant spread of the toxin have been seen in patients who received the medication for a variety of conditions and a wide range of doses; however, the majority have occurred in pediatric patients treated for cerebral palsy-associated limb spasticity. Several children required the placement of feeding tubes and/or mechanical ventilation, and some cases were fatal. In addition, adult cases suggestive of systemic botulism have also been reported after treatment of spasticity or cervical dystonia. In some cases, hospitalization was necessary with several patients requiring the placement of feeding tubes or mechanical ventilation. Several deaths were reported in adults; however, due to the nature of their pre-existing conditions, they can not be attributed to botulinum toxin. These adverse effects have occurred as early as one day 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. The risk of distant spread of botulinum toxin after dermatologic use is not known. Xerophthalmia has been reported with the use of abobotulinumtoxinA in the treatment of glabellar lines. Ocular problems such as reduced tear production, reduced blinking, and corneal disorders may occur with the use of botulinum toxins. Consider referring the patient to an ophthalmologist if symptoms of dry eye (e.g., ocular irritation, photophobia, visual impairment) persist; clinicians should be alert that visual impairment may be a symptom of distant spread of toxins.

    DEA CLASS

    Rx

    DESCRIPTION

    Intramuscular botulinum toxin type A-hemagglutinin complex
    Used to treat spasticity and cervical dystonia; also used cosmetically in adults for glabellar lines
    Spread of toxin effect beyond the site of local injection has been reported

    COMMON BRAND NAMES

    Dysport

    HOW SUPPLIED

    Dysport Intramuscular Inj Pwd F/Sol: 300U, 500U

    DOSAGE & INDICATIONS

    For the treatment of cervical dystonia.
    Intramuscular dosage
    Adults

    500 units IM divided among affected muscles with repeat treatments every 12 weeks or longer, as necessary, based on return of clinical symptoms. If dose modification is necessary, data from uncontrolled open-label studies suggest dose adjustments can be made in 250 unit increments based on individual patient response. Uncontrolled studies also recommend a total dose range per treatment cycle between 250 units and 1,000 units. Doses above 1,000 units in a single treatment have not been systematically studied. The use of electromyography (EMG) during administration of abobotulinumtoxinA may help identify active muscles not located during physical examination.

    For the treatment of glabellar lines (facial wrinkles or vertical lines between the eyebrows).
    Intramuscular dosage
    Adults younger than 65 years

    50 units IM administered in 5 equal aliquots of 10 units each: 2 injections in each corrugator muscle and 1 injection in the procerus muscle. The clinical effect may last for up to 4 months; if needed, repeat doses may be given after no less than 3 months. Repeat dose clinical studies suggest continued efficacy with up to 4 repeated administrations. When used for re-treatment, use the same reconstitution and injection methods as the initial treatment.

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

    500 to 1,000 units divided between selected muscles at a given treatment session. Specific dose range is based on muscle group. PRONATOR TERES: 100 to 200 units (1 injection per muscle). FLEXOR CARPI RADIALIS, FLEXOR CARPI ULNARIS, FLEXOR DIGITORUM PROFUNDUS, or FLEXOR DIGITORUM SUPERFICIALIS: 100 to 200 units (1 to 2 injections per muscle). BRACHIORADIALIS: 100 to 200 units (1 to 2 injections per muscle). BRACHIALIS or BICEPS BRACHII: 200 to 400 units (1 to 2 injections per muscle). Do not administer more than 1 mL per single injection site. The maximum total dose per treatment session (upper limb and lower limb combined) is 1,500 units. Clinical improvement may be expected 1 week after administration. Injections may be repeated to maintain response; do not administer more frequently than every 12 weeks. A majority of patients in clinical trials were retreated in 12 to 16 weeks; some patients may have longer duration of response (i.e., 16 to 20 weeks). Tailor dosing 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 abobotulinumtoxinA. Upon re-injection, the degree and pattern of muscle spasticity may necessitate alterations in the dose of abobotulinumtoxinA and muscles to be injected.

    Children and Adolescents 2 to 17 years

    8 to 16 units/kg IM per limb; divide total dose between the affected spastic muscles. Recommended dose range is based on muscles injected. BRACHIALIS: 3 to 6 units/kg per muscle per limb (up to 2 injections per muscle). BRACHIORADIALIS: 1.5 to 3 units/kg per muscle per limb (1 injection per muscle). BICEPS BRACHII: 3 to 6 units/kg per muscle per limb (up to 2 injections per muscle). PRONATOR TERES: 1 to 2 units/kg per muscle per limb (1 injection per muscle). PRONATOR QUADRATUS: 0.5 to 1 unit/kg per muscle per limb (1 injection per muscle). FLEXOR CARPI RADIALIS (FCR): 2 to 4 units/kg per muscle per limb (up to 2 injections per muscle). FLEXOR CARPI ULNARIS (FCU): 1.5 to 3 units/kg per muscle per limb (1 injection per muscle). FLEXOR DIGITORUM PROFUNDUS (FDP): 1 to 2 units/kg per muscle per limb (1 injection per muscle). FLEXOR DIGITORUM SUPERFICIALIAS (FDS): 1.5 to 3 units/kg per muscle per limb (up to 4 injections per muscle). Do not administer more than 0.5 mL per injection site. The maximum total dose per treatment session is 16 units/kg or 640 units, whichever is less. Injections may be repeated to maintain response; do not administer more frequently than every 16 weeks. Most patients are retreated between 16 to 28 weeks. Individualize dose based on the size, number, and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient response, and/or adverse event history with botulinum toxins.

    For the treatment of lower limb spasticity.
    Intramuscular dosage
    Adults

    1,000 to 1,500 units divided between selected muscles at a given treatment session. Specific dose range is based on muscle group. MEDIAL OR LATERAL HEAD OF GASTROCNEMIUS: 100 to 150 units (1 injection per muscle). SOLEUS: 330 to 500 units (3 injections per muscle). TIBIALIS POSTERIOR: 200 to 300 units (2 injections per muscle). FLEXOR DIGITORUM LONGUS: 130 to 200 units (1 to 2 injections per muscle). FLEXOR HALLUCIS LONGUS: 70 to 200 units (1 injection per muscle). Do not administer more than 1 mL per single injection site. The maximum total dose per treatment session (upper limb and lower limb combined) is 1,500 units. Injections may be repeated to maintain response; do not administer more frequently than every 12 weeks. A majority of patients in clinical trials were retreated in 12 to 16 weeks. Tailor dosing 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 abobotulinumtoxinA. Upon re-injection, the degree and pattern of muscle spasticity may necessitate alterations in the dose of abobotulinumtoxinA and muscles to be injected.

    Children and Adolescents 2 to 17 years

    10 to 15 units/kg IM for unilateral lower limb injections or 20 to 30 units/kg for bilateral lower limb injections is the recommended total dose per treatment session; divide total dose between the affected spastic muscles. Recommended dose range is based on muscles injected. GASTRONEMIUS MUSCLE: 6 to 9 units/kg per muscle per limb (up to 4 injections per muscle). SOLEUS MUSCLE: 4 to 6 units/kg per muscle per limb (up to 2 injections per muscle). When possible, distribute the dose across more than 1 injection site in any single muscle. Do not administer more than 0.5 mL per injection site. The maximum total dose per treatment session is 15 units/kg for unilateral limb injections or 30 units/kg for bilateral limb injections or 1,000 units, whichever is less. Injections may be repeated to maintain response; do not administer more frequently than every 12 weeks. Most patients are retreated between 16 to 22 weeks. Individualize dose based on the size, number, and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient response, and/or adverse event history with botulinum toxins.

    For the treatment of blepharospasm† and hemifacial spasm†.
    For the treatment of bilateral blepharospasm†.
    Subcutaneous dosage†
    Adults

    The recommended initial dose is 120 units subcutaneously per eye: 20 units subcutaneously injected medially and 40 units subcutaneously injected laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of each eye. Symptom relief may begin within 2 to 4 days, with maximal effect within 2 weeks. May repeat no more frequently than every 12 weeks or as needed to prevent recurrence of symptoms. Subsequent treatment sessions may require a dose reduction to 80 units per eye: 20 units medially and 20 units laterally above and below each eye in the manner previously described. The dose may be further reduced to 60 units per eye by omitting the medial lower lid injection.

    For the treatment of unilateral blepharospasm† and hemifacial spasm†.
    Subcutaneous dosage†
    Adults

    The recommended initial dose is 120 units subcutaneously to the affected eye: 20 units subcutaneously injected medially and 40 units subcutaneously injected laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of the affected eye. Patients with hemifacial spasm should be treated as for unilateral blepharospasm. Symptom relief may begin within 2 to 4 days, with maximal effect within 2 weeks. Repeat no more frequently than every 12 weeks or as needed to prevent recurrence of symptoms. Subsequent treatment sessions may require a dose reduction to 80 units per eye: 20 units medially and 20 units laterally above and below each eye in the manner previously described. The dose may be further reduced to 60 units per eye by omitting the medial lower lid injection.

    For the treatment of axillary hyperhidrosis† (excessive sweating).
    Intradermal dosage†
    Adults

    The recommended initial dose is 100 units intradermally per axilla; may be increased to up to 200 units per axilla per treatment session if desired response is not achieved. Maximum effect may be expected within 2 weeks after injection. In the majority of cases, the recommended dose will provide adequate suppression of sweat secretion for approximately 48 weeks. Injections may be repeated if needed, no more frequently than every 12 weeks. There is some evidence for a cumulative effect with repeat doses; assess the needs of each patient individually. In a multicenter trial (n = 145, baseline mean rate of sweat production of 192 +/- 136 mg/minute), 200 units was injected into 1 axilla and placebo was injected into the other. At 2 weeks post-injection, mean rates of sweat production in the axilla treated with abobotulinumtoxinA or placebo were 24 +/- 27 mg/minute and 144 +/- 113 mg/minute, respectively. An additional 100 units was then injected into the previously untreated axilla, which reduced sweat production to 32 +/- 39 mg/minute. At 24 weeks, the mean rate of sweat production was significantly below baseline levels for both axillae in those patients (n = 136) receiving follow-up.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage is not well defined; dosage is dependent upon treatment effect and indication.

    Geriatric

    Maximum dosage is not well defined; dosage is dependent upon treatment effect and indication.

    Adolescents

    16 units/kg IM (Max: 640 units) per treatment session for upper limb spasticity; 15 units/kg IM for unilateral and 30 units/kg IM for bilateral (Max: 1,000 units) per treatment session for lower limb spasticity.

    Children

    2 to 12 years: 16 units/kg IM (Max: 640 units) per treatment session for upper limb spasticity; 15 units/kg IM for unilateral and 30 units/kg IM for bilateral (Max: 1,000 units) per treatment session for lower limb spasticity.
    1 to 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not 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

    For storage information, see specific product information within How Supplied section.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Reconstitution
    Each indication has a recommended concentration.
    Use preservative-free 0.9% Sodium Chloride Injection as a diluent. Gently swirl to dissolve.
    To yield a final concentration of 50 units/0.1 mL:
    Reconstitute the 300 unit vial with 0.6 mL diluent, or
    Reconstitute the 500 unit vial with 1 mL of diluent.
    To yield a final concentration of 25 units/0.1 mL:
    Reconstitute the 500 unit vial with 2 mL of diluent.
    To yield a final concentration of 20 units/0.1 mL:
    Reconstitute the 300 unit vial with 1.5 mL of diluent, or
    Reconstitute the 500 unit vial with 2.5 mL of diluent.
    To yield a final concentration of 12 units/0.1 mL:
    Reconstitute the 300 unit vial with 2.5 mL of diluent.
    To yield a final concentration of 10 units/0.1 mL:
    Reconstitute the 300 unit vial with 3 mL of diluent, or
    Reconstitute the 500 unit vial with 5 mL of diluent. When using 5 mL of diluent for a 500 unit vial, no more than 2.5 mL diluent should be introduced into vial. First, reconstitute the 500 unit vial with 2.5 mL of diluent, gently mix, and set aside. Then, withdraw 2.5 mL of diluent into a 5 mL syringe. Next, draw up the abobotulinumtoxinA solution from the reconstituted vial into that syringe without inverting and mix gently. Use immediately.
    Storage: Once reconstituted, unused drug may be stored refrigerated (2 to 8 degrees C [36 to 46 degrees F]) and protected from light in the original container for up to 24 hours until the time of use. If reconstituted in a syringe, use immediately. Use only for 1 injection session and for only 1 patient; discard any unused portion.

    Intramuscular Administration

    Cervical dystonia:
    Recommended concentration: 25 or 50 units/0.1 mL.
    Localization of the active muscles with electromyographic guidance may be helpful.
     
    Glabellar facial wrinkles:
    Recommended concentration: 12 or 20 units/0.1 mL.
    Injection technique for glabellar facial wrinkles:
    Identify the lateral corrugator and vertical procerus muscles by palpating the tensed muscle mass while having the patient frown.
    To inject abobotulinumtoxinA, advance the needle through the skin into the underlying muscle while applying finger pressure on the superior medial orbital rim.
    Using an appropriate size needle, inject 10 units of abobotulinumtoxinA into each of 5 sites (total dose 50 units): 2 in each corrugator muscle, and 1 in the procerus muscle.
    In order to reduce the complication of ptosis:
    Avoid injection near the levator palpebrae superiosis, particularly in patients with larger brow depressor complexes.
    Place medial corrugator injections at least 1 centimeter above the bony supraorbital ridge.
    Ensure doses used are accurate and keep injected volume to a minimum.
    Do not inject toxin closer than 1 centimeter above the central eyebrow.
    The risk of ptosis may also be mitigated by careful examination of the upper lid for separation or weakness of the levator palpebrae muscle, identification of lash ptosis, and evaluation of lid excursion while manually depressing the frontalis to assess compensation.
     
    Spasticity in adult patients:
    Recommended concentration: 10 or 20 units/0.1 mL.
    In general, do not administer more than 1 mL in any single injection site.
    Localization of the involved muscles with electromyographc guidance or electrical stimulation is recommended.
     
    Spasticity in pediatric patients:
    Recommended concentration: 20 or 50 units/0.1 mL.
    Do not administer more than 0.5 mL in any single injection site.
    Localization of the involved muscles with electromyographc guidance or electrical stimulation is recommended.

    Subcutaneous Administration

    Reconstitution and administration for blepharospasm and hemifacial spasm
    NOTE: AbobotulinumtoxinA is not FDA-approved for this type of administration.
    Reconstitute 500 unit vial with 2.5 mL of diluent to yield a solution containing 200 units/mL.
    Local subcutaneous injection: A sterile 23 or 25 gauge needle should be used for administration. For injections into the upper lid, the needle should be directed away from its center to avoid the levator muscle. AbobotulinumtoxinA is administered by subcutaneous injection medially and laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of the eyes.

    Other Injectable Administration

    Intradermal Administration
    Reconstitution and administration for axillary hyperhidrosis (excessive sweating)
    NOTE: AbobotulinumtoxinA is not FDA-approved for this type of administration.
    Reconstitute 500 unit vial with 2.5 mL of diluent to yield a solution containing 200 units/mL.
    Local intradermal injection: The area to be injected should be determined beforehand using the iodine-starch test. Both axillae should be cleaned and disinfected. Intradermal injections at 10 sites, each site receiving 10 units, are then administered.

    STORAGE

    Dysport:
    - Do not freeze reconstituted product
    - Protect from light
    - Reconstituted product must be used within 4 hours
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The potency units of abobotulinumtoxinA are not interchangeable with other botulinum toxin products; do not compare to or convert into units of any other botulinum toxin products.

    Requires an experienced clinician

    Use of abobotulinumtoxinA requires an experienced clinician as safe and effective use depends upon proper product storage, dose selection, medication reconstitution, and administration technique, in addition to, knowledge of the treated condition. It is important to note that units of abobotulinumtoxinA biological activity 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 may be useful for the treatment of cervical dystonia.

    Albumin hypersensitivity, milk protein hypersensitivity

    AbobotulinumtoxinA is contraindicated in patients with a known hypersensitivity to any botulinum toxin product, cow's milk protein (milk protein hypersensitivity), or any other component in the formulation. The product may contain trace amounts of cow's milk proteins. Commercial preparations contain albumin and should be used cautiously in patients with albumin hypersensitivity. If a hypersensitivity reaction occurs, discontinue the drug and institute appropriate medical treatment immediately. The possibility of an immune reaction when injected intradermally is unknown.[35779]

    Infection

    AbobotulinumtoxinA is contraindicated in the presence of infection at the proposed injection site(s).

    Dysphagia, respiratory insufficiency

    Use abobotulinumtoxinA with caution in patients with cervical dystonia and pre-existing dysphagia or respiratory insufficiency. Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia or respiratory insufficiency within hours to weeks after injection with botulinum toxin. In some cases, immediate medical attention may be required. Patients with pre-existing dysphagia or respiratory insufficiency may be more susceptible to these complications. Rarely, severe dysphagia may result in aspiration, dyspnea, pneumonia, and the need to reestablish an airway. There are reports of death as a complication of severe dysphagia after treatment with botulinum toxin. Because dysphagia may persist for several weeks, a feeding tube may be required to maintain adequate nutrition and hydration. Additionally, when treating 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. Treatment of cervical dystonia with botulinum toxin may weaken neck muscles that serve as accessory muscles for ventilation. Patients with respiratory disorders, who are dependent on these accessory muscles, may experience a critical loss of breathing capacity. There are post marketing reports of serious breathing difficulties, including respiratory failure in cervical dystonia patients.

    Cerebral palsy, children, distant spread of toxin effects, visual impairment

    There have been postmarketing reports of the distant spread of toxin 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. Symptoms of systemic botulism due to distant spread of the toxin have been seen in patients who received the medication for a variety of conditions and a wide range of doses; however, the majority have occurred in pediatric patients treated for cerebral palsy-associated limb spasticity. Several children required the placement of feeding tubes and/or mechanical ventilation, and some cases were fatal. In addition, adult cases suggestive of systemic botulism have also been reported after treatment of spasticity or cervical dystonia. In some cases, hospitalization was necessary with several patients requiring the placement of feeding tubes or mechanical ventilation. Several deaths were reported in adults; however, due to the nature of their pre-existing conditions, they can not be attributed to botulinum toxin. These adverse effects have occurred as early as one day 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. The risk of distant spread of botulinum toxin after dermatologic use is not known. Xerophthalmia has been reported with the use of abobotulinumtoxinA in the treatment of glabellar lines. Ocular problems such as reduced tear production, reduced blinking, and corneal disorders may occur with the use of botulinum toxins. Consider referring the patient to an ophthalmologist if symptoms of dry eye (e.g., ocular irritation, photophobia, visual impairment) persist; clinicians should be alert that visual impairment may be a symptom of distant spread of toxins.

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

    Use abobotulinumtoxinA 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). These patients may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of abobotulinumtoxinA. Caution should be used when abobotulinumtoxinA is administered to patients with surgical alterations to the facial anatomy, marked facial asymmetry, excessive dermatochalasis (loose skin), ptosis, deep dermal scarring, thick sebaceous skin, inflammation at the proposed injection site(s), presence of excessive muscle weakness or muscle atrophy is present in the target muscle(s), or the inability to lessen glabellar lines by physically spreading them apart.

    Geriatric

    Generally, geriatric patients should be observed for their tolerability of abobotulinumtoxinA due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Although only 1% of the total number of patients in the studies of the drug for treatment of glabellar lines were 65 and over, an increased rate of ocular adverse events was observed in geriatric subjects compared to younger subjects (11% vs. 5%). Clinical studies of cervical dystonia patients included insufficient numbers of geriatric subjects to determine whether they respond differently from younger adults. Among those in the lower limb spasticity clinical trials, 18% were 65 and over and 3% were 75 and over. Patients over 65 years of age reported a greater percentage of adverse reactions compared to younger patients (e.g., falls and asthenia). 

    Pregnancy

    Administer abobotulinumtoxinA during pregnancy only if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproduction capacity is unknown. In animal studies daily and intermediate intramuscular injections during organogenesis were associated with an increase in early embryonic death at doses lower than or similar to the maximum recommended human dose (MRHD) of 1,000 units/kg.

    Breast-feeding

    There are no data regarding the presence of abobotulinumtoxinA in human milk, the effects on the breastfed child, or on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for abobotulinumtoxinA and any potential adverse effects on the breastfed infant.

    Diabetes mellitus

    A small increase from baseline in mean blood glucose (0.23 mol/L) was observed in abobotulinumtoxinA-treated patients relative to placebo-treated patients. This increase in blood glucose was not considered clinically significant; however, it may be prudent to use caution when administering abobotulinumtoxinA to patients with poorly controlled diabetes mellitus.

    Viral infection

    AbobotulinumtoxinA 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 viral infection or disease, such as Creutzfeldt-Jakob disease (CJD) exists. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating 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 or the health care surrogate of the patient.[35779]

    Cardiac disease

    AbobotulinumtoxinA should be used cautiously in patients with cardiac disease. In an open-label, non-controlled trial, patients had an average of 3 beats per minute lower heart-rate thirty minutes post abobotulinumtoxinA administration than they had prior to the administration.

    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 abobotulinumtoxinA therapy.

    Surgery

    Administer abobotulinumtoxinA 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. Patients should be instructed to inform all health care professionals if there are plans to have surgery while receiving abobotulinumtoxinA.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0-7.0
    visual impairment / Early / 0-7.0
    respiratory arrest / Rapid / Incidence not known
    distant spread of toxin effects / Early / Incidence not known
    serum sickness / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    myasthenia / Delayed / 1.0-16.0
    dysphagia / Delayed / 0.5-15.0
    dysphonia / Delayed / 6.0-6.0
    antibody formation / Delayed / 0-3.6
    depression / Delayed / 2.0-3.0
    contact dermatitis / Delayed / 2.0-3.0
    dyspnea / Early / 3.0-3.0
    constipation / Delayed / 0-2.0
    peripheral edema / Delayed / 0-2.0
    edema / Delayed / 2.0-2.0
    hematuria / Delayed / 2.0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    hypertriglyceridemia / Delayed / 1.0-2.0
    hypertension / Early / 1.0-2.0
    hypertonia / Delayed / 0.5-0.5
    paresis / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    erythema / Early / Incidence not known
    photophobia / Early / Incidence not known
    blurred vision / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    weakness / Early / 1.0-16.0
    xerostomia / Early / 13.0-13.0
    injection site reaction / Rapid / 0-13.0
    fatigue / Early / 0-12.0
    fever / Early / 7.0-12.0
    headache / Early / 0-11.0
    infection / Delayed / 0-11.0
    pharyngitis / Delayed / 6.0-10.0
    cough / Delayed / 1.0-10.0
    musculoskeletal pain / Early / 7.0-7.0
    arthralgia / Delayed / 2.0-4.0
    dizziness / Early / 3.5-3.5
    myalgia / Early / 0-3.0
    nausea / Early / 0-3.0
    influenza / Delayed / 0-3.0
    back pain / Delayed / 1.0-2.0
    asthenia / Delayed / 1.0-2.0
    diarrhea / Early / 1.0-2.0
    insomnia / Early / 0-2.0
    hypoesthesia / Delayed / 0-2.0
    syncope / Early / 1.0-2.0
    sinusitis / Delayed / 2.0-2.0
    ptosis / Delayed / 2.0-2.0
    vertigo / Early / Incidence not known
    diplopia / Early / Incidence not known
    ocular pruritus / Rapid / Incidence not known
    ocular irritation / Rapid / Incidence not known
    ocular pain / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    urticaria / Rapid / 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).
    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.
    Colistin: (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.
    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).
    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.
    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

    Administer abobotulinumtoxinA during pregnancy only if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproduction capacity is unknown. In animal studies daily and intermediate intramuscular injections during organogenesis were associated with an increase in early embryonic death at doses lower than or similar to the maximum recommended human dose (MRHD) of 1,000 units/kg.

    There are no data regarding the presence of abobotulinumtoxinA in human milk, the effects on the breastfed child, or on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for abobotulinumtoxinA and any potential adverse effects on the breastfed infant.

    MECHANISM OF ACTION

    AbobotulinumtoxinA 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, abobotulinumtoxinA produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. Some evidence suggests reinnervation of the muscle may occur, thereby slowly reversing muscle denervation produced by the neurotoxin. A reduction in sialorrhea may occur by blocking the liberation of acetylcholine in autonomic nerve terminals in the parotid and submandibular glands. There is no evidence of axonal sprouting or consecutive innervation in autonomic nerve fibers in sialorrhea studies.

    PHARMACOKINETICS

    AbobotulinumtoxinA is administered by local intramuscular injection.

    Intramuscular Route

    When used locally at the recommended intramuscular (IM) dose, measurable concentrations of abobotulinumtoxinA are not expected to be present in the peripheral blood. 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. However, sub-clinical systemic effects have been shown by single-fiber electromyography after IM doses of botulinum toxins appropriate to produce clinically observable local muscle weakness. The median onset is 3 days and duration is 88 days of abobotulinumtoxinA effect, when used to treat glabellar lines ; the onset is 7.6 (+/- 3.5) days with a duration of 77 (+/- 11.2) days when used to treat cervical dystonia.