Nabota

Clostridium botulinum toxin type A.

Each vial contains: Clostridium Botulinum Toxin Type A 100 Units.
Stabilizing agent: Human serum albumin 0.5 mg.
Isotonic agent: Sodium Chloride 0.9 mg.
It appears as a white to yellowish, lyophilized powder for injection in a colorless and transparent vial. It should become colorless transparent liquid when dissolved in the diluent (physiological saline solution).

Pharmacology: Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term studies in animals have not been performed to evaluate carcinogenic potential.
Animal Toxicity: In a study of other botulinum toxin product to evaluate inadvertent peribladder administration, bladder stones were observed in one among four male monkeys that were injected with a total of 6.8 U/kg divided into the prostatic urethra and proximal rectum (single administration). No bladder stones were observed in male or female monkeys following injection of up to 36 U/kg (~12X the human dose) directly to the bladder as either single or four times repeat dose injections or in female rats for single injection of up to 100 U/kg (~33X the human dose).

Botulinum Toxin Type A (Nabota) is indicated for the treatment of blepharospasm associated with dystonia, including benign essential blepharospasm, hemifacial spasm or VII^th nerve disorders in patients 12 years or older.
Botulinum Toxin Type A (Nabota) is indicated for the correction of strabismus in patients 12 years or older.
Botulinum Toxin Type A (Nabota) is indicated for the treatment of spasmodic torticollis (cervical dystonia) in adults.
Botulinum Toxin Type A (Nabota) is indicated for the treatment of dynamic equinus foot deformity due to spasticity in pediatric cerebral palsy patients, two years of age or older.
Botulinum Toxin Type A (Nabota) is indicated for the temporary treatment of glabellar lines associated with corrugator and/or procerus muscle activity in adult patients below 65 years of age.
Botulinum Toxin Type A (Nabota) is indicated in the management of focal spasticity, including the treatment of spasticity associated with stroke in adults.
Botulinum Toxin Type A (Nabota) is indicated for the treatment of focal hyperhidrosis of the axilla.
Botulinum Toxin Type A (Nabota) is indicated for the temporary improvement in the appearance of upper facial rhytides (glabellar lines, crow's feet and forehead lines) in adults.
Botulinum Toxin Type A (Nabota) is indicated for the prophylaxis of headaches in adults with chronic migraine.
Botulinum Toxin Type A (Nabota) is indicated for the treatment of urinary incontinence due to neurogenic detrusor overactivity e.g., spinal cord injury (SCI) or multiple sclerosis (MI) in adults.

Blepharospasm: Reconstituted Clostridium Botulinum Toxin Type A (see Table 1) is injected using a sterile, 27-30 gauge needle with or without electromyographic guidance.
Initial Recommended Dose: 1.25-2.5 units in (0.05-0.1 mL volume at each site) injected into the medial and lateral orbicularis oculi of the upper lid and into the lateral orbicularis oculi of the lower lid.
Injection placement may vary based on the patient's presentation. 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. This can be prevented by applying pressure at the injection site immediately after the injection. The hazard of ectropion may be reduced by avoiding injection into the lower lid area.
In general, the initial effect of the injections is seen within 3 days and reaches a peak at 1-2 weeks post-treatment. Each treatment lasts approximately 3 months, following which the procedure can be repeated indefinitely. At repeat-treatment sessions, the dose may be increased up to 2-fold if the response from the initial treatment is considered insufficient (usually defined as an effect that does not last longer than 2 months). However, there appears to be little benefit obtainable from injecting >5 units/site. The initial dose should not exceed 25 units/eye. Normally, no additional benefit is conferred by treating more frequently than every 3 months. It is rare for the effect to be permanent.
In the management of blepharospasm, total dosing should not exceed 100 units every 12 weeks.
Hemifacial Spasm: Patients with hemifacial spasm or VII^th nerve disorders should be treated as for unilateral blepharospasm with other affected facial muscles each being injected as needed. Further injections may be necessary into the corrugator, zygomaticus major, orbicularis oris and/or other facial muscles according to the extent of the spasm. Electromyographic control may be necessary to identify affected small circumoral muscles.
The cumulative dose of botulinum toxin product for treatment of hemifacial spasm in a 2-month period should not exceed 200 units.
Strabismus: Botulinum toxin product 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 techniques.
Botulinum toxin product is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair. The efficacy of botulinum toxin product in deviations >50 prism diopters, in restrictive strabismus, Duane's syndrome with lateral rectus weakness and secondary strabismus caused by prior surgical over-recession of the antagonist is doubtful. In order to enhance efficacy, multiple injections over time may be required.
To prepare the eye for Clostridium Botulinum Toxin Type A injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection.
Note: The recommended volume of Clostridium Botulinum Toxin Type A injected for treatment of strabismus is 0.05-0.15 mL per muscle.
I. Initial Doses in Units: Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.
a. For vertical muscles and for horizontal strabismus of <20 prism diopters: 1.25-2.5 units in any 1 muscle.
b. For horizontal strabismus of 20-50 prism diopters: 2.5-5 units in any 1 muscle.
c. For persistent VII^th nerve palsy of 1 month or longer duration: 1.25-2.5 units in the medial rectus muscle.
II. Subsequent Doses for Residual or Recurrent Strabismus.
a. It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose.
b. Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
c. Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to 2-fold compared to the previously administered dose.
d. Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.
e. The maximum recommended dose as a single injection for any 1 muscle is 25 units.
The initial listed doses of the reconstituted Clostridium Botulinum Toxin Type A (see Table 1) typically create paralysis of injected muscles beginning 1-2 days after injection and increasing in intensity during the 1st week. The paralysis lasts for 2-6 weeks and gradually resolves over a similar time period. Over-corrections lasting over 6 months have been rare. About one-half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose or because of mechanical factors eg, large deviations or restrictions or because of the lack of binocular motor fusion to stabilize the alignment.
Spasmodic Torticollis (Cervical Dystonia): Dosing must be tailored to the individual patient based on the patient's head and neck position, localization of pain, muscle hypertrophy, patient's body weight and patient response. A 25, 27 or 30 gauge needle may be used for superficial muscles and a 22 gauge needle may be used for deeper musculature. For cervical dystonia, localization of the involved muscles with electromyographic guidance may be useful.
As with any drug treatment, initial dosing in a naive patient should begin at the lowest effective dose. The treatment of cervical dystonia typically may include, but is not limited to, injection of Clostridium Botulinum Toxin Type A into the sternocleidomastoid, levator scapulae, scalene, splenius capitis and/or the trapezius muscle(s). In general, a total dose of 6 units/kg every 2 months should not be exceeded for treatment of cervical dystonia.
Diluted Clostridium Botulinum Toxin Type A is injected using an appropriately sized needle (usually 25, 27 or 30 gauge). Table 1 is intended to give dosing guidelines for injection of Clostridium Botulinum Toxin Type A in the treatment of cervical dystonia: See Table 1.

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Table 1 is provided as guidance for the initial injection. The extent of muscle hypertrophy and the muscle groups involved in the dystonic posture may change with time necessitating alterations in the dose of toxin and muscles to be injected. The exact dosage and sites injected must be individualized for each patient.
In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance. No more than 50 units should be given at any 1 site. Limiting the dose injected into the sternocleidomastoid muscle to <100 units may decrease the occurrence of dysphagia (see Precautions). To minimize the incidence of dysphagia, the sternocleidomastoid should not be injected bilaterally. The concentrations of reconstituted material needed are 5 and 10 units/0.1 mL to allow reasonable injection volumes.
Multiple injection sites allow botulinum toxin product to have more uniform contact with the innervation areas of the dystonic muscle and are especially useful in larger muscles. The optimal number of injection sites is dependent upon the size of the muscle to be chemically denervated.
Clinical improvement generally occurs within the first 2 weeks after injection. The maximum clinical benefit generally occurs approximately 6 weeks post-injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes. The duration of therapeutic effect reported in the clinical trials showed substantial variation (from 2-32 weeks), with a typical duration of approximately 12-16 weeks, depending on the patient's individual disease and response. "Booster" injections are not recommended. Dosing intervals should not be more often than every 2 months.
Pediatric Cerebral Palsy: For the treatment of equinus due to spasticity in pediatric cerebral palsy, diluted Clostridium Botulinum Toxin Type A is injected using a sterile 23-26 gauge needle.
Following initial injection to the gastrocnemius muscle, further involvement of the anterior or posterior tibialis may need to be considered for additional improvement in the foot position at heel strike and during standing.
Clinical gait improvement generally begins within the first 2 weeks after injection, with further improvement over the next several weeks. Repeat doses should be administered when the clinical effect of a previous injection diminishes but not more frequently than every 3 months. The dose is recommended 4 units/kg, up to maximum of 200 units at any single treatment session.
Upper Facial Lines (Glabellar Lines, Crow's Feet and Forehead Lines): As optimum dose levels and number of injection sites per muscle may vary among patients, individual dosing regimens should be drawn up. The recommended injection volume per injection site is 0.1 mL.
Glabellar Lines: Clostridium Botulinum Toxin Type A is reconstituted with 0.9% sterile nonpreserved saline (100 units in 2.5 mL or injected as 4 units/0.1 mL) and 0.1 mL is administered using a 30 gauge needle in each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose of 20 units.
In order to reduce the complication of ptosis, avoid injection near the levator palpebrae superioris, particularly in patients with larger brow-depressor complexes. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.
Careful attention should be paid to avoid injection of this product into the blood vessel. The thumb or index finger should be placed firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be oriented superiorly and medially during the injection and careful attention should be paid to inject accurate volume.
Glabella facial lines arise from the activity of corrugator muscle and orbicularis oculi muscle. These muscles move the brow medially, and the procerus muscle and depressor supercilii muscle pull the brow inferiorly. This creates a frown or "furrowed brow". The location, size, and use of the muscles vary markedly among individuals. An effective dose for facial lines is determined by gross observation of the patient's ability to activate the superficial muscles injected. Each treatment lasts approximately for up to 4 months. More frequent injection of this product is not recommended because the safety and efficacy are not established.
Typically the initial doses of reconstituted Clostridium Botulinum Toxin Type A induce chemical denervation of the injected muscles 1-2 days after injection, increasing in intensity during the 1st week. Injection intervals should be no more frequent than every 3 months and should be performed using the lowest effective dose.
Treatment with Clostridium Botulinum Toxin Type A for cosmetic purposes may result in the formation of antibodies that may reduce the effectiveness of subsequent treatments with Clostridium Botulinum Toxin Type A for glabellar lines or for other indications.
Crow's Feet: Clostridium Botulinum Toxin Type A should be injected bilaterally at 3 sites in the lateral aspect of the orbicularis oculi (ie, total of 6 injections), where most lines are seen when a smile is forced. In general, 2-6 units is recommended per injection site at a 2-3 mm depth, for a total dose of 6-18 units per side.
Injection should be at least 1 cm outside the bony orbit, not medial to the vertical line through the lateral canthus and not close to the inferior margin of the zygoma.
Forehead Lines: NABOTA should be injected IM at each of 4 injection sites in the frontalis muscle. In general, 2-6 units is recommended per injection site every 1-2 cm along either side of a deep forehead crease, for a total dose of 8-24 units.
Injections should be at least 2-3 cm above the eyebrow to reduce the risk of brow ptosis.
Focal Spasticity in Adults: The exact dosage and number of injection sites may be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, the presence of local muscle weakness, and the patient response to previous treatment. Clinical improvement of spasticity was observed within the 4 weeks, and also assessed at 8 and 12 weeks after the injection. (See Table 2.)

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In the clinical study, the recommended dose was allowed up to 360 Units, and divided among selected muscles.
Sterile 24-30 gauge needle is recommended. Needle length should be determined based on muscle location and depth. Localisation of the involved muscles with techniques such as electromyographic guidance, or nerve stimulation is recommended.
(revision based on NABOTA's clinical result)
Hyperhidrosis of the Axilla: The hyperhidrotic area to be injected may be defined using standard staining techniques eg, Minor's iodine-starch test. NABOTA is reconstituted with 0.9% nonpreserved sterile saline (100 units/4 mL). Using a 30 gauge needle, NABOTA 50 units (2 mL) is injected intradermally, to each axilla evenly distributed in multiple sites approximately 1-2 cm apart.
At week 1, botulinum toxin product-treated patients demonstrated 95% treatment responder rate based on gravimetric assessment. At 16 weeks, 82% of botulinum toxin product-treated patients were responding to treatment. Approximately 40% of patients received only 1 treatment with botulinum toxin product and had duration of effect for >1 year (median time 68 weeks). When patients received at least 2 consecutive treatments with botulinum toxin product, the mean time to re-treatment following their 1st treatment was 33 weeks (range 15-51 weeks). Repeat injections for axillary hyperhidrosis should be administered when effects from previous injections subside but usually not more frequently than every 2 months.
Chronic Migraine: The recommended dilution is 100 units/2 mL, with a final concentration of 5 units/0.1 mL. Recommended Dose: 155-195 units administered IM using a sterile 30 gauge, 0.5 inch needle as 0.1 mL (5 units) injections should be divided across 7 specific head/neck muscle areas as specified in Table 3 as follows. A 1 inch needle may be needed in the neck region for patients with thick neck muscles. With the exception of the procerus muscle, which should be injected at 1 site (midline), all muscle should be injected bilaterally with the minimum dose per muscle as indicated as follows, with half the number of injection sites administered to the left, and half to the right side of the head and neck. The recommended re-treatment schedule is every 12 weeks. If there is a predominant pain location(s), additional injections to the one or both sides may be administered in up to 3 specific muscle groups (occipitalis, temporalis and trapezius), up to the maximum dose per muscle as indicated in Table 3. (See Table 3.)

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Neurogenic Detrusor Overactivity: Patients should not have an acute urinary tract infection prior to treatment. Prophylactic antibiotics should be administered 1-3 days pre-treatment, on the treatment day and 1-3 days post-treatment.
It is generally recommended that patients discontinue antiplatelet therapy at least 3 days before the injection procedure. Patients on the anticoagulant therapy need to be managed appropriately to decrease the risk of bleeding.
An intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is Clostridium Botulinum Toxin Type A 200 units.
Reconstitute two 100 units vials of NABOTA, each with 6 mL of 0.9% nonpreserved saline solution 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 3rd 10 mL syringe. Complete the reconstitution by adding 6 mL of 0.9 % nonpreserved saline solution into each of the 10 mL syringes and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 units in each), for a total of 200 units of reconstituted Clostridium Botulinum Toxin Type A. Use immediately after reconstitution in the syringe.
Dispose of any unused saline.
Reconstituted Clostridium Botulinum Toxin Type A (200 units/30 mL) is 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, but over-distension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL prior to the start of injections (depending on the needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1 mL each (total volume of 30 mL) should be spaced approximately 1 cm apart. For the final injection, approximately 1 mL of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 min post-injection.
Based on the reported clinical result with other botulinum toxin products, when the clinical effect of the previous injection diminished, patients should be considered for reinjection, but no sooner than 3 months from the prior bladder injection.
Administration: General: The use of one vial for more than patient is not recommended because NABOTA and diluent do not contain a preservative. Once opened and reconstituted, store in a refrigerator and use within 24 hrs. Discard any remaining solution. Do not freeze reconstituted NABOTA.
Reconstituted NABOTA is injected with the purpose of reaching the motor endplate region of the muscle to be treated.
Route of Administration: IM injection. May be SC injection for blepharospasm.
Reconstitution of Vial: Dilution Technique: Prior to injection, reconstitute lyophilized-dried NABOTA with sterile normal saline without a preservative; 0.9% sodium chloride is the recommended diluent.
It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage. Remove the flip-off plastic seal from the NABOTA vial. An appropriate amount of diluent (see Table 4 or for specific instructions for intradetrusor injections for neurogenic detrusor activity, refer to Neurogenic Detrusor Overactivity as previously mentioned) is drawn up into a syringe. The exposed portion of rubber septum of the vials is cleaned with alcohol (70%) prior to insertion of the needle. Draw up the proper amount of diluent in the appropriate syringe size and slowly inject the diluent into the vial.
Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix NABOTA with the saline by rotating the vial. Record the date and time of reconstitution on the space on the label. NABOTA should be administered within 24 hrs after reconstitution.
During this time period, reconstituted NABOTA should be stored in a refrigerator (2-8°C). Reconstituted NABOTA should be clear, colorless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit. (See Table 4.)

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A decrease or increase in NABOTA dose is possible by administering a smaller or larger injection volume. The "unit" by which the potency of preparations of NABOTA is measured should be used to calculate dosages of NABOTA only and is not transferable to other preparations of botulinum toxin.
Doses recommended for NABOTA are not interchangeable with other preparations of botulinum toxin.

Patients with botulism may present with symptoms of ptosis, diplopia, swallowing and speech disorders, cranial nerve findings, generalized weakness or paresis of the respiratory muscles.
Overdose of botulinum toxin is a relative term and depends upon dose, site of injection and underlying tissue properties. Local weakness is usually well tolerated and resolves spontaneously without intervention. However, dysphagia may result in loss of airway protection and aspiration pneumonia. Patients or caregivers should be advised to seek immediate medical consultation if swallowing, speech or respiratory disorders arise.
There have not been any reported instances of systemic toxicity resulting from accidental injection or oral ingestion of botulinum toxin product. Should overdosage occur, the patients should be medically supervised for several days for signs or symptoms of systemic weakness or muscle paralysis.
The entire contents of a vial is below the estimated dose (from primate studies) for toxicity in humans weighing ≥6 kg.

Individuals with known hypersensitivity to any constituent of botulinum toxin product: Patients with myasthenia gravis or Eaton-Lambert syndrome; presence of infection at the proposed injection site(s). The recommended dosages and frequencies of administration of NABOTA should not be exceeded.
Botulinum toxin for treatment of urinary incontinence due to neurogenic detrusor overactivity is also contraindicated in patients who have acute urinary tract infection and in patients with acute urinary retention who are not routinely performing clean intermittent self-catheterization (CIC).

The term "unit" upon which dosing is based, is a specific measurement of toxin activity that is unique to Daewoong's formulation of botulinum toxin type A. Therefore, the "unit" used to describe NABOTA activity are different from those used to describe that of other botulinum toxin preparations and the units representing NABOTA activity are not interchangeable with other products.
NABOTA should only be given by physicians with the appropriate qualifications and experience in the treatment of patients and the use of required equipment. The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering NABOTA and injection into vulnerable anatomic structures must be avoided.
Distant Spread of Toxin Effect: Post-marketing safety data from other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms that are consistent with the mechanism of action of botulinum toxin have been reported hours to weeks after injection, and may include muscular weakness, ptosis, diplopia, blurred vision, facial weakness, swallowing and speech disorders, constipation, aspiration pneumonia, difficulty breathing and respiratory depression. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in patients who have underlying conditions and comorbidities that would predispose them to these symptoms including adults treated for spasticity and other conditions and are treated with high doses. Swallowing and breathing difficulties can be life threatening and death has been reported, although a definitive casual association to botulinum toxin product has not been established.

General: The safe and effective use of botulinum toxin product depends upon proper storage of the product, selection of the correct dose and proper reconstitution and administration techniques.
The relevant anatomy and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering botulinum toxin product and care should be taken when injecting in or near vulnerable anatomic structures. Serious adverse events including fatal outcomes have been reported in patients who had received botulinum toxin product injected directly into salivary glands, the oro-lingual-pharyngeal region, esophagus and stomach. Some patients had preexisting dysphagia or significant debility. Pneumothorax associated with injection procedure has been reported following the administration of botulinum toxin product near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices.
An understanding of standard electromyographic techniques is also required for treatment of strabismus and may be useful for the treatment of cervical dystonia and hemifacial spasm and for the treatment of focal spasticity associated with stroke or pediatric cerebral palsy.
Caution should be used when botulinum toxin product is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle(s).
Caution should also be exercised when botulinum toxin product is utilized for treatment of patients with amyotrophic lateral sclerosis or disorders that produce peripheral neuromuscular dysfunction.
No cases of systemic toxicity have been reported following accidental injection or oral ingestion of botulinum toxin product. Signs of overdose are not apparent immediately post-injection. Should accidental or oral ingestion occur, the patient should be medically supervised for several days on an office or outpatient basis for signs or symptoms of systemic weakness or muscle paralysis.
Anaphylactic reactions to botulinum toxin type A have not been reported so far, but as with all biological products, necessary precautions should be taken, adrenaline (epinephrine) and other anaphylactic measures should be available.
NABOTA contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Blepharospasm: Reduced blinking following the use of botulinum toxin product injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with VII^th nerve disorders. 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. This may require protective drops, ointment, therapeutic soft contact lenses or closures of the eye by patching or other means.
Because of the anticholinergic activity of botulinum toxin, caution should be exercised when treating patients at risk for angle-closure glaucoma, including patients with anatomically narrow angles. Acute angle glaucoma has been reported very rarely following periorbital injections of botulinum toxin.
Strabismus: During the administration of botulinum toxin product for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit. It is recommended that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. An ophthalmoscope to diagnose this condition should be available.
Cervical Dystonia: The most frequently reported severe adverse event associated with the use of botulinum toxin type A in patients with cervical dystonia is dysphagia, with dyspnea also being reported on occasion. On rare occasions, the dysphagia has been severe enough to warrant the insertion of a gastric feeding tube. Dysphagia may persist for 2-3 weeks after injection, but infrequently has been reported to last 5 months post-injection. There have also been at least 2 reported incidents where subsequent to the finding of dysphagia, patients developed aspiration pneumonia and died. Limiting the dose injected into the sternocleidomastoid muscle to <100 units may decrease the occurrence of dysphagia. Patients with smaller neck muscle mass or patients who require bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia. Dysphagia may be attributable to distribution of the pharmacological effect of botulinum toxin product resulting from spread of the toxin in the vicinity of the injection site.
Cerebral Palsy and Focal Spasticity in Adults: Botulinum toxin product is a treatment of focal spasticity that has been studied in association with usual standard of care regimens. Botulinum toxin product is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.
Hyperhidrosis: Patients should be evaluated for potential causes of secondary hyperhidrosis (eg, hyperthyroidism, pheochromocytoma) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease.
Chronic Migraine: Refer to preceding Precautions, including specific information for Cervical Dystonia, Blepharospasm and Strabismus, due to similar injection sites.
Neurogenic Detrusor Overactivity: Appropriate medical caution should be exercised for performing a cystoscopy.
In these patients, autonomic dysreflexia associated with the procedure could occur, which may require prompt medical therapy.
Due to the risk of urinary retention, only who are willing and/or able to initiate catheterization post-treatment, if required, should be considered for treatment.
In patient who are not catheterizing, post-void residual urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Patients should be instructed to contact their physician if they experience difficulties in voiding as catheterization may be required.
Information for Patients: As with any treatment with the potential to allow previously sedentary patients to resume activities, the sedentary patient should be cautioned to resume activity gradually following the administration of botulinum toxin product. Patients should also be advised of the potential for experiencing malaise lasting up to 6 weeks after injection.
After bladder injections for urinary incontinence, patients should be instructed to contact their physician if they experience difficulties in voiding.
Effects on the Ability to Drive or Operate Machinery: There are no known sedative effects of botulinum toxin. Its effects on the neuromuscular junction with consequent effects on muscle activity need to be taken into consideration together with an appraisal of the underlying disease when advising patients on their suitability to drive or operate machinery.
Use in pregnancy & lactation: There are no adequate and well-controlled studies of botulinum toxin administration in pregnant women. Because animal reproductive studies are not always predictive of human response, NABOTA should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. If botulinum toxin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks, including abortion or fetal malformations which have been observed in rabbits.
Use in children: The safety and effectiveness of botulinum toxin in the treatment of blepharospasm, hemifacial spasm and associated focal dystonias, spasmodic torticollis or upper facial lines (forehead, crow's feet and glabellar lines) in children <12 years have not been demonstrated.
Safety and effectiveness in children and adolescents below the age of 20 years were not investigated for improvement of glabellar lines.
The safety and efficacy of upper limb spasticity have not been established in children and adolescents under the age of 18 years.

There are no adequate and well-controlled studies in pregnant women.
When pregnant mice and rats were injected intramuscularly during the period of organogenesis, the developmental NOEL (No Observed Effect Level) of other botulinum toxin was 4 U/kg. Higher doses (8 or 16 U/kg) were associated with reductions in fetal body weights and/or were decreased fetal skeletal ossification. In a range finding study in rabbits, daily injection of 0.125 U/kg/day (days 6 to 18 of gestation) and 2 U/kg (days 6 to 13 of gestation) produced severe maternal toxicity, abortions and/or fetal malformations. Higher doses resulted in death of the dams. The rabbit appears to be a very sensitive species to this drug. The patient should be apprised of the potential risks, including abortion or fetal malformations which have been observed in rabbits.
It is not known whether botulinum toxin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this product is administered to a nursing woman.
Administration of this product is not recommended during pregnancy or lactation.

General: In general, adverse events occur within the 1st week following injection of botulinum toxin products and are transient. As is expected for any IM injection procedure, localized pain, tenderness and/or bruising may be associated with the injection. Local weakness represents the expected pharmacological action of botulinum toxin.
The following list includes adverse drug reactions or other medically relevant adverse events that have been reported since the drug has been marketed, regardless of indication: Denervation/muscle atrophy; respiratory depression and/or respiratory failure (noncosmetic indications); dyspnea; aspiration pneumonia (noncosmetic indications); dysarthria; dry mouth; strabismus, peripheral neuropathy, abdominal pain; diarrhea; nausea; vomiting; pyrexia; anorexia; blurred vision; visual disturbance; hypoacusis; tinnitus; vertigo; facial palsy; facial paresis; brachial plexopathy; radiculopathy; syncope; hypoesthesia; malaise; myalgia; myasthenia gravis; paresthesia; rash; erythema multiforme; pruritus; dermatitis psoriasiform; hyperhidrosis; and alopecia, including madarosis.
There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia and/or other significant debility after treatment with botulinum toxin type A. There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease.
Blepharospasm: In reported study of other botulinum toxin product, adverse events observed mostly were ptosis, superficial punctate keratitis and eye dryness. And in the results from other clinical studies and using experience with other botulinum toxin products, irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia and entropion, diffuse skin rash and local swelling of the eyelid skin lasting for several days following eyelid injection, angle closure glaucoma, visual disturbance and facial weakness have also been reported.
During administration of other botulinum toxin product, in 2 cases of VII^th nerve disorder (1 case of an aphakic eye), reduced blinking from botulinum toxin injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect and corneal ulceration. Perforation occurred in the aphakic eye and required corneal grafting. Vigorous treatment of any corneal epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses or closure of the eye by patching or other means.
Hemifacial Spasm: Adverse events reported after injection of other botulinum toxin products have included blurring of vision, facial droop, dizziness and tiredness, in addition to those listed previously under blepharospasm treatment.
Strabismus: During administration of other botulinum toxin product for treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred owing to penetration of the needle into areas surrounding eyes. It is recommended that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. An ophthalmoscope to diagnose this condition should be available. Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past-pointing. Covering the affected eye may alleviate these symptoms.
Cervical Dystonia: The following adverse events were reported in clinical study of other botulinum product. The frequency of adverse reactions reported defined as follows: Very Common (≥ 1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very Rare (<1/10,000).
Very common: pain, focal weakness, dysphagia.
Common: soreness, malaise, general weakness, upper respiratory infection, nausea, headache, drowsiness, stiffness, dry mouth, dizziness, rhinitis and hypertonia.
Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of botulinum toxin product resulting from the spread of the toxin outside the injected muscles. Dysphagia is usually reported as mild to moderate severity in most patients. However, in an occasional patient, it may be associated with more severe problems (see Precautions). Other treatment-related adverse events include numbness, diplopia, ptosis, dyspnea, fever and flu syndrome.
Cerebral Palsy: As is expected for any IM injection procedure, localized pain may be associated with the injection in these patients. The adverse reactions most frequently reported as related to treatment include falling, leg pain, leg (local) weakness.
Falling may be attributed to a change in the ankle position and gait and/or local weakness. Local weakness represents the expected pharmacological action of botulinum toxin.
Glabellar Lines: Safety of NABOTA was evaluated in multicenter, comparative, double-blinded, randomized studies which included 268 patients aged between 20 to 65, with moderate to severe glabella lines (test group 135, control group 133). Adverse reactions were observed in 20.00% of test group, and in 18.05% of control group.
Most of the adverse reactions were mild, and none was severe. Adverse reactions reported more than 1% in the test group of this drug, listed in the order of frequency are; ptosis (2.22%), raised eyebrows (1.48%), and vertigo (1.48%).
Crow's Feet: In information reported in safety study with other botulinum toxin, most adverse events reported were of mild to moderate severity and all were transient. The most frequently reported treatment-related adverse events were injection site hemorrhage ie, bruising at the injection site and headache.
Other studies have reported the incidence of injection site bruising to be between 4-25% of botulinum toxin product-treated patients, included temporary droop of the lateral portion of the lower eyelid, which is consistent with the pharmacologic action of botulinum toxin product and may be injection technique-related.
Forehead Lines: Adverse events including headache, bruising, eyebrow ptosis, eyelid swelling, aching/itching forehead and nausea were reported in the clinical study of other botulinum toxin product.
Focal Spasticity in Adults: In multicenter, double-blinded, randomized active-controlled trial with 197 post-stroke patients aged over 18 years, more than 6 weeks since stroke onset, safety in upper limb spasticity was evaluated. Adverse reactions occurred in 19.59% of the test group treated NABOTA and 19.39% of the control group.
Most of the adverse reactions were mild, and none was severe. Adverse reactions reported in this clinical study were 3 cases in the test group of this drug and 4 cases in the control group.
The frequency of adverse reactions reported in the clinical trials is defined as follows: Very Common (≥ 1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very Rare (<1/10,000).
Adverse reactions reported commonly in treatment of this drug were listed as follows: See Table 5.

Click on icon to see table/diagram/image

Hyperhidrosis of the Axilla: In studies with other botulinum toxin product, adverse events reported as treatment related in >1% of botulinum toxin product-treated patients were perceived increase in non-axillary sweating, injection site pain, pain and vasodilation (hot flushes).
Chronic Migraine: In studies with other botulinum toxin product, adverse events reported in common were headache, migraine, facial paresis, eyelid ptosis, injection site pain, pruritus, rash, neck pain, musculoskeletal stiffness, muscular weakness, myalgia, musculoskeletal pain, muscle spasms and muscle tightness.

The effect of botulinum toxin products are generally potentiated by concomitant use of aminoglycoside antibiotics or other drugs that interfere with neuromuscular transmission, e.g. tubocurarine-type muscle relaxants or curare-like non-depolarising blockers. Concomitant use of aminoglycosides or spectinomycin is contraindicated. Polymyxin, tetracycline and lincomycin should be carefully used in patients injected with this product. Hence such drugs should be used with caution in patients treated with botulinum toxin.
The effects of administering different botulinum neurotoxin serotypes at the same time or within several months are unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin product before the effects of a previously administered botulinum toxin disappear.

Precautions in Storage & Handling: Unopened vials of this drug product should be stored in a refrigerator (2-8°C). Reconstituted product may be stored in a refrigerator (2-8°C) for up to 24 hours after reconstitution. For safe disposal, all vials including expired vials or equipment directly contacted with the drug should be disposed as medical waste. If inactivation is required (e.g. spillages), use of dilute hypochlorite solution (0.5% or 1%) before disposal as medical waste is recommended.

Store unopened vial in a refrigerator (2-8°C).
Store in refrigerator 2-8°C up to 24 hours after reconstitution.
Do not freeze.

Patients should be encouraged to consult with their doctor about any and all concerns over effectiveness and/or risks of this product. Careful attention should be paid to potential signs or symptoms of adverse events. Call the doctor or get immediate medical help if the patient experience any unusual symptoms after treatment with this product, including difficulty in swallowing, speaking or breathing, or muscle weakness. Such adverse events may happen hours to weeks after injection of this product.
This product blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, this product produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extra junctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by this product.

Muscle Relaxants

M03AX01 - botulinum toxin ; Belongs to the class of other agents used as peripherally-acting muscle relaxants.

Rx

Lyophilized powd for inj (vial) 100 u x 10 mL x 1's.