Neuronox

Neuronox

Manufacturer:

Medytox

Distributor:

Medyceles
Full Prescribing Info
Contents
Clostridium botulinum toxin type A.
Description
Each vial contains: Active ingredient: Clostridium botulinum toxin type A 50, 100, 200  units (U) (Korean Minimum Requirements for Biological Products).
Stabilizer: Human serum albumin 0.5 mg (Korean Minimum Requirements for Biological Products).
Stabilizer and Isotonic agents for 100 Units.
Isotonic agent: Sodium chloride (EP) 0.9 mg.
Stabilizer and Isotonic agent for vial contains 50, 200 Units are in the same ratio of vial contains 100 units.
*One unit (U) of NEURONOX corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice.
It appears as a lyophilized white powder for injection in a colorless transparent vial.
Indications/Uses
Hemifacial spasm: Neuronox is indicated for the treatment of Hemifacial spasm (Idiopathic).
Strabismus: Neuronox is indicated for the treatment of Strabismus in patients 12 years of age and above.
Spasmodic torticollis: Neuronox is indicated for the treatment of Spasmodic torticollis.
Cervical dystonia: Neuronox is indicated for the treatment of Cervical dystonia.
Muscle spasticity: Neuronox is indicated for the treatment of Upper limb post-stroke spasticity in patients 20 years of age and above.
Blepharospasm: Neuronox is indicated for the treatment of benign essential blepharospasm in patients 18 years of age and older.
Dynamic equines foot in Cerebral palsy children: Neuronox is indicated for the treatment of equinus foot deformity due to spasticity in pediatric cerebral palsy patients 2 years of age and older.
Glabellar wrinkles: Temporary improvement of serious glabellar wrinkles ranging from moderate to severe associated with corruptors muscle and/or procerus muscle activities in adults over the age of 20 and below the age of 65.
Dosage/Direction for Use
Blepharospasm: For blepharospasm, reconstituted NEURONOX (see Table 2) is injected using a sterile, 27 - 30 gauge needle without electromyographic guidance. The initial recommended dose is 1.25 - 2.5 U (0.05 ml, to 0.1 ml. volume at each site) injected into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid. In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient-usually defined as an effect that does not last longer than two months. However there appears to be little benefit obtainable from injecting more than 5.0 U per site. Some tolerance may be found when the drug is used in treating blepharospasm if treatments are given any more frequently than every three months, and is rare to have the effect be permanent.
The cumulative dose of NEURONOX treatment in a 30-day period should not exceed 200 U.
Pediatric cerebral palsy: For the pediatric cerebral palsy, reconstituted NEURONOX (see Table 2) is injected using a sterile, 26-30 gauge needle. It is recommended to inject to each of the medial and lateral heads of the gastrocnemius muscles. A total dose of 4U/kg bodyweight is recommended for the affected gastrocnemius muscle in patients with hemiplegia. And in patients with diplegia, the recommended dose is 6U/kg bodyweight divided between both legs. The maximum dose administered must not exceed 200U/patient at a time. After injection, patient should be monitored for at least 30 minutes for any presence of acute adverse event.
Glabellar wrinkles: NEURONOX is reconstituted to make 100U/2.5mL (4U/0.1 mL) with 0.9% non-preserved sterile saline. Using a 30 gauge needle, 20U of NEURONOX is injected to two places on the corrugators muscle for each eye and one place on the procerus muscle, total of 5 sites with 0.1 mL per site. To reduce complications of drooping (ptosis) eyelids, injection is avoided in the levator palpebrae superioris vicinity, especially for patients with large corrugators muscles. When administering injection in the medial end of corrugators muscle and in the midpoint between each eyebrow, it must be done in a place at least 1 cm apart from supraorbital ridge. NEURONOX is injected with caution so that it does not enter the blood vessel, and to prevent effusion from the area below the orbital ridge, firmly place a thumb or an index finger on the area below the orbital ridge prior to injection. During injection, the needle should point upward toward the center and injection dose must be measured accurately. The corrugators muscle and orbicularis oculi muscle move the center of the forehead and generate the glabellar facial wrinkles. The protean muscle and depressor supercilii muscle pull the forehead down. Frowning or glabellar wrinkles are produced by these muscles. Because the position, size, and use of these muscles are different for individuals, an effective dose is determined based on general observations on the patient's ability to move the injected superficial muscles. The treatment effect of NEURONOX for glabellar wrinkles lasts approximately 3-4 months. Frequent injection of NEURONOX has not been clinically evaluated for safety and effectiveness, and it is not recommended. In general, the first NEURONOX injection induces chemical denervation in the injected muscles 1 to 2 days after injection and its intensity increases during the first week.
Muscle Spasticity: The exact dosage and the number of injection should be tailored to the individual based on the size, the number and location of the muscles involved, the severity of spasticity, presence of local muscle weakness, and the patients response to previous treatment. Clinical improvement in muscle tone is seen four to six weeks following treatment.
In controlled clinical trials, the following doses are administered: See Table 1.

Click on icon to see table/diagram/image

In the clinical trial, doses are not over 360U, injected into individual muscles.
Reconstituted NEURONOX is injected using a sterile 24-30 gauge needle for superficial muscles, and a longer needle may be used for deeper musculature. Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques is recommended.
Hemifacial spasm: Dosage: In the first treatment session, the doctor may give multiple injections in the affected muscles with 1.25 to 2.5 Units of NEURONOX into each injection site. The maximum dose for the first treatment session is 25 Units per affected area (for example per eye). For the following treatment sessions, the total maximum dose can be increased up to 100 Units, if needed.
Duration of treatment effect: Patient will usually see an improvement within 3 days after the injection. The maximum effect is usually seen 1 to 2 weeks after treatment. When the effect starts to wear off, patient can have the treatment again if needed, but not more often than every 3 months.
Strabismus: Dosage: In the first treatment session, the doctor may give multiple injections in the affected muscles with 1.25 to 2.5 Units of NEURONOX into each injection site. The maximum dose for the first treatment session is 25 Units per affected area (for example per eye). For the following treatment sessions, the total maximum dose can be increased up to 100 Units, if needed.
Duration of treatment effect: Patient will usually see an improvement within 3 days after the injection. The maximum effect is usually seen 1 to 2 weeks after treatment. When the effect starts to wear off, patient can have the treatment again if needed, but not more often than every 3 months.
Cervical dystonia: Dosage: The doctor may give multiple injections in the affected muscles. The dose and number of injections will vary depending on a number of factors, including patient's needs, the muscles to be injected, the size of the muscles, severity of spasms, etc.
Duration of treatment effect: Patient will usually see an improvement within the first 2 weeks after the injection. The maximum effect is usually seen about 4 to 6 weeks after treatment. When the effect starts to wear off, patient can have the treatment again if needed, but not more often than every 12 weeks.
Spasmodic torticollis: Dosage: The doctor may give multiple injections in the affected muscles with up to 50 Units of NEURONOX into each injection site. The maximum dose for the first treatment session is 200 Units. For the following treatment sessions, the maximum dose can be increased up to 300 Units.
Duration of treatment effect: Patient will usually see an improvement within 2 weeks after the injection. The maximum effect is usually seen about 6 weeks after treatment. When the effect starts to wear off, patient can have the treatment again if needed, but not more often than every 10 weeks.
Dilution technique: Prior to injection, reconstitute freeze-dried NEURONOX with sterile normal saline without a preservative. 0.9% Sodium chloride Injection is the recommended diluent. Draw up the proper amount of diluent in the appropriate size syringe. The diluent should be injected gently into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix NEURONOX with the saline by rotating the vial. NEURONOX should be administered within 24 hours after reconstitution. During this time period, reconstituted NEURONOX should be stored in a refrigerator (2 – 8 °C). Reconstituted NEURONOX should be clear, colorless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Because the drug and diluent do not contain any preservative, one vial of NEURONOX should be used for a single patient. (See Table 2.)

Click on icon to see table/diagram/image

Note: These dilutions are calculated for an injection volume of 0.1 ml. A decrease or increase in dose is also possible by administering a smaller or larger injection volume - from 0.05 mL (50% decrease in dose) to 0.15 ml. (50% increase in dose).
Overdosage
Signs and symptoms of overdose are not apparent immediately post-injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for up to several weeks for signs or symptoms of systemic weakness or muscle paralysis.
An antitoxin is available in the event of immediate knowledge of an overdose or misinjection. The antitoxin will not reverse any botulinum toxin induced muscle weakness effects already appeared by the time of antitoxin administration.
If the musculature of the oropharynx and esophagus at affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive are could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care.
Contraindications
NEURONOX must not be administered to the following patients: Patients with hypersensitivity reactions to any ingredients of NEURONOX.
Patients with systemic neuromuscular junctional disorders (severe myasthenia gravis, Lambert-Eaton syndrome, amyotrophilateral sclerosis, etc) (The muscle relaxing effect of this drug can worsen the disease.)
Patients with severe respiratory dysfunction while using NEURONOX for cervical dystonia.
Women who are pregnant or may be pregnant and nursing mothers.
Warnings
Since the active constituent in this drug is Clostridium botulinum toxin type A neurotoxin which is derived from Clostridium botulinum, the recommended dosages and frequency of administration should be observed with a full understanding of the precautions in use. Physicians administering the drug must understand the relevant neuromuscular anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. An understanding of standard electromyographic techniques is also required for the administration of the drug. The recommended dosage and frequency of administration for NEURONOX should not be exceeded.
Spread of toxin effect: In some cases, botulinum toxin effect may be observed beyond the site of local injection. The symptoms may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions. Symptoms with spread of toxin effect have been reported as doses comparable to or lower than doses used to treat cervical dystonia.
Hypersensitivity reactions: Serious and/or immediate hypersensitivity reactions have been rarely reported with other botulinum toxin products. These reactions include anaphylaxis, urticaria, soft tissue edema and dyspnea. One fatal case of anaphylaxis with other botulinum toxin product has been reported in which lidocaine was used as a diluent but the causal agent cannot be reliably determined. If such a reaction occurs, further injection of the drug should be discontinued and appropriate medical therapy should be immediately instituted.
Pre-existing neuromuscular disorders: Individuals with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of botulinum toxin injection. Published medical literature with other botulinum toxin product has reported rare cases of administration of a botulinum toxin to patients with known or unrecognized neuromuscular disorders where the patients have shown extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases. dysphagia has lasted several months and required placement of a gastric feeding tube.
Dysphagia: Treatment of patients with Cervical Dystonia with all botulinum toxin products can result in swallowing difficulty and it is a common adverse reaction reported. In those patients, it has been rarely reported to use of a feeding tube due to severe dysphagia. Deaths as aspiration pneumonia have been reported after treatment with botulinum toxin that is developed after dysphagia.
There have been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes in case of other botulinum toxin treatment. Some of these patients had risk factors including cardiovascular disease.
During the administration of other botulinum toxin product for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit. In order to decompress the orbit which can be easily affected, it is recommended that appropriate instruments be accessible. Ocular penetrations by needles have also occurred. An ophthalmoscope to diagnose this condition should be available. However, 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.
Corneal exposure and ulceration in patient treated with botulinum toxin products for blepharospasm Reduced blinking from botulinum toxin injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. One case of corneal perforation in an aphakic eye requiring corneal grafting has occurred because of this effect. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.
Lack of interchangeability between Botulinum toxin products.
The potency units of biological activity of NEURONOX can not be compared to or convened into units of any other botulinum toxin products assessed with any other specific assay method.
Injections In or Near Vulnerable Anatomic Structures: 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 other botulinum toxin products injected directly into salivary glands, the oro-lingual-pharyngeal region, esophagus and stomach. Some patients had pre-existing dysphagia or significant debility. (Safety and effectiveness have not been established for indications pertaining to these injection sites.) Pneumothorax associated with injection procedure has been reported following the administration of other botulinum toxin product near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices.
Pulmonary Effects of botulinum toxin product in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity associated with a Neurologic Condition.
In Patients with compromised respiratory status treated with other botulinum toxin for upper limb spasticity, reduced lung function and upper respiratory tract infections were reported and patients with Detrusor Overactivity associated with a Neurologic Condition treated with Botox, reduced lung function was reported.
Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity: Bronchitis was reported more frequently as an adverse reaction in patients treated for upper limb spasticity with botulinum toxin, compared to placebo. In patients with reduced lung function treated for upper limb spasticity, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with botulinum toxin compared to placebo.
Special Precautions
General precautions: This drug contains albumin, a derivative of human blood. When a medicinal product derived from human blood or serum is administered in human body, the theoretical risk of infectious diseases by transmissible agents cannot be completely excluded, though is considered extremely remote. It may include any pathogenic agent that is still unknown. In order to decrease the risks of infection by transmissible agents, particular cares including appropriate assay methods are given to the controls of the donors and donation site, to the manufacturing process and to the virus removal/inactivation process.
Cerebral Palsy: NEURONOX treatment is used for local seizure studied in association with the standard treatment; it does not replace these treatment modalities. NEURONOX does not appear that it will be effective in improving limited movement of joints permanently.
Glabellar Wrinkles: In the phase III clinical trial study, those patients who have the history of facial nerve paralysis or the symptoms of eyelid ptosis, history of treatment of glabellar pan like face lifting and permanent implant or with scars which may affect the treatment results, satisfactorily not improved with physical method since the lines are not flattened even using hands, they were excluded; therefore warnings should be given. The interval between administrations of NEURONOX should not be less than 3 months, and the minimum effective dose must be used.
Muscle Spasticity: NEURONOX is used only for treating localized spasticity studied in association with typical standard treatment. NEURONOX is not effective in improving the range of movement in joints affected by fixed limitation.
NEURONOX should be administered with caution for the following patients: Patients who are taking a muscle relaxant (Sodium Tubocurarine, Dantrolen Sodium, etc.) [may be at risk of developing dysphagia or increasing muscle relaxing effect].
Patients who are taking Spectinomycin Hydrochloride, aminoglycoside antibiotics (Gentamycin Sulfate, Neomycin Sulfate, etc.), polypeptide antibiotic (Polymixin B Sulfate, etc.), tetracycline antibiotics, lincosamide antibiotics, muscle relaxant (Baclofen, etc.), anticholinergics (Butylscopolamine Bromide, Trihexyphenidyl Hydrochloride, etc.), benzodiazepines and similar drugs (Diazepam, Etizolam, etc.), benzamides (Tiapride Hydrochloride, Sulpiride, etc.), and such drugs with muscle relaxing effect may be at risk of developing dysphagia or increasing muscle relaxing effect.
Effects on the Ability to Drive or Operate Machinery: Due to the nature of the disease being treated, the effects of the drug on the ability to drive or to operate machines cannot be predicted.
Carcinogenesis, mutagenesis, impairment of fertility, Animal toxicity: Long term studies in animals have not been performed to evaluate carcinogenic potential of botulinum toxin. The result of the animal toxicology with other botulinum toxin product is following. In a study to evaluate inadvertent peribladder administration, bladder stones were observed in 1 of 4 male monkeys that were injected with a total of 6.8 Units/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 Units/kg (~12X the human dose) directly to the bladder as either single or 4 repeat dose injections or in female rats for single injections up to 100 Units/kg (~33X the human dose).
Use in Pregnancy & Lactation: Safety in pregnant women and nursing mothers has not been established in this drug. Other botulinum toxin injection has been shown to produce abortions and effects at daily doses of 0.125 U/kg/day and at 2 U/kg and higher in rabbits; whereas in rats and mice, no abortions or effects were observed when up to 4 U/kg of botulinum toxin were injected. Doses of 8 and 16 U/kg in rats and mice have been shown to be associated with reduced fetal body weight and/or delayed ossification of the hyoid bone, which may be reversible.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NEURONOX is administered to a nursing woman.
NEURONOX is contraindicated in pregnancy and lactation.
Use in Children: Blepharospasm: Safety and effectiveness in children below the age of 18 years have not been established.
Pediatric cerebral palsy: Safety and effectiveness in children over the age of 11 years have not been established.
Use In Pregnancy & Lactation
Safety in pregnant women and nursing mothers has not been established in this drug. Other botulinum toxin injection has been shown to produce abortions and effects at daily doses of 0.125 U/kg/day and at 2 U/kg and higher in rabbits; whereas in rats and mice, no abortions or effects were observed when up to 4 U/kg of botulinum toxin were injected. Doses of 8 and 16 U/kg in rats and mice have been shown to be associated with reduced fetal body weight and/or delayed ossification of the hyoid bone, which may be reversible.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NEURONOX is administered to a nursing woman.
NEURONOX is contraindicated in pregnancy and lactation.
Adverse Reactions
General: There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility oranaphylaxis, after treatment with botulinum toxin.
There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. The exact relationship of these events to the botulinum toxin injection has not been established.
The following events have been reported with other botulinum toxin products and a causal relationship to the botulinum toxin injected is unknown: skin rash (including erythema multiforme, urticaria and psoriasiform eruption), pruritus, and allergic reaction. In general, adverse events occur within the first week following injection of the drug and while generally transient nay have a duration of several months.
Local pain, tenderness and/or bruising, traction, swelling, hot feeling or hypertonia at injection site or adjacent muscles may be associated with the injection. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of adjacent muscles may also occur due to spread of toxin. When injected in patients with blepharospasm or cervical dystonia, some distant muscles from injection site can show increased electrophysiologic jitter (rapid variation in a waveform) which is not associated with clinical weakness or other types of electrophysiological normalitics.
Strabismus: Extraocular muscle near the injection site can be affected causing eyelid drooping or vertical deviation, especially when a high dose is administered. The incidence rate of adverse events when 2,058 adult patients were treated with other botulinum toxin product for horizontal strabismus with 3,650 injections is as follows: Eyelid drooping: 15.7%; vertical deviation: 16.9%.
Spatial disorientation, double field of vision, and past-pointing can be developed by inducing paralysis in one or more of extraocular muscles. These symptoms can be reduced by covering up the affected eye. The incidence rate of eyelid ptosis was 0.9% for inferior rectus injection and 37.7% for superior recurs. The incidence rate of adverse menu that lasted for 6 months after 3.104 patients received series of 5,587 injections in the horizontal muscle is as follows: Eyelid drooping: 0.3%; vertical deviation of greater than 2 prism diopters: 2.1%.
From those patients, 9 cases developed sclera perforation due to the injection process itself. One case developed vitreous hemorrhage but improved afterward. There were no cases of retinal detachment or loss of vision. There were 16 cases of retrobulbar hemorrhage. After 5 minutes, the eye socket was decompressed in order to recover the retinal circulation. There was no loss of vision due to posterior eyelid hemorrhage. A pupil change that comes with ciliary ganglion damage occurred in 5 cases. There was reported a case of anterior segment ischemia after administering other botulinum toxin product in the medical rectus muscle 4 to treat estropia (Adies pupil).
Blepharospasm: In a study of blepharospasm patients who received an avenge dose per eye of 33 U (injected at 3 to 5 sites) of other botulinum toxin injections, the most frequently reported treatment-related adverse reactions were ptosis (20.8%), superficial punctuate keratitis (6.3%) and eye dryness (6.3%). All of these events were mild to moderate except for one case of ptosis which was rated severe. Other events reported in prior clinical studies with other botulinum toxin injections in decreasing order of incidence include: 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. In two cases of VII nerve disorder (one case of an aphakic eye.), reduced blinking from other botulinum toxin injections 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.
In a study of blepharospasm patients with other botulinum toxin product. one case of acute closed angle glaucoma has been reported one day after the injection. The patient was treated with laser itidotomy and trabeculetomy and recovered in four months. After a treatment for blepharospasm, worsening myasthenia, local facial paralysis, and fainting cases were reported. In case of cloudy vision and conjunctivitis, appropriate treatment should be initiated. Through the post marketing surveillance study of other botulinum toxin products for the last 6 years, 41 cases (6.2%) of adverse events were reported out of 660 total cases. Major adverse events were 17 cases of ptosis (2.6%), 5 cases of local swelling (0.8%), 3 cases of illacrimation (0.5%). 3 can of eye irritation (0.5%), 3 cases of lagophthalmos (0.5%), 3 cases of muscle weakness (0.5%), and 3 cases of ophthalmoxerosis (0.5%). The following are adverse events have been reported, 2 cases of pulling at the injection site (0.3%). 2 cases of conjunctival hyperaemia (0.3%), 2 cases of hypertonia (0.3%), and lease of ophthalmalgia (0.2%).
Cervical Dystonia: The most common adverse events associated with spasmodic torticollis in other botulinum toxin product are as follows: Dysphasia, soreness at injection site, localized lassitude and symptomatic, systemic lassitude and malaise. However, malaise was also reported in patients with placebo. Dysphasia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX' resulting from the spread of the toxin outside the injected muscles. These dose-related adverse events are more common among women. Therefore, the dose must be adjusted appropriately as the muscle size is smaller. Other adverse events are reported nausea, drowsiness, headache, numbness, spasticity, and bruising.
Pediatric cerebral palsy: Safety of NEURONOX for the treatment of equinus foot deformity due to spasticity in pediatric cerebral palsy patients was evaluated in a clinical trial in Korea. In this clinical trial, 60 patients who injected NEURONOX showed common adverse reactions (>1%) such as nasopharyngitis (5%), upper respiratory tract infection (1.67%), pyrexia (3.3%), gait disturbance (1.67%), pain in extremity (1.67%), musculoskeletal and connective tissue disorders (1.67%), febrile convulsion (1.67%), constipation (1.67%), and lower limb fracture (1.67%). Additionally the common adverse reactions (> I%) which are shown from 59 patients who injected the control medicine at the comparison clinical trials are as follows; nasopharyngitis (5.08%), haemophilia infection (1.69%), pneumonia (1.69%), pyrexa (5.08%), asthenia (1.69%), joint contracture(1.69%), muscular weakness (1.69%), unequal limb length (1.69%), conjunctivitis (1.69%), headache (1.69%), and anaemia (1.69%). These kinds of adverse reactions may be occurred depending on the patients characteristics. In the literatures about other botulinum toxin products, similar adverse reactions which are related to the use of botulinum toxin are mentioned such as respiratory infection, brochitis, nasopharyngitis, asthma, muscular weakness, urinary incontinence, falling down, convulsion, pyrexia, pain and others.
Glabellar Wrinkles: In multicenter, double-blind, active-controlled, parallel study of the same protocol, the efficacy and safety for those patients, who are in the age 18 to 65 years old with serious glabellar wrinkles were evaluated (n=313, NEURONOX treatment group 156 patients, BOTOX placebo group 157 patients). Adverse events were reported from 26.92% of the treatment group and 22.29% of the control group. Most frequently reported adverse events associated with the treatment were eyelid drooping from 3.21% of the treatment group (5/156) and 1.91% of the control group (3/157). The 8 cases of eyelid drooping reported in both groups were all mild and temporary. To list the adverse events reported in more than 1% of NEURONOX treatment group in the order of highest to lowest incidence frequency, it is as follows: nasopharyngitis (4.49%), eyelid drooping (3.21%), headache (1.92%), hyperglycemia (1.28%), and articulation sprain (1.28%), pyuria (1.28%), eyelids disease (1.28%). Most of reported adverse events were mild to moderate and temporary.
Muscle Spasticity: The use of NEURONOX in treatment for 196 patients (NEURONOX group: 98 patients, BOTOX group: 98 patients) with upper extremity spasticity related to stroke was evaluated for safety. In general, most of the reported adverse events were mild or moderate. The adverse events in the clinical trial were reported total 174 cases and were reported in 39 of 98 patents of treatment group (39.80%, 93 cases) and 41 of 98 patients of control group (41.84%, 87 cases). The adverse events reported by ≥2% of NEURONOX treated patients are listed in the order of frequency: nasopharyngitis (4.08%), pain in extremity (4.08%), cough (4.08%), diarrhea (3.06%), vomiting (3.06%), backache (3.06%), peripheral edema (3.06%), abdominal distension (2.04%), dyspepsia (2.04%), nausea (2.04%), Upper Respiratory Tract Infections (214%), musculoskeletal pain (2.04%), hematoma of injection site (2.04%), pyrexia (2.04%), acute cholecystitis (2.04%). Most of reported adverse events were mild to moderate and temporary.
Post-Marketing Experience: There have been the post marketing surveillance and phase IV trials in 641 patients with Benign Essential Blepharospasm for 6 years in Korea. It has been reported that rate of adverse reaction was 12.5% (80/541, 116 cases), in which 7.8% (50/641 57 cases) cases could not be excluded by causality with the drug and ptosis was reported 3.9% (25 cases, 25 of 641 patients). Other treatment-related adverse events reported by ≤ 1% were as follows: facial swelling (6 cases). ocular abnormality (4 cases), rash (3 cases), itching, paresthesia, lid leg, abnormal tear secretion, ophthalmalgia (2 cases), corneal ulcer, diplopia, arrhythmia, periorbital swelling, oculomotor nerve palsy, headache, paralysis, dizziness, and purpura (I case). The rate of serious adverse events was reported 3 of 641 patients (0.5%, 5 cases): spinal stenosis (2 cases), melosalgia (1 case), myocardial infarction case), and arrhythmia (1 case).
Unexpected adverse drug reactions were reported in 11 of 641 patients (1.7%), but there was no unexpected serious adverse event among them. The unexpected and non serious adverse drug reactions were reported as follows: facial swelling (6 cases), ocular abnormality (2 cases), headache, paresthesia. dizziness (1 case).
In PMS (Post Marketing Surveillance) study in 210 patients with equinus foot deformity due to cerebral palsy in Korea, it has been reported that the rate of adverse event was 21.4% (45/210, 84 cases). Among them, the rate of adverse drug reaction which could not be excluded by causality was 1.4% (3/210 patients, 3 cases) and the rate of inflammation of injection site was 1% (2/210 patients, 2 cases). Another adverse drug reaction, myalgia was reported ≤ 1%. The rate of serious adverse event was reported 14% (3/210 patients, 3 cases) by 2 cases of pneumonia and 1 case of urinary tract infection. However, there was no reported unexpected serious adverse event among them.
Drug Interactions
The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or other drugs that interfere with neuromuscular transmission e.g. tubocurarine-type muscle relaxants. Continuous concomitant use of NEURONOX with aminoglycosides or spectinomycin is contraindicated. Use of polymyxin, tetracycline, or lincomycin for patients taking NEURONOX should be done with caution.
The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.
Caution For Usage
Unopened vials of NEURONOX should be stored in a freezer (-15 to -5°C or refrigeration 2-8°C). After reconstitution, NEURONOX should be stored in a refrigerator (2-8°C) for up to 24 hours prior to use. For safe disposal, unused vials should be sterilized after melting it with a little amount of water. Equipment used with the drug (such as syringes) should also be sterilized. The residual NEURONOX should be inactivated using dilute hypochlorite solution(0.5%).
Storage
The unopened lyophilized vial should be stored in a freezer (-15 to -5°C) or refrigeration 2-8°C.
Shelf-Life: The shelf-life of NEURONOX is 36 months from the manufacturing date.
Patient Counseling Information
The effect and risk of NEURONOX should be consulted by a physician. Attention should be paid to any signs and symptoms of adverse events. The immediate medical support should be sought when a patient experiences shortness of breath, muscle weakening or difficulty in swallowing or speaking, after the treatment. Adverse events may appear within couple of hours or weeks after the treatment. Patients with blepharospasm may have been extremely sedentary for a longtime. Such patients should be cautioned to resume activity slowly and carefully after the administration of NEURONOX. NEURONOX blocks neuromuscular transmission binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, NEURONOX produces partial chemical denervation of the muscle resulting in a localized muscle activity reduction. 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 NEURONOX. The paralysis activity of botulinum toxin is effective for the relief of excessive abnormal contraction associated with blepharospasm.
In case of other botulinum toxin product which was injected to the neck muscle, the botulinum toxin treatment mitigated subject and objective symptoms of paroxysmal spasmodic tonicollis and reduced the rotation angle of head as well as the rising of shoulder. And it also reduced the size and the intension of hypertrophic muscles and relieved the pain. In case of other botulinum toxin product, the efficacy of the botulinum toxin product has not been established in case of deviations over 50 prism diopters, or restrictive strabismus, or Duane's syndrome with symptoms of contralateral superior recurs weakness, or secondary strabismus caused by over-recession of the antagonist muscle during the surgery and repetitive injection may be required. In case of other botulinum toxin product, botulinum toxin was ineffective in chronic paralytic strabismus except when used in conjunction with surgical repair to reduce antagonist contracture. If neutralizing antibodies to botulinum toxin type A is exist, it may reduce the effectiveness of botulinum toxin treatment. In clinical studies, reduction in effectiveness due to antibody production has occurred in one patient with blepharospasm receiving 3 doses of botulinum toxin over a 6 weeks period totaling 92 U, and in several patients with torticollis who received multiple doses experimentally, totaling over 300 U in a one month period. For this reason, the cumulative dose of NEURONOX treatment in a one month period should not exceed 200 Units for treating blepharospasm.
MIMS Class
ATC Classification
M03AX01 - botulinum toxin ; Belongs to the class of other agents used as peripherally-acting muscle relaxants.
Presentation/Packing
Powd for inj (vacuum dried vial) 50 U x 1's. 100 U x 1's. 200 U x 1's.
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