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7) Blepharospasm: Reduced blinking from injection of botulinum toxin into orbicularis muscle can lead to corneal exposure, persist- ent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. In the use of other botulinum toxin product for treatment of blepharospasm, 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 should be conducted and injection into the lower lid area should be avoided to reduce the risk of ectropion. 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 8) Lack of Interchangeability between botulinum toxin products: Since the potency units of botulinum toxin are specific to individual products, they are not interchangeable with other botulinum toxin product. Therefore, units of biological activity of botulinum tox- in cannot be compared or converted into units of any other botulinum toxin product assessed with other specific assay method.
9) Injections in or near vulnerable anatomic structures: Care should be taken when injecting in or near vulnerable anatomic struc- tures. Serious adverse reactions, including fatal outcomes, have been reported in patients who had received other botulinum toxin product injected directly into salivary glands, 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 near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices.
10) Pulmonary effects in patients with compromised respiratory status treated for upper limb spasticity or for detrusor overactivity associated with a neurologic condition: In patients with upper limb spasticity and respiratory disorder, upper respiratory tract infections and reduced lung function were reported when administered with other botulinum toxin. Reduced lung functions were also reported in patients treated with other botulinum toxin for detrusor overactivity associated with a neurologic condition.
11) Bronchitis and upper respiratory tract infections in patients treated for upper limb spasticity: Bronchitis was reported more frequently as an adverse reaction in patients treated with other botulinum toxin for upper limb spasticity, compared to placebo. In patients with reduced lung function treated for upper limb spasticity, upper respiratory tract infections were also reported more frequently in patients treated with botulinum toxins, compared to placebo.
2. This drug product should not be administered to the fol owing patients:
1) Patients who are hypersensitive to any ingredient in the formulation of this product.
2) Patients who have neuromuscular junctional disorders (e.g., myasthenia gravis, Lambert-Eaton syndrome or amyotrophic lateral Composition
sclerosis). The diseases may be exacerbated due to the muscle relaxation activity of this drug product.
3) Patients with severe respiratory disorders, when used for treatment of cervical dystonia.
4) Pregnant women, women of childbearing age or nursing mothers. Active ingredient : Clostridium botulinum toxin type A (Strain: Clostridium botulinum CBFC26) 3. This drug product should be careful y administered to the fol owing patients:
(KFDA-approved specifications) 200units(U)* 1) Patients under treatment with other muscle relaxants (e.g., tubocurarine chloride, dantrolene sodium, etc.) - Muscle relaxation Stabilizer : Human serum albumin (Korean Minimum Requirements for Biological Products) may be potentiated or risks of dysphagia may be increased.
Tonic adjuster : Sodium chloride (Korean Pharmacopoeia) 2) Patients under treatment with drugs with muscle relaxation activity, e.g., spectinomycin HCl, aminoglycoside antibiotics (gen- * One unit(U) of BOTULAX® Injection 200 Units/Vial corresponds to the calculated median intraperitoneal lethal tamicin sulfate, neomycin sulfate, etc.), polypeptide antibiotics (polymyxin B sulfate, etc.), tetracycline antibiotics, lincomycin antibiotics (lincosamides), muscle relaxants (baclofen etc.), anti-cholinergic agents (scopolamine butylbromide, trihexylphenidil HCl, etc.), benzodiazepine and other similar drugs (diazepam, etizolam, etc.), and benzamide drugs (thiapride HCl, sulpiride, etc.). Description
Muscle relaxation may be potentiated or risks of dysphagia may be increased.
It appears as a lyophilized white powder for injection in a colorless transparent vial and should become colorless 4. Adverse drug reactions
transparent liquid when the diluent (physiological saline) is added. 1) General : There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with other botulinum toxin. There have also been reports of adverse reactions Indication
involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. The exact relation- ship of these events to the botulinum toxin injection has not been established. 1. Benign essential blepharospasm in adult patients, 18 years age or above The following events have been reported with other botulinum toxin and a causal relationship to the botulinum toxin injected is 2. Temporary improvement of serious glabellar wrinkles ranging from moderate to severe associated with corruga- unknown: skin rash (including erythema multiforme, urticaria and psoriasiform eruption), pruritus, and allergic reaction. In general, adverse reactions occur within the first week following injection and, while generally transient, may have a duration tors muscle and/or procerus muscle activities in adults over the age of 18 and below the age 65 of several months. Localized pain, tenderness, 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 pharmacologi- Dosage and administration
cal action of botulinum toxin. However, weakness of adjacent muscles may also occur due to spread of toxin. When injected to patients with blepharospasm or cervical dystonia, some muscles distant from the injection site can show increased electrophysi- ological jitter (rapid variation in a waveform) which is not associated with clinical weakness or other types of electrophysiological For blepharospasm, reconstituted BOTULAX® 200(see Dilution Table) is injected using a sterile, 27-30 gauge needle without electro- myographic guidance. The initial recommended dose is 1.25-2.5U (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, 2) Strabismus: Extraocular muscles adjacent to the injection site can be affected, causing ptosis or vertical deviations, especially with the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment higher doses of this drug product. The incidence rates of these adverse reactions with other botulinum toxin in 2,058 adults who lasts approximately three months. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the received a total of 3,650 injections for horizontal strabismus were as follows; 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 this product is used in treating blepharospasm if treatments are given more frequently than every three months, and is rare to have the effect be Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past-pointing. Cover- permanent. The cumulative dose of BOTULAX® 200 treatment in a 30-day period should not exceed 200 U.
ing the affected eye may alleviate these symptoms.
The incidence rates of ptosis were 0.9% after inferior rectus injection and 37.7% after superior rectus injection. The incidence rates of adverse reactions observed for 6 months, with other botulinum toxin in 3,104 patients after a series of 5,587 injections Reconstitute this product with 0.9% preservative-free, sterile saline to make 200 U/5.0 mL (4 U/0.1 mL). Using a 30-gauge needle, inject a dose of 0.1 mL into each of 5 sites, 2 in each corrugators muscle and 1 in procerus muscle, for a total of 20 U.
Vertical deviation of greater than 2 prism diopters 2.1% In order to reduce the complication of ptosis, avoid injection near the levator palpebrae superioris, In these patients, the injection procedure itself caused nine scleral perforations. A vitreous hemorrhage occurred in one case particularly in patients with larger brow depressor complexes. Injections into inner corrugators and later cleared. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar hemorrhages occurred without muscle and central eyebrow should be placed at least 1 cm above the bony supraorbital ridge.
visual loss. Decompression of the orbit after five minutes was done to restore retinal circulation. Five eyes had pupillary change Careful attention should be paid to avoid injection of this product into the blood vessel. In order to consistent with ciliary ganglion damage (Adies pupil). prevent exudation below the orbital ridge, be sure to firmly place the thumb or index finger below Anterior segment ischemia after other botulinum toxin injection into the medial rectus muscle for treatment of esotropia was the orbital ridge, prior to injection. The needle should be toward the upper center during injection and careful attention should be paid to inject accurate volume. 3) Blepharospasm: Adverse reactions were observed in 39% of those who received this product in clinical study in blepharospasm Glabellar facial lines arise from the activity of corrugator muscle and orbicularis oculi muscle. These muscles move the brow medi- patients of 18 years of age and above. The most common adverse reactions were ptosis, lagophthalmos and eye dryness, and ally, 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.
Regardless of causal relationship, adverse reactions per occurrence site are as follows: Each treatment lasts approximately three to four months. More frequent injection of this product is not recommended because the safety and efficacy are not established.
Ptosis (6.61%), Lagophthalmos (6.61%), Dry eye (6.61%), Watery eye (4.13%), Blepharoedema (1.65%), Dilution Technique
Photophobia (2.48%), Conjunctivitis (2.48%), Myodesopsia (1.65%), Keratitis (1.65%), Chalasis (0.83%), Prior to injection, reconstitute freeze-dried this product with a preservative-free, sterile saline. 0.9% Sodium Chloride Injection is the Chalazion (0.83%), Foreign body sensation (0.83%) recommended diluent. Draw up the proper amount of diluent in the syringe of appropriate size. Since this product is denatured by bubbling or similar violent agitation, the diluent should be injected gently into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Record the date and time of reconstitution on the space of the label. This product should be administered within Reactions at injection sites (4.13%), Flushing (0.83%) 24 hours after reconstitution. During this period, reconstituted product should be stored in a refrigerator (2-8°C). Reconstituted product 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 this product and the diluent do not contain any preservative, one vial of Hernia (0.83%), Stomach ulcer (0.83%), Stomatitis (0.83%) this product should be used for a single patient.
Anxiety (0.83%), Depression (0.83%), Dizziness (0.83%), Masked face (0.83%) Adverse drug reactions that causal relationship with this product cannot be excluded are as follows: Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in dose is also possible by administer- Ptosis (6.61%), Lagophthalmos (6.61%), Dry eye (6.61%), Photophobia (2.48%), ing a smaller or larger injection volume - from 0.05 mL (50% decrease in dose) to 0.15 mL (50% increase in dose). Blepharoedema (0.83%), Chalasis (0.83%), Foreign body sensation (0.83%), Precautions
1. Warnings Since the active ingredient of this drug product is Clostridium botulinum toxin type A which is derived from
Clostridium botulinum, the information in this section should be fully understood and the recommended dosage and administra- tion methods should be strictly followed. . Physicians administering this drug product should sufficiently understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. Understanding of standard electromyographic techniques is also required. The recommended dosages and administration frequen- Other events reported in 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. 1) Spread of toxin effect: Botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms In two cases of VII nerve disorder (one case of an aphakic eye), reduced blinking from injection of other botulinum toxin into may include asthenia, generalized muscle weakness, dysphonia, dysarthria, stuttering, urinary incontinence, breathing difficul- orbicularis muscle led to serious corneal exposure, persistent epithelial defect, and corneal ulceration. Perforation occurred in a ties, dysphagia (swallowing difficulties), diplopia, blurred vision, and ptosis. Swallowing and breathing difficulties can be life patient with aphakic eye, requiring corneal grafting. One case of acute angle closure glaucoma was reported one day after injec- threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest tion of botulinum toxin for blepharospasm, with recovery four months later after laser iridotomy and trabeculectomy. Focal facial in children treated for spastic cerebral palsy, but symptoms can also occur in adults treated for spastic cerebral palsy and other paralysis, syncope and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm. Frequently, conditions. Cases of the above adverse reactions have occurred at doses comparable to those used to treat cervical dystonia anopia or conjunctivitis has been reported and, in such instances, appropriate measures should be taken. In 660 patients with other botulinum toxin injections for 6 years in Korea, a total of 41 patients (6.2%) showed adverse reactions. 2) Hypersensitivity reactions: Serious and/or immediate hypersensitivity reactions have been reported for other botulinum toxin Adverse reactions include ptosis in 17 patients (2.6%), local swelling in 5 (0.8%), lacrimal disorders in 3 (0.5%), bulbar irritation product. These reactions include anaphylaxis, urticaria, soft tissue edema and dyspnea. One fatal case of anaphylaxis has been in 3 (0.5%), logophthalmos in 3 (0.5%), muscle weakness in 3 (0.5%), and eye dryness in 3 (0.5%). Unknown adverse reactions reported in which lidocaine was used as a diluent, and consequently, the causal agent cannot be reliably determined. If such include traction at injection site in 2 patient (0.3%), hypertonia in 2 (0.3%), conjunctival congestion in 2 (0.3%), and eye pain in a reaction occurs, further injection of this drug product should be discontinued and appropriate medical therapy should be 3) Pre-existing neuromuscular disorders: Individuals with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis 4) Glabellar lines: In Korean clinical studies in subjects with moderate to severe glabellar lines and ≥18 years of age and ≤65 years or motor neuropathy) or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at of age, adverse reactions were observed in 28.4% of subjects who received this product. Most adverse reactions were mild to increased risk of clinically significant systemic effects, including severe dysphagia and respiratory compromise from typical doses moderate and no serious adverse reaction was reported during clinical studies. The most frequently reported adverse reactions of this product. Published medical literatures with other botulinum toxin product have reported rare cases of administration include infections and infestations in 10 subjects (7.5%), eye disorders in 10 (7.5%), general disorders and administration site of a botulinum toxin to patients with known or unrecognized neuromuscular disorders where patients have shown serious condition in 6 (4.5%), and skin and subcutaneous tissue disorders in 6 (4.5%).
hypersensitivity to systemic effects of typical clinical doses. In some cases, dysphagia lasted several months and placement of a Adverse reactions for which causal relationship with this drug product could not be eliminated include injection site reaction in 4 subjects (3.0%) and eyelid ptosis in 6 (4.5%).
4) Dysphagia: Dysphagia is a commonly reported adverse reaction after treatment of cervical dystonia patients with all botulinum toxins. In these patients, rare cases of severe dysphagia requiring the use of a gastric feeding tube were reported. In addi- 5) Cervical dystonia: In cervical dystonia patients evaluated for safety in double-blind and open-label studies following injection of tion, deaths owing to aspiration pneumonia, as a complication of severe dysphagia, have been reported after treatment with other botulinum toxin, the most frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), 5) There have also been reports of adverse reactions with other botulinum toxin product, involving cardiovascular system, including Other events reported in 2-10% of patients in another study in decreasing order of incidence include: increased cough, flu arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular syndrome, lumbago, rhinitis, dizziness, hypertonia, pain at injection sites, asthenia, oral dryness, speech disorder, fever, nausea and drowsiness. Very rare cases of stiffness, numbness, diplopia, ptosis and dyspnea have been reported.
6) During administration of other botulinum toxin product for treatment of strabismus, retrobulbar hemorrhages sufficient to com- The most common severe adverse reaction associated with the use of other botulinum toxin in patients with cervical dystonia is promise retinal circulation have occurred owing to penetration of the needle into areas surrounding eyes. It is recommended dysphagia with about 20% of these cases also reporting dyspnea. Most dysphagia is reported as mild or moderate in severity. that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. However, it may be associated with more severe signs and symptoms in rare cases.
An ophthalmoscope to diagnose this condition should be available. Inducing paralysis in one or more extraocular muscles may In addition, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection produce spatial disorientation, double vision or past-pointing. Covering the affected eye may alleviate these symptoms.
of 120 Units of other botulinum toxin for treatment of cervical dystonia, and reports of dysphonia in patients who have been The most frequently reported adverse reactions with other botulinum toxin injections in the treatment of spasmodic torticollis 5. General precautions
include: dysphagia, pain and soreness at injection sites, local weakness, symptomatic general weakness and fatigue. However, 1) This drug product contains albumin, a derivative of human blood. When a drug product derived from human blood or plasma is fatigue was also reported in the placebo group. Dysphagia, local weakness and symptomatic general weakness may be attribut- administered into human body, the potential of infectious diseases by transmissible agents cannot be completely excluded. It may able to an extension of the pharmacology of botulinum toxin resulting from the spread of the toxin from injected muscles. Since include pathogenic agent that is still unknown. In order to minimize the risks of such infection by transmissible agents, particular the adverse reactions associated with dosage are more frequently observed in female patients, muscle mass should be taken cares are given to the albumin manufacturing process, including virus removal and/or inactivation processes, in addition to careful into consideration when selecting the appropriate dose. Other adverse reactions include nausea, dizziness, headache, numbness, screening of donors and appropriate testing of donation units.
stiffness, and bruising. Post-marketing surveillance in Korea revealed that adverse reactions were observed in 3 patients out of 2) Due to the nature of the disease being treated, the effects of this drug product on the ability to drive or to operate machines total 68 patients (4.4%), including 2 case of unknown one of myalgia (2.9%) and 1 case of muscle stiffness (1.5%).
3) Cervical dystonia: Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleido- 6) Pediatric cerebral palsy: Safety of other botulinum toxin product for treatment of dynamic equinus foot deformity due to spasticity mastoid muscle have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid in pediatric cerebral palsy patients was investigated. As is expected for any intramuscular injection procedure, localized pain was muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of associated with the injection in the patients. All treatment-related adverse reactions were mild to moderate in severity. Adverse upper respiratory infection and dysphagia.
reactions most frequently reported as related to treatment include recession, leg pain, leg (local) weakness, and general weak- 4) Pediatric cerebral palsy: Botulinum toxin product is a drug product developed for treatment of local spasm in connection with ness. The percentages of patients who experienced these events at least once during the study are as follows: standard treatments, but it is not intended to replace such treatment modalities. Botulinum toxin product is not likely to improve the motion at a joint affected by a permanent contracture. 5) Muscular stiffness: Botulinum toxin product is used for treatment of local stiffness investigated in connection with conventional standard treatments. Botulinum toxin product has not been shown to improve the range of motion at a joint affected by a fixed 6) Glabellar lines: Patients with facial palsy or ptosis symptoms, patients with infections, skin disorders or scars at proposed injection sites, patients who received facial plastic surgery, such as tissue augmentation, brow lift, and dermal resurfacing and patients who were deemed inappropriate because their glabellar lines were not flattened with fingers and so, their conditions could not be sufficiently improved by physical measures were excluded from the phase 3 study. Injection of this product should not be more Recession may be attributable to change in ankle position and gait pattern and/or local weakness. Local weakness represents frequent than every three months and minimum effective dose should be used.
the expected pharmacological action of botulinum toxin. Other treatment-related adverse reactions reported in 1% of patients were: leg cramps, fever, knee pain, ankle pain, pain at the injection site post-treatment, and lethargy. 6. Drug interactions
Adverse reactions reported from clinical experience are as follows; [very frequent (>1/10); frequent (>1/100, <1/10)] 1) The effects of other botulinum toxin were potentiated by concomitant use of aminoglycoside antibiotics or other drugs that inter- • Very frequent: viral infections, otitis fere with neuromuscular transmission, e.g. tubocurarine-type muscle relaxants. Concomitant use of aminoglycosides or spectino- • Frequent: myalgia, myasthenia, urinary incontinence, delirium, gait disturbance, fatigue, erythema, and feeling of burning.
mycin is contraindicated. Polymyxin, tetracycline and lincomycin should be carefully used in patients injected with this product.
In the post-marketing surveillance study conducted in Korea, adverse reactions were reported from 8 cases out of 572 cases 2) The effects of administering different botulinum neurotoxin serotypes at the same time or within several months are unknown. in total (1.4%) as follows: 4 cases of pain at injection sites (0.7%), 3 cases of fever (0.5%) and 1 case of eruption (0.2%). No Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin before the effects of a unknown adverse reaction was reported in this study.
previously administered botulinum toxin disappear.
7) Primary axillary hyperhidrosis: Adverse reactions reported in clinical studies of other botulinum toxin are as follows: [frequent 7. Pregnancy and lactation
(1>100, <1/10); rare (>1/1000, <1/100)] There are no adequate and well-controlled studies of this product in pregnant women. When pregnant mice and rats were injected Nervous system: headache (frequent); vascular system: flushing (frequent); gastrointestinal system: vomiting (rare); skin and intramuscularly with other botulinum toxin product during the period of organogenesis, the developmental NOEL (No Observed subcutaneous tissue: hyperhidrosis (at sites other than axilla) (frequent), pruitus (rare); musculoskeletal and connective tissues: Effect Level) was 4 U/kg. Higher doses (8 U/kg or 16 U/kg) were associated with reductions in fetal body weights and/or delayed muscular weakness, myalgia, arthralgia, and severe pain (rare); general disorders and injection site conditions: reactions and 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/day (days pains at injection sites (frequent), weakness, edema at injection sites, and pain at injection sites (rare).
6 and 13 of gestation) produced severe maternal toxicity, abortions and/or fetal malformations. Higher doses resulted in death of When used for treatment of primary axillary hyperhidrosis, hidrosis at sites other than axilla was reported in 4.5% of patients dams. The rabbit appears to be a very sensitive species to this product. If the patient becomes pregnant after administration of this within one month after injection. However, anatomical pattern for such hidrosis was not identified. This symptom disappeared product, the patient should be apprised of potential risks, including abortion or fetal malformations that have been observed in within four months in 30% of those patients.
rabbits. It is not known whether botulinum toxin is excreted in human milk. Because many drugs are excreted in human milk, caution Arm weakness was reported in rare cases (0.7%). However, it was mild and transient, and did not require medical treatment. should be exercised when this product is administered to a nursing woman. Administration of this product is not recommended Recovery was completed without any aftereffects. This adverse reaction is expected to be associated with treatment or injection skills, or combination of thereof. In rare cases of reported muscular weakness, neurological examination may be considered. In addition, in order to assure correct intradermal injection, it is recommended to re-evaluate the injection skill prior to the second 8. Pediatric use
Safety and effectiveness of this product in patients below the age of 12 years (below the age of 16 years, for cervical dystonia) have
8) Muscular stiffness: Safety in 339 patients treated with other botulinum toxin product for upper limb spasticity associated with not been established for blepharospasm and strabismus.
cerebral apoplexy was investigated. In general, most reported adverse reactions were mild to moderate.
Safety and effectiveness in children and adolescents below the age of 18 years were not investigated for improvement of glabellar Adverse reactions reported in 1~4% of subjects and considered to have relationship with treatment include arm pain and lines or treatment of primary axillary hyperhidrosis and detrusor overactivity associated with a neurologic condition.
hypertonia in decreasing order of incidence.
Fever and cold symptoms were also reported in about 1% of subjects. Adverse reactions reported in less than 1% of subjects and 9. Carcinogenicity, mutagenicity, teratogenicity and animal toxicity
considered to have relationship with treatment include in decreasing order of incidence: hyperaphia, arthralgia, asthenia, bursitis, Long-term studies in animals have not been performed to evaluate carcinogenic potential of this product.
dermatitis, headache, hypersensitivity at injection sites, dysphoria, vomit, paresthesia, postural hypotension, and pruritus.
Safety in 82 patients treated with other botulinum toxin product for lower limb spasticity associated with cerebral apoplexy In a study of other botulinum toxin product to evaluate inadvertent peribladder administration, bladder stones were observed in was investigated. Reported adverse reactions considered to have relationship with treatment include injury by accident (1.2%), 1 of 4 male monkeys that were injected with a total of 6.8 U/kg divided into the prostatic urethra and proximal rectum (single imbalance (1.2%), and paresthesia (1.2%). Reported adverse reactions were mild or moderate.
administration). No bladder stones were observed in male or female monkeys following injection of up to 36 U/kg (~12X the The second injection was given to 44 subjects in the open-label study, among 56 subjects injected with other botulinum toxin in human dose) directly to the bladder as either single or 4 repeat dose injections or in female rats for single injection of up to 100 a double-blind situation. Additionally reported, treatment-related adverse reactions include hypertonia (4.5%), asthenia (2.3%), headache (2.3%) and hyperkinesis (2.3%).
10. Overdosage
9) Chronic migraine: The most frequently reported adverse reactions in double-blind, placebo-controlled study of other botulinum toxin product in 687 patients are summarized in the following table.
Signs and symptoms of overdose are not apparent immediately after injection. Should accidental injection or oral intake occur, the person should be medically supervised for up to several weeks for signs or symptoms of systemic weakness or muscle paralysis. An <Table> Adverse reactions more frequently (≥2%) reported in patients injected with other botulinum toxin product than in antitoxin may be used in the event of immediate knowledge of overdose or wrong administration. The antitoxin will not reverse any placebo-treated patients in two chronic migraine double-blind, placebo-controlled clinical trials botulinum toxin-induced muscle weakness effects already appeared by the time of antitoxin administration.
If the muscles of the oropharynx and esophagus are 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 required until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventila- tion, in addition to other general supportive care. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization.
11. Precautions in administration
Prior to injection, reconstitute freeze-dried this product with a preservative-free, sterile saline. 0.9% Sodium Chloride Injection is the recommended diluent. Draw up the proper amount of diluent in the syringe of appropriate size. Since this product is denatured by bubbling or similar violent agitation, the diluent should be injected gently into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Record the date and time of reconstitution on the space of the label. This product should be administered within 24 hours after reconstitution. During this period, reconstituted product should be stored in a refrigerator (2-8°C). Reconstituted product 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 this product and the diluent do not contain any preservative, one vial of this product should be used for a single patient.
12. Precautions in storage and 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, unused vials should be sterilized after dissolution in a small amount of water. Containers used (such as vials and syringes) should also be sterilized. Any residuals in vials or syringes should be inactivated using dilute hypochlorite solution (0.5%).
13. Information for patients
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 reactions. Call your doctor or get immediate medical help if you experience any unusual symptoms after treatment with this product, including difficulty in swallowing, speaking or breathing, Discontinuations due to adverse reaction were 4% in the botulinum toxin group and 1% in the placebo group. The most frequent or muscle weakness. Such adverse reactions may happen hours to weeks after injection of this product.
adverse reactions leading to discontinuation in the botulinum toxin group were neck pain, headache, worsening migraine, Patients with blepharospasm may have been in the extremely sedentary posture for a long time. Such patients should be cautioned muscular weakness and eyelid ptosis.
to resume activity slowly and carefully after administration of this product. Other adverse reactions that occurred more frequently in the botulinum toxin group compared to the placebo group at a fre- This product blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve termi- quency of not more than 1% include: vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain. Severe worsening nals, and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, this product produces partial of migraine requiring hospitalization occurred in approximately 1% in botulinum toxin group and approximately 0.3% in the chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal placebo group within the first week after treatment.
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.
10) Detrusor overactivity associated with a neurologic condition: In double-blind, placebo-control ed study of other botulinum toxin The paralysis activity of botulinum toxin is effective for the relief of excessive abnormal contraction associated with blepharospasm. product, the following adverse reactions were frequently reported within 12 weeks of injection for detrusor overactivity associ- When injected into neck muscles, other botulinum toxin injection acts to provide relief from both objective signs and subjective symptoms of spasmodic torticollis (cervical dystonia). These improvements may include reduced pain/discomfort, reduced head rota- tion, reduced shoulder elevation, decreased size and strength of hypertrophic muscles. The efficacy of other botulinum toxin product <Table> Adverse reactions more frequently (≥2%) reported in patients injected with other botulinum toxin product than in in deviations of over 50 prism diopters, restrictive strabismus, Duane’s syndrome with lateral rectus weakness, and secondary strabis- placebo-treated patients within the first 12 weeks after intradetrusor injection in double-blind, placebo-controlled clinical trials mus caused by prior surgical over-recession of the antagonist has not been clearly established or repeated injections may be required for treatment of such conditions. For other botulinum toxin product, it was reported that botulinum toxin is ineffective in chronic paralytic strabismus and only surgical procedure is effective in reducing conjunctiva antagonist contracture. The presence of antibod- ies to botulinum toxin type A may reduce the effectiveness of botulinum toxin therapy. In clinical studies, reduced effectiveness due to antibody production was observed in one patient with blepharospasm receiving 3 doses of botulinum toxin (92 U in total) over a 6-week period and in several patients with torticollis who received multiple doses experimentally (over 300 U) in one month. For this reason, the dose of this product for blepharospasm and strabismus should be kept in any case below 200 U in one month.
Renal and urinary disorders Urinary retention Storage and Expiry date
General disorders and injection site Store at 2-8°C in hermetic container, 36 months from the date of manufacture How supplied
The following adverse reaction rates with other botulinum toxin product 200 U were reported at any time following initial injec- tion and prior to re-injection or study exit (median duration of 44 weeks of exposure): urinary tract infections (49%), urinary retention (17%), fatigue (6%), constipation (4%), muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance (3%), Manufacturer : HUGEL, Inc.
insomnia (3%), and muscle spasm (2%).
In the multiple sclerosis patients enrolled in the double-blind, placebo-controlled trials, the multiple sclerosis exacerbation an- 941 Yulmun-ri, Sinbuk-eup, Chuncheon-si, Gangwon-do, Korea nualized rate (i.e., the number of multiple sclerosis exacerbation events per patient-year) was 0.23 for other botulinum toxin No change was observed in the overall safety profile with repeat dosing.
11) Post-marketing experience in foreign markets: There have been spontaneous reports of death, sometimes associated with dys- phagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with other botulinum toxin product. ※ You can get updated information from our web site (www.hugel.co.kr).
[see 2) and 4) of “1. Warnings” under “Precautions”]. There have also been reports of adverse reactions 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 New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established. The following adverse reactions have been identified during postapproval use of other botulinum toxin product: abdominal pain, anorexia, brachial plexopathy, diarrhea, dyspnea, facial palsy, facial paresis, hyperhidrosis, hypoacusis, hypoaesthesia, localized numbness, malaise, muscle weakness, myalgia, paresthesia, pyrexia, radiculopathy, skin rash (including erythema multiforme and psoriasiform eruption), tinnitus, vertigo, visual disturbances and vomiting.
Because these events were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

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