A white to yellowish, vacuum-dried powder for injection in a colourless and transparent vial, forming a clear and transparent liquid when dissolved in the diluent (physiological saline solution).

· Active ingredient: Clostridium botulinum toxin type A (in-house) 150 units
· Other excipients: Human serum albumin 0.75 mg, Sodium chloride 1.35 mg

1. Temporary improvement of moderate to severe glabellar lines associated with corrugator muscle and/or procerus muscle activity in adults of ages over 20 to under 65.
2. Muscle Spasticity: Treatment of upper limb spasticity associated with stroke in adults over 18 years of age.
3. Temporary improvement of moderate to severe lateral canthal lines (crow's feet) associated with orbicularis oculi activity in adults of ages over 18 to under 65.
4. Treatment of benign essential blepharospasm in adults over 18 years of age.

1. Glabellar Lines

Dilute to 150 U/3.75 mL (4 U/0.1 mL) with 0.9% preservative-free sterile saline solution.
Using a 30-gauge needle, inject 0.1 mL each into five sites, two in each corrugator muscle and one in the procerus muscle, totaling 20 U.

To reduce the complication of eyelid drooping, avoid injections near the levator palpebrae superioris, especially in patients with prominent brow depressor muscles.
When injecting into the inner corrugator muscle and the mid-eyebrow, ensure the injection is at least 1 cm away from the orbital rim.
Care must be taken not to inject into a blood vessel, and to prevent extravasation below the orbital rim, firmly place a thumb or index finger below the orbital rim before injecting.
During injection, the needle should be oriented upward and midline, and the injection volume should be precise.
The corrugator and orbicularis oculi muscles move the middle of the forehead and create glabellar facial wrinkles.
The procerus and depressor supercilii muscles pull the forehead downward.
These muscles contribute to frowning or glabellar lines. Since muscle location, size, and use vary individually, the effective dose is determined based on overall observation of the patient's ability to activate the injected superficial muscles.
The treatment effect of this drug for glabellar lines lasts about 3-4 months. The safety and efficacy of frequent administrations of this drug have not been clinically evaluated and are not recommended.
Typically, the initial administration of botulinum toxin induces chemical denervation in the injected muscles after 1-2 days, with the intensity increasing during the first week.



2. Muscle Spasticity

The exact dosage and number of injection sites can vary depending on the size, number, and location of the involved muscles, the degree of spasticity, the presence of local muscle weakness, and the patient's response to previous treatments.
Clinical improvement in muscle tension is observed after 4 weeks of injection, and this effect can last up to 8 and 12 weeks.

The dosages administered in clinical trials were as follows:

In clinical trials, the dosage did not exceed a total of 360 U, and it was divided among the muscles.
Sterilized needles ranging from 24-30 gauge are used for superficial muscles, and needles of appropriate length are used for deeper muscle tissues.
Electromyography guidance and nerve stimulation techniques are useful in locating the relevant muscles.


3. Lateral Canthal Lines (Crow's Feet)

Lateral canthal lines primarily result from the activity of the orbicularis oculi muscle surrounding the eye, which is used during blinking or closing the eyes.
Strong contraction of the orbicularis oculi muscle creates lateral, fan-shaped folds (crow's feet) starting at the outer corner of the eyes. The distribution of these fan-shaped wrinkles varies among patients.
Inject from the outside direction of the eye, ensuring the bevel of the needle is facing upwards.
Using a 30-33 gauge needle, inject 0.1 mL (4 U) into three sites on each lateral side of the orbicularis oculi muscles (a total of 6 sites, 24 U on both sides).
The first injection site is the lateral orbital rim, 1.5-2.0 cm away from the outer corner of the eye towards the temple.
When the maximum smile-induced wrinkles are above and below the outer corner of the eye, inject as shown in the diagram.

The treatment effect of this drug for lateral canthal lines lasts about 3 months.
The safety and efficacy of re-administration periods have not been clinically evaluated.


4. Eyelid Spasm

For the treatment of eyelid spasms, use a sterile 27-30 gauge needle without electromyography guidance, diluting the drug as per the dilution table.
The recommended initial dose for the pretarsal orbicularis oculi muscle of both the upper and lower eyelids is 1.25 U - 2.5 U (0.05 ㎖ - 0.1 ㎖ per area).
When spasms obstruct vision, injections can be administered to the corrugator muscle and the orbicularis oculi muscle on the upper lateral side, as injection sites on the inner and outer parts of the eyebrows.
For subsequent treatments (not the initial administration), up to a maximum of 5 U can be injected per site, equivalent to the most recent total administered dose.

＜Dilution Method＞
To dissolve the lyophilized drug, use preservative-free sterile saline solution. A 0.9% sodium chloride injection is the recommended diluent. Draw an appropriate amount of the diluent into a syringe of suitable size. Introduce the diluent slowly into the vial to avoid creating foam or similar vigorous agitation, which can cause the drug to degrade. If the diluent does not enter the vial due to vacuum, discard the vial. Record the date and time of reconstitution on the label and administer within 24 hours after dilution. Store the diluted solution in refrigeration (2-8°C). Upon reconstitution, the solution should be colorless, clear, and free from visible particles. Non-oral formulations should be carefully inspected for visible particles and discoloration prior to administration. Since neither the drug nor the diluent contains preservatives, do not use one vial for more than one patient.

[Dilution Table]

Note: This diluent is calculated based on a 0.1 ml injection. Additionally, the dose can be adjusted by varying the volume of injection. 0.05 ml (50% reduction in dose) - 0.15 ml (50% increase in dose)

Shelf Life: 24 months from the date of manufacture

1 vial/box [Vial (150 Units)]

Sealed container, refrigerated (2-8°C) storage

1. Warning

The active ingredient of this drug is Botulinum Toxin Type A, produced by Clostridium botulinum. Therefore, it is crucial to be aware of and adhere strictly to the prescribed usage and dosage. Physicians administering this drug must have a thorough understanding of the anatomical structure of the related neuromuscular and periorbital areas, any anatomical alterations due to previous surgeries, and standard electromyographic techniques.
The recommended dosage and frequency of administration must not be exceeded.

A. Distant Spread of Toxin Effect
Botulinum toxin can spread from the site of injection to other areas, potentially causing botulism. Symptoms such as rapid muscle weakness, fatigue, hoarseness, speech disorders, stuttering, loss of bladder control, respiratory difficulty, swallowing difficulty, double vision, blurred vision, and drooping eyelids may occur. Symptoms such as respiratory difficulty or swallowing difficulty can be life-threatening, and there have been reported cases of death due to the spread of the toxin. Children treated for spastic cerebral palsy are particularly at high risk. However, adults treated for spastic cerebral palsy or other conditions may also exhibit the same symptoms. There have been instances of such adverse reactions occurring at the recommended doses for treating cervical dystonia, as well as at lower doses.

B. Hypersensitivity Reactions
Rare cases of serious or immediate hypersensitivity reactions to other botulinum toxin products have been reported. These reactions have included anaphylaxis, urticaria, tissue swelling, and respiratory difficulties. One instance of anaphylaxis was reported when lidocaine was used as a solvent; however, the causative agent was not conclusively identified. If such reactions occur following the administration of this drug, the treatment should be discontinued and appropriate measures taken.

C. In Patients with Neuromuscular Disorders
Patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junction disorders (e.g. myasthenia gravis, Lambert-Eaton syndrome) may experience an increased risk of significant systemic reactions, including severe dysphagia and respiratory depression, even with conventional doses of botulinum toxin products. According to clinical literature, rare cases have been reported where patients with known or unrecognized neuromuscular disorders exhibited severe hypersensitivity to the systemic effects of typical doses of botulinum toxin. In some of these cases, dysphagia persisted for several months, necessitating the use of a feeding tube.

D. Dysphagia
Dysphagia is a commonly reported adverse reaction in patients treated with any botulinum toxin for cervical dystonia. Rarely, dysphagia has been severe enough in some patients to require the use of a feeding tube. There have been reports of cases where dysphagia led to aspiration pneumonia, resulting in death.

E. Rarely, cardiovascular adverse reactions, including arrhythmias and myocardial infarctions, have been reported following the administration of other botulinum toxin products, some of which have been fatal. Several of these cases involved patients with pre-existing cardiovascular risk factors.

F. In the treatment of strabismus with other botulinum toxin products, retrobulbar hemorrhage, which can jeopardize retinal circulation, has occurred due to needle penetration around the eye. It is recommended to use appropriate techniques to reduce the pressure susceptible around the eye. There have also been cases of needle penetration into the eye. Ophthalmoscopic examination should be used to diagnose these conditions. One or more external ocular muscle paralyses can induce spatial disorientation, double vision, and past-pointing. Covering the affected eye can alleviate these symptoms.

G. Eyelid Spasm
After the injection of botulinum toxin into the orbicularis oculi muscle, especially in patients with facial nerve (CN VII) disorders, there can be a reduction in blinking leading to corneal exposure, persistent epithelial defects, and corneal ulcers. There has been a reported case where corneal perforation occurred in an anophthalmic eye due to the effects of another botulinum toxin product, necessitating a corneal transplant. In patients with a history of eye surgery, a careful examination of corneal sensation should be conducted, and avoiding injections in the lower eyelid area can reduce the risk of ectropion. Any corneal epithelial defects require thorough treatment. This may include protective eye drops, ointments, therapeutic soft lenses, or eye patches, among other measures.

H. Non-Interchangeability
As the toxin content can vary between different botulinum toxin products, the units of one product are not convertible to the units of another.

I. Injection into or around Anatomically Vulnerable Structures
Caution is required when injecting into or around anatomically vulnerable structures. Serious adverse events, including fatal outcomes, have been reported with the injection of other botulinum toxin products into the salivary glands, the area around the mouth-tongue-pharynx, esophagus, and stomach. Some of these patients had pre-existing dysphagia or significant weakness. (The safety and efficacy for these indications, including those injection sites, have not been established.) Cases of pneumothorax associated with the injection process of other botulinum toxin products into the thoracic region have been reported. Caution is especially advised when injecting near the apex of the lung.

In patients with respiratory disorders undergoing treatment for upper limb spasticity, a decrease in pulmonary function (a reduction in Forced Vital Capacity [FVC] by ≥ 15%) and upper respiratory infections have been reported more frequently with the administration of other botulinum toxin products compared to placebo. Also, a decrease in pulmonary function (FVC reduction ≥ 15%) has been reported in patients with respiratory disorders and neurogenic detrusor overactivity treated with other botulinum toxin products.

K. Bronchitis and Upper Respiratory Infections in Adult Patients Treated for Upper Limb Spasticity
Among patients treated for upper limb spasticity, bronchitis has been reported more frequently in those treated with other botulinum toxin products than in the placebo group. In patients with reduced lung function undergoing treatment for upper limb spasticity, upper respiratory infections have been reported more frequently with other botulinum toxin products compared to placebo. In a therapeutic confirmatory clinical trial conducted on 195 adults for the treatment of upper limb spasticity using this drug, there were two cases of upper respiratory infection adverse reactions reported in the treatment group and one case in the control group.


2. Do Not Administer to the Following Patients:

A. Patients who have hypersensitivity to the components of this drug
B. Patients with systemic neuromuscular junction disorders (such as myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, etc.) - The muscle-relaxing action of the drug can exacerbate these conditions.
C. Pregnant or potentially pregnant women and nursing mothers


3. Administer with Caution to the Following Patients

A. Patients currently being treated with muscle relaxants (such as tubocurarine chloride, dantrolene sodium, etc.) - There is a risk of enhanced muscle-relaxing action or increased incidence of dysphagia.
B. Patients receiving drugs with muscle-relaxing properties, such as spectinomycin hydrochloride, aminoglycoside antibiotics (gentamicin sulfate, neomycin sulfate, etc.), polypeptide antibiotics (polymyxin B sulfate, etc.), tetracycline antibiotics, lincosamide antibiotics (lincosamides), muscle relaxants (baclofen, etc.), anticholinergics (scopolamine butylbromide, trihexyphenidyl hydrochloride, etc.), benzodiazepines and similar drugs (diazepam, etizolam, etc.), and benzamide drugs (tiapride hydrochloride, sulpiride, etc.) - There is a risk of enhanced muscle-relaxing action or increased incidence of dysphagia.


4. Adverse Reactions

A. General Information
Rare cases of difficulty swallowing, pneumonia, and/or severe lethargy or anaphylaxis-related deaths have been reported following treatment with botulinum toxin.
Additionally, cardiovascular adverse reactions, including arrhythmia or myocardial infarction that can lead to fatal outcomes, have been rarely reported. The precise causal relationship between these adverse reactions and botulinum toxin has not been established.
Other botulinum toxin products have reported adverse reactions, whose association with botulinum toxin remained unknown, including skin rashes (multiform erythema, urticaria, psoriatic rash), itching, and allergic reactions.
Adverse reactions typically appear within a week of injection, are usually transient but can persist for several months. Local pain, tenderness, bruising, tightness at the injection site, swelling, warmth at the injection site, and increased muscle tension in the injection area and neighboring muscles can occur in relation to the injection. Local weakness at the injection site reflects the anticipated pharmacological action of botulinum toxin. However, weakness in adjacent muscles may be attributed to the spread of the toxin. In patients treated with this drug for eyelid spasms or cervical muscle dystonia, there is a possibility of increased electromyographic jitter (sudden disruption in waveform) unrelated to electromyographic abnormalities in muscles distant from the injection site.

B. Glabellar Lines
A safety assessment was conducted on 268 subjects of ages of ages over 20 to under 65 with moderate to severe glabellar lines across multiple centers. This was a double-blind (neither patients nor doctors were aware), randomized, active-controlled study (135 subjects in the test group for this drug, 133 in the Botox control group). Adverse events occurred in 20.00% of the test group and 18.05% of the control group.
Most adverse events were mild, with no severe cases reported. The drug-related adverse reactions reported in more than 1% of the test group for this drug, in order of frequency, were as follows: Eyelid ptosis (2.22%), eyebrow elevation (1.48%), and dizziness (1.48%).

A safety assessment was conducted on 197 subjects of ages 18 and above who were diagnosed with a stroke at least 6 weeks prior. This was a multi-center, active-controlled, double-blind (where neither patients nor doctors are aware of the study), randomized study (99 subjects in the test group for this drug, 98 in the Botox control group). Adverse events were reported in 19.59% (19 out of 97 subjects, 30 events) of the test group and 19.39% (19 out of 98 subjects, 22 events) of the control group. Among these, drug-related adverse reactions were reported in 3 cases in the test group and 4 cases in the control group. The table below lists the reported drug-related adverse reactions by body system. The frequencies are defined as follows: very common (≥ 10%), common (≥ 1%, < 10%), uncommon (≥ 0.1%, < 1%), rare (≥ 0.01%, < 0.1%), very rare (< 0.01%).

D. Lateral Canthal Lines (Crow's Feet)
In a multicenter study involving 204 participants aged between 18 and 75 years with moderate to severe lateral canthal lines, a safety assessment was conducted using an active control, double-blind (a clinical trial method where neither the patients nor doctors know who is receiving treatment), and randomized assignment. Adverse reactions unrelated to the lateral canthal line area were observed in 9.80% of the subjects (20 out of 204 subjects, 28 events). There were 9 mild cases and 19 moderate cases. None were acute reactions, and they were not related to the treatment with this drug.
Drug-related adverse reactions in the area of lateral canthal lines occurred in 1 subject (0.49%, 1 event each) in both the test and control groups, and all were mild in severity. (Test group administration site: Itching , Control group administration site: Tenderness)

E. Eyelid Spasm
A safety assessment was conducted on 230 patients diagnosed with essential eyelid spasms, aged 18 and above, in a multicenter study using active control, double-blind (neither patients nor doctors were aware), and randomized assignment (test group of this drug: 117 subjects, Botox control group: 113 subjects). Adverse events occurred in 39.32% of the test group (46 out of 117 subjects, 76 events) and 27.43% of the control group (31 out of 113 subjects, 51 events). Among these, drug-related adverse reactions associated with the treatment occurred in 11.97% of the test group (14 out of 117 subjects, 16 events) and 13.27% of the control group (15 out of 113 subjects, 18 events). The table below lists the reported drug-related adverse reactions by body system.

＜Table 2＞

F. Post-Market Surveillance Results in South Korea
□ Glabellar Lines
Over 4 years, a post-market usage survey was conducted in South Korea with 914 subjects. The incidence of adverse events was 2.5% (23 out of 914 subjects, 25 events). Of these, the incidence of drug adverse reactions with a possible causal relationship to this product was 1.6% (15 out of 914 subjects, 17 events). Reported adverse events included headaches at 0.5% (5 out of 914 subjects, 5 events), eye fatigue and periorbital edema each at 0.2% (2 out of 914 subjects, 2 events), and chills, fatigue, facial paralysis, reaction at injection site, rash at injection site, pressure sensation at injection site, pain at injection site, and itching each at 0.1% (1 out of 914 subjects, 1 event). No serious adverse events or serious drug adverse reactions were identified.
The incidence of unexpected adverse events was 1.5% (14 out of 914 subjects, 16 events), with headaches at 0.8% (7 out of 914 subjects, 7 events), eye fatigue and pharyngitis each at 0.2% (2 out of 914 subjects, 2 events), and back pain, chills, fatigue, facial paralysis, and skin wrinkling each at 0.1% (1 out of 914 subjects, 1 event). Among these, the incidence of unexpected drug adverse reactions that cannot be ruled out as causally related to this product was 0.9% (8 out of 914 subjects, 10 events), with headaches reported at 0.5% (5 out of 914 subjects, 5 events), eye fatigue at 0.2% (2 out of 914 subjects, 2 events), and chills, fatigue, facial paralysis each reported at 0.1% (1 out of 914 subjects, 1 event). No serious and unexpected adverse events or serious and unexpected drug adverse reactions were identified.
Upon the comprehensive evaluation at the time of re-examination conclusion, using the domestic post-marketing adverse event and spontaneous adverse reaction report data for this drug in comparison with the reported adverse event data for all other approved drugs in South Korea, the following newly identified adverse events were reported more statistically significantly in this drug compared to other drugs. However, these results do not imply a proven causal relationship between the respective ingredient and the following adverse events:

• Skin and Subcutaneous Tissue Disorders: Periorbital Edema (Eyelid Edema)
• Nervous System Disorders: Headache



5. General Precautions

A. This drug contains human albumin derived from human blood. When administering drug products manufactured from human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded. This also applies to pathogens that are currently unknown. To reduce the risk of transmission of infectious agents, the manufacturing process includes appropriate measures such as the screening of donors and donation sites, as well as processes for the removal and/or inactivation of infectious agents.
B. The impact of this drug on the ability to operate machinery or drive cannot be predicted, as it may be influenced by the disease being treated.
C. Glabellar Lines/Lateral Canthal Lines (Crow's Feet)
The reduction in blinking following the injection of botulinum toxin products into the muscles around the eyes can lead to corneal exposure, persistent epithelial defects, and corneal ulceration, especially in patients with 7th nerve disorders.
Caution is advised in cases such as when there is infection or skin diseases, scars, or other skin abnormalities at the injection site, a history of facial plastic surgery (face lifting), treatment with permanent implants, a history of facial nerve paralysis or eyelid spasms, or when physical improvement of glabellar lines is unlikely, such as when wrinkles do not smooth out upon manually spreading them. These patients were excluded from Phase 3 safety and efficacy clinical trials.
The interval between injections of this drug should not be more frequent than every three months, and the minimum effective dose should be used.
D. Upper Limb Spasticity
This drug is only used for the treatment of focal spasticity studied in conjunction with conventional standard therapies. It is not effective in improving the range of motion in joints affected by fixed contractures.


6. Drug Interactions

A. Generally, when botulinum toxin products are taken in conjunction with aminoglycoside antibiotics or drugs that interfere with muscle and nerve transmission (such as tubocurarine muscle relaxants), the efficacy of the botulinum toxin products is increased. Continuous concurrent use of aminoglycoside antibiotics or spectinomycin is contraindicated.
The use of polymyxin, tetracycline, or lincomycin in patients treated with this drug should be approached with caution.
B. The effects of administering a different botulinum neurotoxin serotype concurrently or within several months are not known. Administering a different botulinum toxin before the effects of a previously administered botulinum toxin have dissipated may excessively exacerbate muscle and nerve weakness.


7. Administration in Pregnant and Nursing Women

There are no adequate and well-controlled studies of this drug in pregnant women. In studies where pregnant rats were injected intramuscularly with this drug (0.5, 1, 4 U/kg) during the organogenesis period (day 6-16 of pregnancy), maternal effects such as bent toes, paralytic gait, and curled toes were observed. In the fetuses, a decrease in ossification numbers was noted in the 4 U/kg dosage group, but this was not statistically significant.
It is not known whether botulinum toxin is secreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when administering the drug to nursing mothers.
The use of this drug is not recommended during pregnancy or breastfeeding.


8. Administration in Children

This drug has not been studied for safety and efficacy in children and adolescents under 20 years of age for the improvement of glabellar lines.
The safety and efficacy for upper limb spasticity have not been studied in children and adolescents under 18 years of age.


9. Carcinogenicity, Mutagenicity, Teratogenicity, Animal Toxicity

Long-term studies to evaluate the carcinogenic potential in animals have not been conducted.


10. Treatment for Overdose

Symptoms and signs of overdose may not be immediately apparent post-injection.
In cases of accidental administration or oral ingestion, medical observation for signs or symptoms of systemic weakness or muscle paralysis should be conducted for several weeks. If an overdose or misadministration is immediately recognized, an antitoxin can be used. The antitoxin does not reverse muscle weakness effects that have already manifested at the time of its administration.
If the muscles of the oropharynx and esophagus are affected, aspiration may occur, which can lead to aspiration pneumonia. If respiratory muscles are paralyzed or weakened, intubation and assisted breathing may be necessary until recovery. In addition to other general supportive treatments, tracheotomy and/or prolonged mechanical ventilation may be required.
Such patients should consider immediate and appropriate measures, including additional medical evaluation and hospitalization.


11. Storage and Handling Precautions

Unopened drug must be stored refrigerated (2-8℃). Once reconstituted, the drug can be refrigerated (2-8℃) for up to 24 hours.
All vials, including those past their expiration date, and any supplies that have come into direct contact with the product, must be disposed of as medical waste. In cases requiring deactivation of the toxin (e.g. spillage), it is recommended to use diluted hypochlorite (0.5 or 1%) before disposal as medical waste.


12. Information for Patients

Discuss any concerns regarding the effects and risks of this drug with your doctor. Be vigilant for signs and symptoms of adverse reactions. Seek immediate medical attention if you experience difficulty swallowing or speaking, breathing difficulties, or muscle weakness after treatment. Adverse reactions may occur within hours after treatment or several weeks later.
This drug binds to receptors at the neuromuscular junction, enters the nerve endings, and inhibits the release of acetylcholine, thereby blocking neuromuscular transmission. When injected into muscles in therapeutic doses, it causes localized muscle paralysis through chemical denervation. When muscles are chemically denervated, they become weakened and can develop acetylcholine receptors outside the synapse. The regeneration of nerves and the resumption of nerve impulses to the muscles demonstrate that the 'loss of strength' is reversible.

1) Pharmacological Action
This drug binds to receptors at the neuromuscular junction, enters the nerve endings, and inhibits the release of acetylcholine, thereby blocking neuromuscular transmission.

2) Clinical Trial Information

〈Lateral Canthal Lines〉
(A Phase 3 Clinical Trial) A double-blind, randomized, multi-center clinical trial was conducted with 204 adult patients (men and women aged between 18 and 75) requiring improvement of moderate to severe lateral canthal lines.
Participants were randomly assigned to receive either this drug or another botulinum toxin product, administered to either the right or left lateral canthal lines. Results showed that 4 weeks post-administration, the improvement rate of lateral canthal lines when smiling maximally was 65.02% (132 out of 203 participants) for the area treated with this drug, compared to 62.56% (127 out of 203 participants) for the area treated with the other botulinum toxin product. The lower limit of the 95% confidence interval for the difference in improvement rates of lateral canthal lines between the two treatment sites was -0.91%, indicating that the efficacy of this drug was not inferior compared to other botulinum toxin products. (Extended Clinical Trial) A single-group, open-label, multi-center extension clinical trial was conducted with 109 adults requiring improvement of moderate to severe lateral canthal lines and glabellar lines, who had participated in the aforementioned Phase 3 clinical trial.
Each participant received a single injection of 24 U into the lateral canthal lines and 20 U into the glabellar lines. As a result, the improvement rate of lateral canthal lines when smiling maximally 4 weeks after administration, as assessed by the investigators, was similar to the results of the Phase 3 clinical trial.

A white to yellowish, vacuum-dried powder for injection in a colourless and transparent vial, forming a clear and transparent liquid when dissolved in the diluent (physiological saline solution).

- Per vial -
· Active ingredient: Clostridium botulinum toxin type A (in-house) 100 units
· Other excipients: Human serum albumin 0.5mg, Sodium chloride 0.9mg

1. Temporary improvement of moderate to severe glabellar lines associated
with corrugator muscle and/or procerus muscle activity in adults aged 20 to 65.
2. Muscle Spasticity: Treatment of upper limb spasticity associated with stroke in adults over 18 years of age.
3. Treatment of benign essential blepharospasm in adults over 18 years of age.

1. Glabellar Lines

Dilute to 100 U/2.5 mL (4 U/0.1 mL) with 0.9% preservative-free sterile saline solution.
Using a 30-gauge needle, inject 0.1 mL each into five sites, two in each corrugator muscle and one in the procerus muscle, totaling 20 U.

To reduce the complication of eyelid drooping, avoid injections near the levator palpebrae superioris, especially in patients with prominent brow depressor muscles. When injecting into the inner corrugator muscle and the mid-eyebrow, ensure the injection is at least 1 cm away from the orbital rim.
Care must be taken not to inject into a blood vessel, and to prevent extravasation below the orbital rim, firmly place a thumb or index finger below the orbital rim before injecting. During injection, the needle should be oriented upward and midline, and the injection volume should be precise.
The corrugator and orbicularis oculi muscles move the middle of the forehead and create glabellar facial wrinkles. The procerus and depressor supercilii muscles pull the forehead downward. These muscles contribute to frowning or glabellar lines. Since muscle location, size, and use vary individually, the effective dose is determined based on overall observation of the patient's ability to activate the injected superficial muscles.
The treatment effect of this drug for glabellar lines lasts about 3-4 months. The safety and efficacy of frequent administrations of this drug have not been clinically evaluated and are not recommended.
Typically, the initial administration of botulinum toxin induces chemical denervation in the injected muscles after 1-2 days, with the intensity increasing during the first week.


2. Muscle Spasticity

The exact dosage and number of injection sites can vary depending on the size, number, and location of the involved muscles, the degree of spasticity, the presence of local muscle weakness, and the patient's response to previous treatments.
Clinical improvement in muscle tension is observed after 4 weeks of injection, and this effect can last up to 8 and 12 weeks.

The dosages administered in clinical trials were as follows:

In clinical trials, the dosage did not exceed a total of 360 U, and it was divided among the muscles.

Sterilized needles ranging from 24-30 gauge are used for superficial muscles, and needles of appropriate length are used for deeper muscle tissues. Electromyography guidance and nerve stimulation techniques are useful in locating the relevant muscles.


3. Eyelid Spasm

For the treatment of eyelid spasms, use a sterile 27-30 gauge needle without electromyography guidance, diluting the drug as per the dilution table. The recommended initial dose for the pretarsal orbicularis oculi muscle of both the upper and lower eyelids is 2.5 U (0.1 ㎖ per area). When spasms obstruct vision, injections can be administered into the corrugator muscle near the inner part of the eyebrows and the orbicularis oculi muscle on the upper outer side. For subsequent treatments (not the initial administration), up to a maximum of 5 U can be injected per site, equivalent to the most recent total administered dose. (Total 50 U)
The safety and efficacy for eyelid spasms have been evaluated for a single dose over a 12-week period.
The safety and efficacy of re-administration periods have not been clinically evaluated.

＜Dilution Method＞
To dissolve the decompression dried drug, use sterile saline without preservatives. A 0.9% sodium chloride injection is the recommended diluent. Draw an appropriate amount of the diluent into a syringe of suitable size. Introduce the diluent slowly into the vial to avoid creating foam or similar vigorous agitation, which can cause the drug to degrade. If the diluent does not enter the vial due to vacuum, discard the vial. Record the date and time of reconstitution on the label and administer within 24 hours after dilution. Store the diluted solution in refrigeration (2-8°C). Upon reconstitution, the solution should be colorless, clear, and free from visible particles. Non-oral formulations should be carefully inspected for visible particles and discoloration prior to administration. Since neither the drug nor the diluent contains preservatives, do not use one vial for more than one patient.

[Dilution Table]

Note: This diluent is calculated based on a 0.1 ml injection. Additionally, the dose can be adjusted by varying the volume of injection. 0.05 ml (50% reduction in dose) - 0.15 ml (50% increase in dose)

[Storage Method]
Sealed container, refrigerated (2-8°C) storage

[Shelf Life]
36 months from the date of manufacture

1 vial/box [Vial (100 Units)]

Sealed container, refrigerated (2-8°C) storage

1. Warning

The active ingredient of this drug is Botulinum Toxin Type A, produced by Clostridium botulinum. Therefore, it is crucial to be aware of and adhere strictly to the prescribed usage and dosage. Physicians administering this drug must have a thorough understanding of the anatomical structure of the related neuromuscular and periorbital areas, any anatomical alterations due to previous surgeries, and standard electromyographic techniques.
The recommended dosage and frequency of administration must not be exceeded.

A. Distant Spread of Toxin Effect
Botulinum toxin can spread from the site of injection to other areas, potentially causing botulism. Symptoms such as rapid muscle weakness, fatigue, hoarseness, speech disorders, stuttering, loss of bladder control, respiratory difficulty, swallowing difficulty, double vision, blurred vision, and drooping eyelids may occur. Symptoms such as respiratory difficulty or swallowing difficulty can be life-threatening, and there have been reported cases of death due to the spread of the toxin. Children treated for spastic cerebral palsy are particularly at high risk. However, adults treated for spastic cerebral palsy or other conditions may also exhibit the same symptoms. There have been instances of such adverse reactions occurring at the recommended doses for treating cervical dystonia, as well as at lower doses.

B. Hypersensitivity Reactions
Rare cases of serious or immediate hypersensitivity reactions to other botulinum toxin products have been reported. These reactions have included anaphylaxis, urticaria, tissue swelling, and respiratory difficulties. One instance of anaphylaxis was reported when lidocaine was used as a solvent; however, the causative agent was not conclusively identified. If such reactions occur following the administration of this drug, the treatment should be discontinued and appropriate measures taken.

C. In Patients with Neuromuscular Disorders
Patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junction disorders (e.g. myasthenia gravis, Lambert-Eaton syndrome) may experience an increased risk of significant systemic reactions, including severe dysphagia and respiratory depression, even with conventional doses of botulinum toxin products. According to clinical literature, rare cases have been reported where patients with known or unrecognized neuromuscular disorders exhibited severe hypersensitivity to the systemic effects of typical doses of botulinum toxin. In some of these cases, dysphagia persisted for several months, necessitating the use of a feeding tube.

D. Dysphagia
Dysphagia is a commonly reported adverse reaction in patients treated with any botulinum toxin for cervical dystonia. Rarely, dysphagia has been severe enough in some patients to require the use of a feeding tube. There have been reports of cases where dysphagia led to aspiration pneumonia, resulting in death.

E. Rarely, cardiovascular adverse reactions, including arrhythmias and myocardial infarctions, have been reported following the administration of other botulinum toxin products, some of which have been fatal. Several of these cases involved patients with pre-existing cardiovascular risk factors.

F. In the treatment of strabismus with other botulinum toxin products, retrobulbar hemorrhage, which can jeopardize retinal circulation, has occurred due to needle penetration around the eye. It is recommended to use appropriate techniques to reduce the pressure susceptible around the eye. There have also been cases of needle penetration into the eye. Ophthalmoscopic examination should be used to diagnose these conditions. One or more external ocular muscle paralyses can induce spatial disorientation, double vision, and past-pointing. Covering the affected eye can alleviate these symptoms.

G. Eyelid Spasm
After the injection of botulinum toxin into the orbicularis oculi muscle, especially in patients with facial nerve (CN VII) disorders, there can be a reduction in blinking leading to corneal exposure, persistent epithelial defects, and corneal ulcers. There has been a reported case where corneal perforation occurred in an anophthalmic eye due to the effects of another botulinum toxin product, necessitating a corneal transplant. In patients with a history of eye surgery, a careful examination of corneal sensation should be conducted, and avoiding injections in the lower eyelid area can reduce the risk of ectropion. Any corneal epithelial defects require thorough treatment. This may include protective eye drops, ointments, therapeutic soft lenses, or eye patches, among other measures.

H. Non-Interchangeability
As the toxin content can vary between different botulinum toxin products, the units of one product are not convertible to the units of another.

I. Injection into or around Anatomically Vulnerable Structures
Caution is required when injecting into or around anatomically vulnerable structures. Serious adverse events, including fatal outcomes, have been reported with the injection of other botulinum toxin products into the salivary glands, the area around the mouth-tongue-pharynx, esophagus, and stomach. Some of these patients had pre-existing dysphagia or significant weakness. (The safety and efficacy for these indications, including those injection sites, have not been established.) Cases of pneumothorax associated with the injection process of other botulinum toxin products into the thoracic region have been reported. Caution is especially advised when injecting near the apex of the lung.

In patients with respiratory disorders undergoing treatment for upper limb spasticity, a decrease in pulmonary function (a reduction in Forced Vital Capacity [FVC] by ≥ 15%) and upper respiratory infections have been reported more frequently with the administration of other botulinum toxin products compared to placebo. Also, a decrease in pulmonary function (FVC reduction ≥ 15%) has been reported in patients with respiratory disorders and neurogenic detrusor overactivity treated with other botulinum toxin products.

K. Bronchitis and Upper Respiratory Infections in Adult Patients Treated for Upper Limb Spasticity
Among patients treated for upper limb spasticity, bronchitis has been reported more frequently in those treated with other botulinum toxin products than in the placebo group. In patients with reduced lung function undergoing treatment for upper limb spasticity, upper respiratory infections have been reported more frequently with other botulinum toxin products compared to placebo. In a therapeutic confirmatory clinical trial conducted on 195 adults for the treatment of upper limb spasticity using this drug, there were two cases of upper respiratory infection adverse reactions reported in the treatment group and one case in the control group.


2. Do Not Administer to the Following Patients:

A. Patients who have hypersensitivity to the components of this drug
B. Patients with systemic neuromuscular junction disorders (such as myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, etc.) - The muscle-relaxing action of the drug can exacerbate these conditions.
C. Pregnant or potentially pregnant women and nursing mothers


3. Administer with Caution to the Following Patients


A. Patients currently being treated with muscle relaxants (such as tubocurarine chloride, dantrolene sodium, etc.) - There is a risk of enhanced muscle-relaxing action or increased incidence of dysphagia.
B. Patients receiving drugs with muscle-relaxing properties, such as spectinomycin hydrochloride, aminoglycoside antibiotics (gentamicin sulfate, neomycin sulfate, etc.), polypeptide antibiotics (polymyxin B sulfate, etc.), tetracycline antibiotics, lincosamide antibiotics (lincosamides), muscle relaxants (baclofen, etc.), anticholinergics (scopolamine butylbromide, trihexyphenidyl hydrochloride, etc.), benzodiazepines and similar drugs (diazepam, etizolam, etc.), and benzamide drugs (tiapride hydrochloride, sulpiride, etc.) - There is a risk of enhanced muscle-relaxing action or increased incidence of dysphagia.


4. Adverse Reactions

A. General Information
Rare cases of difficulty swallowing, pneumonia, and/or severe lethargy or anaphylaxis-related deaths have been reported following treatment with botulinum toxin.
Additionally, cardiovascular adverse reactions, including arrhythmia or myocardial infarction that can lead to fatal outcomes, have been rarely reported. The precise causal relationship between these adverse reactions and botulinum toxin has not been established.
Other botulinum toxin products have reported adverse reactions, whose association with botulinum toxin remained unknown, including skin rashes (multiform erythema, urticaria, psoriatic rash), itching, and allergic reactions.
Adverse reactions typically appear within a week of injection, are usually transient but can persist for several months. Local pain, tenderness, bruising, tightness at the injection site, swelling, warmth at the injection site, and increased muscle tension in the injection area and neighboring muscles can occur in relation to the injection. Local weakness at the injection site reflects the anticipated pharmacological action of botulinum toxin. However, weakness in adjacent muscles may be attributed to the spread of the toxin. In patients treated with this drug for eyelid spasms or cervical muscle dystonia, there is a possibility of increased electromyographic jitter (sudden disruption in waveform) unrelated to electromyographic abnormalities in muscles distant from the injection site.

B. Glabellar Lines
A safety assessment was conducted on 268 subjects aged 20 to 65 years with moderate to severe glabellar lines across multiple centers. This was a double-blind (neither patients nor doctors were aware), randomized, active-controlled study (135 subjects in the test group for this drug, 133 in the Botox control group). Adverse events occurred in 20.00% of the test group and 18.05% of the control group.
Most adverse events were mild, with no severe cases reported. The drug-related adverse reactions reported in more than 1% of the test group for this drug, in order of frequency, were as follows: Eyelid ptosis (2.22%), eyebrow elevation (1.48%), and dizziness (1.48%).

C. Upper Limb Spasticity
A safety assessment was conducted on 197 subjects aged 18 and over who were diagnosed with a stroke at least 6 weeks prior. This was a multi-center, active-controlled, double-blind (neither patients nor doctors were aware), randomized study (99 subjects in the test group for this drug, 98 in the Botox control group). Adverse events were reported in 19.59% (19 out of 97 subjects, 30 events) of the test group and 19.39% (19 out of 98 subjects, 22 events) of the control group. Among these, drug-related adverse reactions were reported in 3 cases in the test group and 4 cases in the control group. The table below lists the reported drug-related adverse reactions by body system. The frequencies are defined as follows: Very common (≥ 10%), common (≥ 1%, < 10%), uncommon (≥ 0.1%, < 1%), rare (≥ 0.01%, < 0.1%), very rare (< 0.01%).

D. Eyelid Spasm

A safety assessment was conducted on 230 patients diagnosed with essential eyelid spasms, aged 18 and above, in a multicenter study using active control, double-blind (neither patients nor doctors were aware), and randomized assignment (this drug's test group: 117 subjects, Botox control group: 113 subjects). Adverse events occurred in 39.32% of the test group (46 out of 117 subjects, 76 events) and 27.43% of the control group (31 out of 113 subjects, 51 events). Among these, drug-related adverse reactions associated with the treatment occurred in 11.97% of the test group (14 out of 117 subjects, 16 events) and 13.27% of the control group (15 out of 113 subjects, 18 events). The table below lists the reported drug-related adverse reactions by body system.

E. Post-Market Surveillance Results in South Korea
□ Glabellar Lines
Over 4 years, a post-market usage survey was conducted in South Korea with 914 subjects. The incidence of adverse events was 2.5% (23 out of 914 subjects, 25 events). Of these, the incidence of drug adverse reactions with a possible causal relationship to this product was 1.6% (15 out of 914 subjects, 17 events). Reported adverse events included headaches at 0.5% (5 out of 914 subjects, 5 events), eye fatigue and periorbital edema each at 0.2% (2 out of 914 subjects, 2 events), and chills, fatigue, facial paralysis, reaction at injection site, rash at injection site, pressure sensation at injection site, pain at injection site, and itching each at 0.1% (1 out of 914 subjects, 1 event). No serious adverse events or serious drug adverse reactions were identified.
The incidence of unexpected adverse events was 1.5% (14 out of 914 subjects, 16 events), with headaches at 0.8% (7 out of 914 subjects, 7 events), eye fatigue and pharyngitis each at 0.2% (2 out of 914 subjects, 2 events), and back pain, chills, fatigue, facial paralysis, and skin wrinkling each at 0.1% (1 out of 914 subjects, 1 event). Among these, the incidence of unexpected drug adverse reactions that cannot be ruled out as causally related to this product was 0.9% (8 out of 914 subjects, 10 events), with headaches reported at 0.5% (5 out of 914 subjects, 5 events), eye fatigue at 0.2% (2 out of 914 subjects, 2 events), and chills, fatigue, facial paralysis each reported at 0.1% (1 out of 914 subjects, 1 event). No serious and unexpected adverse events or serious and unexpected drug adverse reactions were identified.
Upon the comprehensive evaluation at the time of re-examination conclusion, using the domestic post-marketing adverse event and spontaneous adverse reaction report data for this drug in comparison with the reported adverse event data for all other approved drugs in South Korea, the following newly identified adverse events were reported more statistically significantly in this drug compared to other drugs. However, these results do not imply a proven causal relationship between the respective ingredient and the following adverse events:

• Skin and Subcutaneous Tissue Disorders: Periorbital Edema (Eyelid Edema)
• Nervous System Disorders: Headache



5. General Precautions

A. This drug contains human albumin derived from human blood. When administering drug products manufactured from human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded. This also applies to pathogens that are currently unknown. To reduce the risk of transmission of infectious agents, the manufacturing process includes appropriate measures such as the screening of donors and donation sites, as well as processes for the removal and/or inactivation of infectious agents.
B. The impact of this drug on the ability to operate machinery or drive cannot be predicted, as it may be influenced by the disease being treated.
C. Glabellar Lines
The reduction in blinking following the injection of botulinum toxin products into the muscles around the eyes can lead to corneal exposure, persistent epithelial defects, and corneal ulceration, especially in patients with 7th nerve disorders.
Caution is advised in cases such as when there is infection or skin diseases, scars, or other skin abnormalities at the injection site, a history of facial plastic surgery (face lifting), treatment with permanent implants, a history of facial nerve paralysis or eyelid spasms, or when physical improvement of glabellar lines is unlikely, such as when wrinkles do not smooth out upon manually spreading them. These patients were excluded from Phase 3 safety and efficacy clinical trials.
The interval between injections of this drug should not be more frequent than every three months, and the minimum effective dose should be used.
D. Upper Limb Spasticity
This drug is only used for the treatment of focal spasticity studied in conjunction with conventional standard therapies. It is not effective in improving the range of motion in joints affected by fixed contractures.


6. Drug Interactions

A. Generally, when botulinum toxin products are taken in conjunction with aminoglycoside antibiotics or drugs that interfere with muscle and nerve transmission (such as tubocurarine muscle relaxants), the efficacy of the botulinum toxin products is increased. Continuous concurrent use of aminoglycoside antibiotics or spectinomycin is contraindicated.
The use of polymyxin, tetracycline, or lincomycin in patients treated with this drug should be approached with caution.
B. The effects of administering a different botulinum neurotoxin serotype concurrently or within several months are not known. Administering a different botulinum toxin before the effects of a previously administered botulinum toxin have dissipated may excessively exacerbate muscle and nerve weakness.


7. Administration in Pregnant and Nursing Women

There are no adequate and well-controlled studies of this drug in pregnant women. In studies where pregnant rats were injected intramuscularly with this drug (0.5, 1, 4 U/kg) during the organogenesis period (day 6-16 of pregnancy), maternal effects such as bent toes, paralytic gait, and curled toes were observed. In the fetuses, a decrease in ossification numbers was noted in the 4 U/kg dosage group, but this was not statistically significant.
It is not known whether botulinum toxin is secreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when administering the drug to nursing mothers.
The use of this drug is not recommended during pregnancy or breastfeeding.


8. Administration in Children

This drug has not been studied for safety and efficacy in children and adolescents under 20 years of age for the improvement of glabellar lines.
The safety and efficacy for upper limb spasticity have not been studied in children and adolescents under 18 years of age.


9. Carcinogenicity, Mutagenicity, Teratogenicity, Animal Toxicity

Long-term studies to evaluate the carcinogenic potential in animals have not been conducted.


10. Treatment for Overdose

Symptoms and signs of overdose may not be immediately apparent post-injection. In cases of accidental administration or oral ingestion, medical observation for signs or symptoms of systemic weakness or muscle paralysis should be conducted for several weeks. If an overdose or misadministration is immediately recognized, an antitoxin can be used. The antitoxin does not reverse muscle weakness effects that have already manifested at the time of its administration.
If the muscles of the oropharynx and esophagus are affected, aspiration may occur, which can lead to aspiration pneumonia. If respiratory muscles are paralyzed or weakened, intubation and assisted breathing may be necessary until recovery. In addition to other general supportive treatments, tracheotomy and/or prolonged mechanical ventilation may be required.
Such patients should consider immediate and appropriate measures, including additional medical evaluation and hospitalization.


11. Storage and Handling Precautions

Unopened drug must be stored refrigerated (2-8℃). Once reconstituted, the drug can be refrigerated (2-8℃) for up to 24 hours.
All vials, including those past their expiration date, and any supplies that have come into direct contact with the product, must be disposed of as medical waste. In cases requiring deactivation of the toxin (e.g. spillage), it is recommended to use diluted hypochlorite (0.5 or 1%) before disposal as medical waste.


12. Information for Patients

Discuss any concerns regarding the effects and risks of this drug with your doctor. Be vigilant for signs and symptoms of adverse reactions. Seek immediate medical attention if you experience difficulty swallowing or speaking, breathing difficulties, or muscle weakness after treatment. Adverse reactions may occur within hours after treatment or several weeks later.
This drug binds to receptors at the neuromuscular junction, enters the nerve endings, and inhibits the release of acetylcholine, thereby blocking neuromuscular transmission. When injected into muscles in therapeutic doses, it causes localized muscle paralysis through chemical denervation. When muscles are chemically denervated, they become weakened and can develop acetylcholine receptors outside the synapse. The regeneration of nerves and the resumption of nerve impulses to the muscles demonstrate that the 'loss of strength' is reversible.

A white to yellowish, vacuum-dried powder for injection in a colourless and transparent vial, forming a clear and transparent liquid when dissolved in the diluent (physiological saline solution).

· Active ingredient: Clostridium botulinum toxin type A (in-house) 50 units
· Other excipients: Human serum albumin 0.25mg, Sodium chloride 0.45mg

1. Temporary improvement of moderate to severe glabellar lines associated with corrugator muscle and/or procerus muscle activity in adults aged 20 to 65.
2. Muscle Spasticity: Treatment of upper limb spasticity associated with stroke in adults over 18 years of age.
3. Temporary improvement of moderate to severe lateral canthal lines (crow's feet)
associated with orbicularis oculi activity in adults aged 18 to 65.
4. Treatment of benign essential blepharospasm in adults over 18 years of age.

1. Glabellar Lines

Dilute to 50 U/1.25 mL (4 U/0.1 mL) with 0.9% preservative-free sterile saline solution.
Using a 30-gauge needle, inject 0.1 mL each into five sites, two in each corrugator muscle and one in the procerus muscle, totaling 20 U.

To reduce the complication of eyelid drooping, avoid injections near the levator palpebrae superioris, especially in patients with prominent brow depressor muscles.
When injecting into the inner corrugator muscle and the mid-eyebrow, ensure the injection is at least 1 cm away from the orbital rim.
Care must be taken not to inject into a blood vessel, and to prevent extravasation below the orbital rim, firmly place a thumb or index finger below the orbital rim before injecting.
During injection, the needle should be oriented upward and midline, and the injection volume should be precise.
The corrugator and orbicularis oculi muscles move the middle of the forehead and create glabellar facial wrinkles.
The procerus and depressor supercilii muscles pull the forehead downward.
These muscles contribute to frowning or glabellar lines. Since muscle location, size, and use vary individually, the effective dose is determined based on overall observation of the patient's ability to activate the injected superficial muscles.
The treatment effect of this drug for glabellar lines lasts about 3-4 months. The safety and efficacy of frequent administrations of this drug have not been clinically evaluated and are not recommended.
Typically, the initial administration of botulinum toxin induces chemical denervation in the injected muscles after 1-2 days, with the intensity increasing during the first week.



2. Muscle Spasticity

The exact dosage and number of injection sites can vary depending on the size, number, and location of the involved muscles, the degree of spasticity, the presence of local muscle weakness, and the patient's response to previous treatments.
Clinical improvement in muscle tension is observed after 4 weeks of injection, and this effect can last up to 8 weeks and 12 weeks.

The dosages administered in clinical trials were as follows:

In clinical trials, the dosage did not exceed a total of 360 U, and it was divided among the muscles.
Sterilized needles ranging from 24-30 gauge are used for superficial muscles, and needles of appropriate length are used for deeper muscle tissues. Electromyography guidance and nerve stimulation techniques are useful in locating the relevant muscles.


3. Lateral Canthal Lines (Crow's Feet)

Lateral canthal lines primarily result from the activity of the orbicularis oculi muscle surrounding the eye, which is used during blinking or closing the eyes.
Strong contraction of the orbicularis oculi muscle creates lateral, fan-shaped folds (crow's feet) starting at the outer corner of the eyes. The distribution of these fan-shaped wrinkles varies among patients.
Inject from the outside direction of the eye, ensuring the bevel of the needle is facing upwards.
Using a 30-33 gauge needle, inject 0.1 mL (4 U) into three sites on each lateral side of the orbicularis oculi muscles (a total of 6 sites, 24 U on both sides).
The first injection site is the lateral orbital rim, 1.5-2.0 cm away from the outer corner of the eye towards the temple.
When the maximum smile-induced wrinkles are above and below the outer corner of the eye, inject as shown in the diagram.

The treatment effect of this drug for lateral canthal lines lasts about 3 months.
The safety and efficacy of re-administration periods have not been clinically evaluated.


4. Eyelid Spasm

For the treatment of eyelid spasms, use a sterile 27-30 gauge needle without electromyography guidance, diluting the drug as per the dilution table.
The recommended initial dose for the pretarsal orbicularis oculi muscle of both the upper and lower eyelids is 1.25 U to 2.5 U (0.05 ㎖ to 0.1 ㎖ per area).
If the spasm obscures vision, injections can be administered to the corrugator muscle and the upper lateral orbicularis oculi muscle at the medial and lateral aspects of the eyebrows.
For subsequent treatments (not the initial administration), up to a maximum of 5U can be injected per site, equivalent to the most recent total administered dose.

＜Dilution Method＞
To dissolve the lyophilized drug, use preservative-free sterile saline solution. A 0.9% sodium chloride injection is the recommended diluent. Draw an appropriate amount of the diluent into a syringe of suitable size. Introduce the diluent slowly into the vial to avoid creating foam or similar vigorous agitation, which can cause the drug to degrade. If the diluent does not enter the vial due to vacuum, discard the vial. Record the date and time of reconstitution on the label and administer within 24 hours after dilution. Store the diluted solution in refrigeration (2-8°C). Upon reconstitution, the solution should be colorless, clear, and free from visible particles. Non-oral formulations should be carefully inspected for visible particles and discoloration prior to administration. Since neither the drug nor the diluent contains preservatives, do not use one vial for more than one patient.

[Dilution Table]

Note: This diluent is calculated based on a 0.1 ml injection. Additionally, the dose can be adjusted by varying the volume of injection. 0.05 ml (50% reduction in dose) - 0.15 ml (50% increase in dose)

Shelf Life: 36 months from the date of manufacture

1 Vial/Box [Vial (50 Units)]

Sealed container, refrigerated (2-8°C) storage

1. Warning

The active ingredient of this drug is Botulinum Toxin Type A, produced by Clostridium botulinum. Therefore, it is crucial to be aware of and adhere strictly to the prescribed usage and dosage. Physicians administering this drug must have a thorough understanding of the anatomical structure of the related neuromuscular and periorbital areas, any anatomical alterations due to previous surgeries, and standard electromyographic techniques.
The recommended dosage and frequency of administration must not be exceeded.

A. Distant Spread of Toxin Effect
Botulinum toxin can spread from the site of injection to other areas, potentially causing botulism. Symptoms such as rapid muscle weakness, fatigue, hoarseness, speech disorders, stuttering, loss of bladder control, respiratory difficulty, swallowing difficulty, double vision, blurred vision, and drooping eyelids may occur. Symptoms such as respiratory difficulty or swallowing difficulty can be life-threatening, and there have been reported cases of death due to the spread of the toxin. Children treated for spastic cerebral palsy are particularly at high risk. However, adults treated for spastic cerebral palsy or other conditions may also exhibit the same symptoms. There have been instances of such adverse reactions occurring at the recommended doses for treating cervical dystonia, as well as at lower doses.

B. Hypersensitivity Reactions
Rare cases of serious or immediate hypersensitivity reactions to other botulinum toxin products have been reported. These reactions have included anaphylaxis, urticaria, tissue swelling, and respiratory difficulties. One instance of anaphylaxis was reported when lidocaine was used as a solvent; however, the causative agent was not conclusively identified. If such reactions occur following the administration of this drug, the treatment should be discontinued and appropriate measures taken.

C. In Patients with Neuromuscular Disorders
Patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junction disorders (e.g. myasthenia gravis, Lambert-Eaton syndrome) may experience an increased risk of significant systemic reactions, including severe dysphagia and respiratory depression, even with conventional doses of botulinum toxin products. According to clinical literature, rare cases have been reported where patients with known or unrecognized neuromuscular disorders exhibited severe hypersensitivity to the systemic effects of typical doses of botulinum toxin. In some of these cases, dysphagia persisted for several months, necessitating the use of a feeding tube.

D. Dysphagia
Dysphagia is a commonly reported adverse reaction in patients treated with any botulinum toxin for cervical dystonia. Rarely, dysphagia has been severe enough in some patients to require the use of a feeding tube. There have been reports of cases where dysphagia led to aspiration pneumonia, resulting in death.

E. Rarely, cardiovascular adverse reactions, including arrhythmias and myocardial infarctions, have been reported following the administration of other botulinum toxin products, some of which have been fatal. Several of these cases involved patients with pre-existing cardiovascular risk factors.

F. In the treatment of strabismus with other botulinum toxin products, retrobulbar hemorrhage, which can jeopardize retinal circulation, has occurred due to needle penetration around the eye. It is recommended to use appropriate techniques to reduce the pressure susceptible around the eye. There have also been cases of needle penetration into the eye. Ophthalmoscopic examination should be used to diagnose these conditions. One or more external ocular muscle paralyses can induce spatial disorientation, double vision, and past-pointing. Covering the affected eye can alleviate these symptoms.

G. Eyelid Spasm
After the injection of botulinum toxin into the orbicularis oculi muscle, especially in patients with facial nerve (CN VII) disorders, there can be a reduction in blinking leading to corneal exposure, persistent epithelial defects, and corneal ulcers. There has been a reported case where corneal perforation occurred in an anophthalmic eye due to the effects of another botulinum toxin product, necessitating a corneal transplant. In patients with a history of eye surgery, a careful examination of corneal sensation should be conducted, and avoiding injections in the lower eyelid area can reduce the risk of ectropion. Any corneal epithelial defects require thorough treatment. This may include protective eye drops, ointments, therapeutic soft lenses, or eye patches, among other measures.

H. Non-Interchangeability
As the toxin content can vary between different botulinum toxin products, the units of one product are not convertible to the units of another.

I. Injection into or around Anatomically Vulnerable Structures
Caution is required when injecting into or around anatomically vulnerable structures. Serious adverse events, including fatal outcomes, have been reported with the injection of other botulinum toxin products into the salivary glands, the area around the mouth-tongue-pharynx, esophagus, and stomach. Some of these patients had pre-existing dysphagia or significant weakness. (The safety and efficacy for these indications, including those injection sites, have not been established.) Cases of pneumothorax associated with the injection process of other botulinum toxin products into the thoracic region have been reported. Caution is especially advised when injecting near the apex of the lung.

J. Impact on Pulmonary Function in Adult Patients with Respiratory Disorders Undergoing Treatment for Upper Limb Spasticity or Neurogenic Detrusor Overactivity
In patients with respiratory disorders undergoing treatment for upper limb spasticity, a decrease in pulmonary function (a reduction in Forced Vital Capacity [FVC] by ≥ 15%) and upper respiratory infections have been reported more frequently with the administration of other botulinum toxin products compared to placebo. Also, a decrease in pulmonary function (FVC reduction ≥ 15%) has been reported in patients with respiratory disorders and neurogenic detrusor overactivity treated with other botulinum toxin products.

K. Bronchitis and Upper Respiratory Infections in Adult Patients Treated for Upper Limb Spasticity
Among patients treated for upper limb spasticity, bronchitis has been reported more frequently in those treated with other botulinum toxin products than in the placebo group. In patients with reduced lung function undergoing treatment for upper limb spasticity, upper respiratory infections have been reported more frequently with other botulinum toxin products compared to placebo. In a therapeutic confirmatory clinical trial conducted on 195 adults for the treatment of upper limb spasticity using this drug, there were two cases of upper respiratory infection adverse reactions reported in the treatment group and one case in the control group.


2. Do Not Administer to the Following Patients:

A. Patients who have hypersensitivity to the components of this drug
B. Patients with systemic neuromuscular junction disorders (such as myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, etc.) - The muscle-relaxing action of the drug can exacerbate these conditions.
C. Pregnant or potentially pregnant women and nursing mothers


3. Administer with Caution to the Following Patients

A. Patients currently being treated with muscle relaxants (such as tubocurarine chloride, dantrolene sodium, etc.) - There is a risk of enhanced muscle-relaxing action or increased incidence of dysphagia.
B. Patients receiving drugs with muscle-relaxing properties, such as spectinomycin hydrochloride, aminoglycoside antibiotics (gentamicin sulfate, neomycin sulfate, etc.), polypeptide antibiotics (polymyxin B sulfate, etc.), tetracycline antibiotics, lincosamide antibiotics (lincosamides), muscle relaxants (baclofen, etc.), anticholinergics (scopolamine butylbromide, trihexyphenidyl hydrochloride, etc.), benzodiazepines and similar drugs (diazepam, etizolam, etc.), and benzamide drugs (tiapride hydrochloride, sulpiride, etc.) - There is a risk of enhanced muscle-relaxing action or increased incidence of dysphagia.


4. Adverse Reactions

A. General Information
Rare cases of difficulty swallowing, pneumonia, and/or severe lethargy or anaphylaxis-related deaths have been reported following treatment with botulinum toxin.
Additionally, cardiovascular adverse reactions, including arrhythmia or myocardial infarction that can lead to fatal outcomes, have been rarely reported. The precise causal relationship between these adverse reactions and botulinum toxin has not been established.
Other botulinum toxin products have reported adverse reactions, whose association with botulinum toxin remained unknown, including skin rashes (multiform erythema, urticaria, psoriatic rash), itching, and allergic reactions.
Adverse reactions typically appear within a week of injection, are usually transient but can persist for several months. Local pain, tenderness, bruising, tightness at the injection site, swelling, warmth at the injection site, and increased muscle tension in the injection area and neighboring muscles can occur in relation to the injection. Local weakness at the injection site reflects the anticipated pharmacological action of botulinum toxin. However, weakness in adjacent muscles may be attributed to the spread of the toxin. In patients treated with this drug for eyelid spasms or cervical muscle dystonia, there is a possibility of increased electromyographic jitter (sudden disruption in waveform) unrelated to electromyographic abnormalities in muscles distant from the injection site.

B. Glabellar Lines
A safety assessment was conducted on 268 subjects aged 20 to 65 years with moderate to severe glabellar lines across multiple centers. This was a double-blind (neither patients nor doctors were aware), randomized, active-controlled study (135 subjects in the test group for this drug, 133 in the Botox control group). Adverse events occurred in 20.00% of the test group and 18.05% of the control group.
Most adverse events were mild, with no severe cases reported. The drug-related adverse reactions reported in more than 1% of the test group for this drug, in order of frequency, were as follows: eyelid ptosis (2.22%), eyebrow elevation (1.48%), and dizziness (1.48%).

C. Upper Limb Spasticity
A safety assessment was conducted on 197 subjects aged 18 and over who were diagnosed with a stroke at least 6 weeks prior. This was a multi-center, active-controlled, double-blind (neither patients nor doctors were aware), randomized study (99 subjects in the test group for this drug, 98 in the Botox control group). Adverse events were reported in 19.59% (19 out of 97 subjects, 30 events) of the test group and 19.39% (19 out of 98 subjects, 22 events) of the control group. Among these, drug-related adverse reactions were reported in 3 cases in the test group and 4 cases in the control group. The table below lists the reported drug-related adverse reactions by body system. The frequencies are defined as follows: very common (≥ 10%), common (≥ 1%, < 10%), uncommon (≥ 0.1%, < 1%), rare (≥ 0.01%, < 0.1%), very rare (< 0.01%).

D. Post-Market Surveillance Results in South Korea
Over 4 years, a post-market usage survey was conducted in South Korea with 914 subjects. The incidence of adverse events was 2.5% (23 out of 914 subjects, 25 events). Of these, the incidence of drug adverse reactions with a possible causal relationship to this product was 1.6% (15 out of 914 subjects, 17 events). Reported adverse events included headaches at 0.5% (5 out of 914 subjects, 5 events), eye fatigue and periorbital edema each at 0.2% (2 out of 914 subjects, 2 events), and chills, fatigue, facial paralysis, reaction at injection site, rash at injection site, pressure sensation at injection site, pain at injection site, and itching each at 0.1% (1 out of 914 subjects, 1 event). No serious adverse events or serious drug adverse reactions were identified.
The incidence of unexpected adverse events was 1.5% (14 out of 914 subjects, 16 events), with headaches at 0.8% (7 out of 914 subjects, 7 events), eye fatigue and pharyngitis each at 0.2% (2 out of 914 subjects, 2 events), and back pain, chills, fatigue, facial paralysis, and skin wrinkling each at 0.1% (1 out of 914 subjects, 1 event). Among these, the incidence of unexpected drug adverse reactions that cannot be ruled out as causally related to this product was 0.9% (8 out of 914 subjects, 10 events), with headaches reported at 0.5% (5 out of 914 subjects, 5 events), eye fatigue at 0.2% (2 out of 914 subjects, 2 events), and chills, fatigue, facial paralysis each reported at 0.1% (1 out of 914 subjects, 1 event). No serious and unexpected adverse events or serious and unexpected drug adverse reactions were identified.
Upon the comprehensive evaluation at the time of re-examination conclusion, using the domestic post-marketing adverse event and spontaneous adverse reaction report data for this drug in comparison with the reported adverse event data for all other approved drugs in South Korea, the following newly identified adverse events were reported more statistically significantly in this drug compared to other drugs. However, these results do not imply a proven causal relationship between the respective ingredient and the following adverse events:

• Skin and Subcutaneous Tissue Disorders: Periorbital Edema (Eyelid Edema)
• Nervous System Disorders: Headache

5. General Precautions

A. This drug contains human albumin derived from human blood. When administering drug products manufactured from human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded. This also applies to pathogens that are currently unknown. To reduce the risk of transmission of infectious agents, the manufacturing process includes appropriate measures such as the screening of donors and donation sites, as well as processes for the removal and/or inactivation of infectious agents.
B. The impact of this drug on the ability to operate machinery or drive cannot be predicted, as it may be influenced by the disease being treated.
C. Glabellar Lines/Lateral Canthal Lines (Crow's Feet)
The reduction in blinking following the injection of botulinum toxin products into the muscles around the eyes can lead to corneal exposure, persistent epithelial defects, and corneal ulceration, especially in patients with 7th nerve disorders.
Caution is advised in cases such as when there is infection or skin diseases, scars, or other skin abnormalities at the injection site, a history of facial plastic surgery (face lifting), treatment with permanent implants, a history of facial nerve paralysis or eyelid spasms, or when physical improvement of glabellar lines is unlikely, such as when wrinkles do not smooth out upon manually spreading them. These patients were excluded from Phase 3 safety and efficacy clinical trials.
The interval between injections of this drug should not be more frequent than every three months, and the minimum effective dose should be used.
D. Upper Limb Spasticity
This drug is only used for the treatment of focal spasticity studied in conjunction with conventional standard therapies. It is not effective in improving the range of motion in joints affected by fixed contractures.


6. Drug Interactions

A. Generally, when botulinum toxin products are taken in conjunction with aminoglycoside antibiotics or drugs that interfere with muscle and nerve transmission (such as tubocurarine muscle relaxants), the efficacy of the botulinum toxin products is increased. Continuous concurrent use of aminoglycoside antibiotics or spectinomycin is contraindicated.
The use of polymyxin, tetracycline, or lincomycin in patients treated with this drug should be approached with caution.
B. The effects of administering a different botulinum neurotoxin serotype concurrently or within several months are not known. Administering a different botulinum toxin before th


7. Administration in Pregnant and Nursing Women

There are no adequate and well-controlled studies of this drug in pregnant women. In studies where pregnant rats were injected intramuscularly with this drug (0.5, 1, 4 U/kg) during the organogenesis period (day 6-16 of pregnancy), maternal effects such as bent toes, paralytic gait, and curled toes were observed. In the fetuses, a decrease in ossification numbers was noted in the 4 U/kg dosage group, but this was not statistically significant.
It is not known whether botulinum toxin is secreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when administering the drug to nursing mothers.br> The use of this drug is not recommended during pregnancy or breastfeeding.


8. Administration in Children

This drug has not been studied for safety and efficacy in children and adolescents under 20 years of age for the improvement of glabellar lines.
The safety and efficacy for upper limb spasticity have not been studied in children and adolescents under 18 years of age.


9. Carcinogenicity, Mutagenicity, Teratogenicity, Animal Toxicity

Long-term studies of this drug to evaluate the carcinogenic potential in animals have not been conducted.


10. Treatment for Overdose

Symptoms and signs of overdose may not be immediately apparent post-injection.
In cases of accidental administration or oral ingestion, medical observation for signs or symptoms of systemic weakness or muscle paralysis should be conducted for several weeks. If an overdose or misadministration is immediately recognized, an antitoxin can be used. The antitoxin does not reverse muscle weakness effects that have already manifested at the time of its administration.
If the muscles of the oropharynx and esophagus are affected, aspiration may occur, which can lead to aspiration pneumonia. If respiratory muscles are paralyzed or weakened, intubation and assisted breathing may be necessary until recovery. In addition to other general supportive treatments, tracheotomy and/or prolonged mechanical ventilation may be required.
Such patients should consider immediate and appropriate measures, including additional medical evaluation and hospitalization.


11. Storage and Handling Precautions

Unopened drug must be stored refrigerated (2-8℃). Once reconstituted, the drug can be refrigerated (2-8℃) for up to 24 hours.
All vials, including those past their expiration date, and any supplies that have come into direct contact with the product, must be disposed of as medical waste. In cases requiring deactivation of the toxin (e.g. spillage), it is recommended to use diluted hypochlorite (0.5 or 1%) before disposal as medical waste.


12. Information for Patients

Discuss any concerns regarding the effects and risks of this drug with your doctor. Be vigilant for signs and symptoms of adverse reactions. Seek immediate medical attention if you experience difficulty swallowing or speaking, breathing difficulties, or muscle weakness after treatment. Adverse reactions may occur within hours after treatment or several weeks later.
This drug binds to receptors at the neuromuscular junction, enters the nerve endings, and inhibits the release of acetylcholine, thereby blocking neuromuscular transmission. When injected into muscles in therapeutic doses, it causes localized muscle paralysis through chemical denervation. When muscles are chemically denervated, they become weakened and can develop acetylcholine receptors outside the synapse. The regeneration of nerves and the resumption of nerve impulses to the muscles demonstrate that the 'loss of strength' is reversible.


13. Information for Professionals

1) Pharmacological Action
This drug binds to receptors at the neuromuscular junction, enters the nerve endings, and inhibits the release of acetylcholine, thereby blocking neuromuscular transmission.
2) Clinical Trial Information

＜Lateral Canthal Lines＞
(A Phase 3 Clinical Trial) A double-blind, randomized, multi-center clinical trial was conducted with 204 adult patients (men and women aged between 18 and 75) requiring improvement of moderate to severe lateral canthal lines.
Participants were randomly assigned to receive either this drug or another botulinum toxin product, administered to either the right or left lateral canthal lines. Results showed that 4 weeks post-administration, the improvement rate of lateral canthal lines when smiling maximally was 65.02% (132 out of 203 participants) for the area treated with this drug, compared to 62.56% (127 out of 203 participants) for the area treated with the other botulinum toxin product. The lower limit of the 95% confidence interval for the difference in improvement rates of lateral canthal lines between the two injection sites was -0.91%, indicating that the efficacy of this drug was not inferior compared to other botulinum toxin products.
(Extension Clinical Trial) A single-group, open-label, multi-center extension clinical trial was conducted with 109 adults who participated in the aforementioned Phase 3 clinical trials and required improvement of moderate to severe lateral canthal lines and glabellar lines.
Each participant received a single injection of 24 U into the lateral canthal lines and 20U into the glabellar lines. As a result, the improvement rate of lateral canthal lines when smiling maximally 4 weeks after administration, as assessed by the investigators, was similar to the results of the Phase 3 clinical trial.