Botulinum

nabota

Product Information

Product English Name NABOTA inj.
Efficacy Effects Temporary improvement in the appearance of moderate to severe glabella wrinkles associated with corrugator musleand/or procerus muscle activities
Main Ingredients Clostridium botulinum toxin type A (standard) -100 units
Description White or light yellow lyophilizate in a colorless transparent vial that becomes clear and transparent when dissolved in physiological saline
Classification Professional medicines (ETC)

Key Information

– In one vial –
100 units of Clostridium botulinum toxin type A (standard), serum albumin (vitality), sodium chloride (USP)

Temporary improvement in the appearance of moderate to severe glabella wrinkles (vertical lines between the eyebrows) associated with corrugator muscle and/or procerus muscle activities, in adults aged between 20 to 65.

[ Glabellar Lines ]

Dilute to 100 U / 2.5 mL (4 U / 0.1 mL) with 0.9% non-preservative sterile saline solution. Using a 30-gauge injection needle, inject 0.1 mL in two parts of the corrugator muscles of each eyebrow and one part in procerus muscle, resulting in total of 5 parts, to inject 20 units total.

Avoid injections near the levator palpebrae superioris, especially in patients with large eyebrow depressor muscles to reduce complications of lid ptosis. When injecting into the inner corrugator supercilii muscle and middle eyebrows, inject at least 1 cm away from the perimeter of the eye.

Be cautious not to inject into the blood vessels when administering this drug and place a thumb or index finger tightly under the perimeter of the eye before injection to prevent the exudation below the edge around the eye. During the injection, the needle should be directed to the upper middle, and the injection volume should be accurate.

Avoid injections near the levator palpebrae superioris, especially in patients with large eyebrow depressor muscles to reduce complications of lid ptosis. When injecting into the inner corrugator supercilii muscle and middle eyebrows, inject at least 1 cm away from the perimeter of the eye.

Be cautious not to inject into the blood vessels when administering this drug and place a thumb or index finger tightly under the perimeter of the eye before injection to prevent the exudation below the edge around the eye. During the injection, the needle should be directed to the upper middle, and the injection volume should be accurate.

The corrugator muscle and the orbicularis oculi muscle move in the middle of the forehead to make glabella facial wrinkles. Procerus muscle and depressor supercilii muscle pull the forehead down. These muscles produce frowning or wrinkles. Since muscle positions, sizes, and uses vary from person to person, effective dose is determined by complete observation of the patient’s ability to manage implanted surface muscles.

The curative effect of this medicine on glabella wrinkles lasts approximately 3-4 months. The safety and validity of frequent dosing of NSAIDs has not been clinically evaluated and is not recommended. Generally the first dose of the botulinum toxin formulation induces chemical denervation of the injected muscle after 1 or 2 days, and the intensity increases during the first week.

[ Dilution Methods ]

In order to dissolve the lyophilized pesticide, sterile physiological saline is used without the preservative. 0.9% sodium chloride injection is the recommended dilution. Add an appropriate amount of diluent to a suitable size syringe. Slowly add dilution to the vial as this drug will fizzle or become highly denatured if a similar violent disturbance occurs. If the diluent is not put into the vial under vacuum, then this vial should be discarded. Record the date and time of dissolution on the label and it should be injected within 24 hours after dissolution. Store the diluted solution in a refrigerated state (2-8 ° C). When this medicine is dissolved, it should be colorless, transparent and free from foreign matters. Parenteral preparation should be carefully examined for foreign matter incorporation and discoloration before administration. Do not use one vial for more than one patient as this medicine and diluent do not contain any preservatives.

[ Dilution Chart ]
Added diluent
(0.9% sodium chloride injection)
Concentration in the dissolved state
(U / 0.1 ml)
1.0 ml 10.0 U
2.0 ml 5.0 U
4.0 ml 2.5 U
8.0 ml 1.25 U

Sealed container, refrigerated (2 ~ 8 ℃) Storage

36 months from date of manufacture

Detailed Information

1. Warning

The active ingredient of this medicine is botulinum toxin A, produced by botulinum, so be aware of the usage precautions and strictly comply with dosage methods and amounts. The physician administering this drug should have a thorough understanding of the associated neuromuscular and anatomical structures around the eye, anatomical changes by previous surgery, and the standard EMG techniques.
Do not exceed the recommended dosage and number of administrations.

A. Long-range diffusion of toxic effects

Botulinum toxin can spread from injected site to other sites and cause botulism poisoning. Symptoms such as sudden muscle weakness, loss of energy, hoarse throat, speech disorders, stuttering, loss of bladder control, dyspnea, difficulty in swallowing, diplopia , blurred vision and ptosis can occur. Symptoms such as difficulty in breathing or swallowing can be life-threatening, and there are reports of deaths due to the spread of toxins. Children with spastic cerebral palsy are particularly at high risk. However, adults who have been treated for spastic cerebral palsy or other symptoms may also have the same symptoms. There have been instances in which the above-mentioned adverse events occurred when dosing and lower doses for treatment of neck muscle tension disorders were administered.

B. Allergic reactions

Serious or immediate allergic reactions in other botulinum toxin preparations are rarely reported. These reactions were anaphylaxis, urticaria, swelling of the soft tissue, and difficulty breathing. One example of an anaphylaxis was the use of lidocaine as a solvent, and the causative agent was not reliably identified. If these reactions occur after injecting this drug, administration should be discontinued and appropriate measures should be conducted.

C. In case of neuromuscular disorder

In patients with peripheral motor neuropathy (e.g., amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junction disorder (e.g. severe ataxia syndrome), Lambert-Eaton syndrome), the usual dose of botulinum toxin formulation may increase the risk of significant systemic reactions including severe dysphagia and respiratory depression. Clinical studies have seldomly reported that botulinum toxin has been shown to exert severe allergic reactions to the usual dose of systemic effects in neuromuscular patients with known or unknown neuromuscular disease. In these cases, some patients had difficulty in swallowing for months, requiring gastric tubes.

D. Difficulty in swallowing

Dysphagia is a commonly reported allergic reaction to botulinum toxin in the treatment of cervical muscle tension disorders. Among these patients, rarely but difficulty in swallowing became critical, resulting in requiring a gastric tube. After the occurrence of dysphagia, it was reported that the patient developed an aspiration pneumonia and died.

E. Cardiovascular adverse reactions, including arrhythmia and myocardial infarction, were rarely reported with the administration of other botulinum toxin preparations, and some cases were fatal. Some of these patients have previously had risk factors including cardiovascular disorders.

F. When applied to strabismus treatment in other botulinum toxin preparations, injection needle penetration around the eyes causes posterior ocular hemorrhage which jeopardizes the retinal circulation. It is recommended that proper instruments be installed to reduce the pressure around the susceptible eye. Moreover, there are cases where an injection needle penetrates the eye. Ophthalmoscopy should be used to diagnose these kinds of conditions. One or more extraocular muscles can induce spatial disorientation, double vision, and past-pointing. Covering the affected eye can alleviate these symptoms.

G. Eyelid seizure

After injecting the botulinum toxin preparation to the orbicularis muscle, eye flickering may be reduced in patients with the seventh neuropathy, resulting in corneal exposure, persistent epithelium defects, and corneal ulcers. In another botulinum toxin formulation, an aphakic eye requiring a corneal transplantation required a corneal transplantation in 1 case because of this effect Careful examination of the corneal sensation should be performed if there were any previous surgical procedures and avoiding subcutaneous injection may reduce the risk of eyelid paralysis. Any corneal epithelium defect requires thorough treatment. Treatment methods include eye drops for protection, ointment, soft lens for treatment, or blindness by eye patches or other means.

H. Not interchangeable

Since the toxin content may vary between botulinum toxin preparations, a unit of a product can not be exchanged to another product unit.

I. Injection into or around anatomically weak structures

Caution should be taken when injecting into or around anatomically vulnerable structures. Significant adverse incidents have been reported, including fatal consequences of injection of other botulinum toxin preparations into the salivary glands, around the mouth-tongue-pharynx, and on the esophagus. Some patients had previously had difficulty in swallowing or significant debility (safety and efficacy of indications including these injection sites were not established). Air chest symptoms related with the injection process were reported when injecting other botulinum toxin preparations into the thoracic region. Caution is required when injecting into areas near the lungs, especially the apex of lungs.

J. Effects on pulmonary function when treating upper limb stiffness or neurogenic detrusor overactivity of adult patients with respiratory diseases

Pulmonary function reductions (forced lung capacity [FVC] reduction ≥15%) and upper respiratory tract infections were frequently reported compared to placebo in patients with upper respiratory stiffness, and pulmonary function reductions (forced lung capacity [FVC] reduction ≥15%) have been reported in patients with respiratory disturbance in neurogenic detrusor overactivity when administered with other botulinum toxin formulations.

K. Bronchitis and upper respiratory tract infection in adult patients with upper limb stiffness

Bronchitis infection was more frequently reported in patients with upper limb stiffness than those in the placebo group Upper airway infections have been reported more frequently in other botulinum toxin agent groups than in placebo groups when upper limb stiffness was treated in patients with reduced pulmonary function.

2. Do not administer to the following patients

A. Patients with hypersensitivity to the components of this drug

B. Patients with systemic neuromuscular junction disorders (severe myasthenia gravis), Lambert-Eaton syndrome, amyotrophic lateral sclerosis, etc.)
It can make these diseases worse due to the muscle relaxation effect.

C. Patients with severe respiratory dysfunction when used for neck muscle tension disorders

D. Women who are pregnant and possibly pregnant & breastfeeding

E. Patients with acute urinary tract infections among patients with neurogenic detrusor overactivity and those who have acute urinary retention and do not routinely clean intermittent catheterization

3. The following patients should be treated with caution

A. Patients who are taking a muscle relaxant (tuberculin hydrochloride, dantrolene sodium, etc.) – there is a possibility that the muscle relaxation effect is enhanced or the expression of difficulty in swallowing is increased.

B. Spectinomycin hydrochloride, Aminoglycoside antibiotics (gentamycin sulfate, neomycin sulfate, etc.), Polypeptide antibiotics (such as polyamicin sulfate B), Tetracycline antibiotics, Lincosamides antibiotics, Muscle relaxants (such as baclofen), Anticholinergic agents (such as butyl scopolamine bromide and trihexyphenidyl hydrochloride), Benzodiazepines and similar agents (diazepam, etizolam, etc.), patients who are taking medicines with muscle relaxation effects such as benzamidine drugs (thiapride hydrochloride, sulfiride, etc.) – there is a possibility that the expression of muscular relaxation or difficulty in swallowing may increase.

4. Adverse drug reactions

A. General information

From time to time after treatment with botulinum toxin, difficulty in swallowing, pneumonia and / or death associated with severe helplessness or anaphylaxis have been seldomly reported. Cardiovascular adverse incidents, including arrhythmia or myocardial infarction, which sometimes lead to fatal outcomes, are rarely reported. The causal relationship between these adverse reactions and botulinum toxin was not confirmed.

The following adverse reactions have been reported in other botulinum toxin preparations, and the associations with botulinum toxin were unknown: skin rash (including polymorphic red spots, urticaria, and dry rash), itching, allergic reactions

In general, adverse reactions occur within one week of injection and are usually transient, but may last for months. With regard to injection, topalgia, oppressive pain, contusions, and sensations of pulling , adherence, thermagia and muscle tensions around injected site may occur. The localized weakness around injected area reflects the predicted pharmacological action of the botulinum toxin. However, the weakness of adjacent muscles can be attributed to the spread of toxins. After administrating this drug in patients with eyelid seizures and neck muscle dystonia, there is a possibility of an increase in electrophysiological jitter (jitter, momentary disturbance of the waveform) not associated with muscle weakness or electrophysiological abnormality in the muscles away from the administered site.

B. Glabella wrinkles

Safety was assessed in 268 patients with ages ranging from 20 to 65 years old who had severe wrinkles or more, with active control, double-blind (randomized clinical trials where both doctors and patients are not aware of) with randomization. (135 patients in the test group and 133 patients in the Botox control group). Adverse incidents were 20.00% in the test group and 18.05% in the control group.

Most of the adverse reactions were mild and not severe. Adverse reactions reported in more than 1% of patients in this group were: eyelid ptosis (2.22%), eyebrow lifting up (1.48%), and dizziness (1.48%)

5. General caution

A. This drug contains human albumin derived from human blood. Infectious diseases caused by the transfer of infectious agents cannot be entirely excluded when administering medicines manufactured from human blood or plasma. This may also be the case with unknown hospital materials. To reduce the risk of transmission of such infectious agents, screening of donor or donor sites is carried out using appropriate methods in the manufacturing process, as well as the removal and / or inactivation of infectious agents.

B. Due to the disease itself being treated, the effect of this drug on machine operation and driving ability is unpredictable.

C. Glabella wrinkles

Reduced blinking of eyes when injecting botulinum toxin preparation into the eyes may result in corneal exposure, persistent epithelial defects, and corneal ulceration, especially in patients with the seventh neurological disorder. Caution needs to be taken with the patients who were excluded from the third phase safety efficacy trial, when there is a history of infection, skin disease, scarring, skin abnormality, face lifting, permanent implant, facial nerve palsy or eyelid seizure, and when wrinkles were not physically improved sufficiently as in the case where wrinkles were not stretched when opened by hands, etc.

The interval between injections of this drug should not be more frequent than 3 months and the minimum effective dose should be used.

6. Drug interaction

A. The efficacy of botulinum toxin preparations was increased generally with the use of aminoglycoside antibiotics or drugs that block muscle / nerve transmission (tubocurarine-based muscle relaxants) in botulinum toxin preparations. Continuous usage with aminoglycoside antibiotics or spectinomycin is contraindicated.

In patients who are administered with this drug, the use of polymyxin, tetracycline, and lincomycin should be taken with caution.

B. The effects of other botulinum neurotoxin serotypes administered simultaneously or within months were not known. Neuromuscular breakdown may be exacerbated when other botulinum toxin is injected before the effect of the previously administered botulinum toxin disappears.

7. Administration for pregnant and lactating women

There are no adequate and well-controlled studies on pregnant women and this drug. NOEL (No Observed Effect Level) was 4 U / kg when injected intramuscularly to conceived mice and rats that received other botulinum toxin preparations and high dose (8 or 16 U / kg) resulted in fetal weight loss and / or ossification delay. In a dose-setting study with rabbits, severe reproductive toxicity, miscarriage, and fatal anomalies have been noted, and high-dose causes fetal death when tested with daily doses of 0.125 U / kg / day (from 6 to 18 days of fertilization) and 2 U / kg / day (from 6 to 13 days of fertilization) Rabbits appeared to be a very sensitive species to this drug. If became pregnant following administration of this drug, the patient should be informed of any hazards, including miscarriage or fatal malformations observed in the tested rabbits.

It is not known whether the botulinum toxin is secreted in the milk. Because many drugs are secreted in the milk, they should be observed carefully when administered to the lactation site. The use of this drug during pregnancy or during lactation is not recommended.

8. Administration to children

The safety and efficacy of this drug on the improvement of wrinkles for children and adolescents younger than 20 years of age have not been studied.

9. Carcinogenicity, mutagenicity, teratogenicity, animal toxicity

No long-term studies of carcinogenic potential in animals have been conducted.

Toxicity on animals

Bladder stones were observed in one of four male monkeys with a dose of 6.8 U / kg given in the prostate urine and upper rectum in a study to evaluate the erroneous injection cases into the bladder periphery of other botulinum toxin preparations . When male or female monkeys were directly injected into bladder once or four times up to 36 U / kg (approximately 12 times the human dose), or when administered to female rats at a dose of 100 U / kg (approximately 33 times the human dose), no bladder stone was observed.

10. Treatment during overdose

Symptoms during and after the time of overdose are not apparent immediately after injection. When administered accidentally or orally, signs or symptoms of systemic debility or muscle paralysis should be medically observed for several weeks. Antitoxin can be used if it is immediately recognized that it has been overdosed or misapplied. Antitoxin does not reverse the already occurred muscle weakening effects at the time of antitoxin administration.

If the oral pharyngeal and esophageal muscles are affected, aspiration can occur, which can lead to aspiration pneumonia. If the respiratory muscles are paralyzed or weakened, intubation and assisted breathing may be necessary until recovery. In addition to other general ancillary therapies, tracheostomy and / or long-term mechanical ventilation may be required.

These patients should consider immediate appropriate measures including additional medical evaluation and admission.

11. Storage and handling precautions

Unopened Drugs should be stored in refrigerated state(2-8 ° C). The dissolved drug can be stored in refrigerated state (2-8 ° C) for 24 hours.

All vials, including vials that have passed the expiration date, or those in direct contact with the product should be discarded as medical waste. If toxin inactivation is required (e.g. efflux), it is recommended to use diluted hypochlorite (0.5 or 1%) before disposal into medical waste.

12. Information for patients

Talk to your doctor about any concerns about the effects and risks of this medicine. Pay attention to signs or symptoms of adverse reactions. If you experience difficulty swallowing or speaking after the treatment, or experience difficulty breathing or muscular weaknesses, seek immediate medical help. Adverse events may occur within hours or weeks after the treatment.

This drug binds the receptors at the distal end of the nerve, enters the nerve endings and inhibits the secretion of acetylcholine, thereby blocking conduction of the nerve. When injected intramuscularly within therapeutic doses, the drug causes localized muscle paralysis by chemical denervation action. When the muscles are chemically denervated, the muscles become weak and can develop acetylcholine receptors outside the junctions. New nerves and nerve stimulation can flow back to the muscles, proving that the sense of lassitude is reversible.