BOTULAX APPLICATION jabhealthlimited.com
Active ingredient: Clostridium botulinum toxin type A 100 units (U)* (attached specifications).
Stabilizer: Human serum albumin 0.5 mg (attached specifications).
Tonic adjuster: Sodium chloride (KP) 0.9 mg
*One unit (U) of BOTULAX inj. 100 units corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice.
It appears as a lyophilized white powder for injection in a colorless transparent vial.
Benign essential blepharospasm in adult patients, 18 years age or above.
Temporary improvement of serious glabellar wrinkles ranging from moderate to severe associated with corrugators muscle and/or procerus muscle activities in adults aged between 18 and 65.
Dosage/Direction for Use
Blepharospasm: For blepharospasm, reconstituted Botulax inj. 100 units (see Dilution Table) is injected using a sterile, 27-30 gauge needle without electromyographic guidance. The initial recommended dose is 1.25-2.5 U (0.05 mLto 0.1 mL volume at each site) injected into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid. In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient-usually defined as an effect that does not last longer than two months. However there appears to be little benefit obtainable from injecting more than 5.0 U per site. Some tolerance may be found when the drug is used in treating blepharospasm if treatments are given any more frequently than every three months, and is rare to have the effect be permanent. The cumulative dose of Botulax inj. 100 units treatment in a 30-day period should not exceed 200 U.
Glabellar lines: Reconstitute this product with 0.9% preservative-free, sterile saline to make 100 U/2.5 mL (4 U/0.1 mL). Using a 30-gauge needle, inject a dose of 0.1 mL into each of 5 sites, 2 in each corrugators muscle and 1 in procerus muscle, for a total of 20 U.
In order to reduce the complication of ptosis, avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. Injections into inner corrugators muscle and central eyebrow should be placed at least 1 cm above the bony supraorbital ridge.
Careful attention should be paid to avoid injection of this product into the blood vessel. In order to prevent exudation below the orbital ridge, be sure to firmly place the thumb or index finger below the orbital ridge, prior to injection. The needle should be toward the upper center during injection and careful attention should be paid to inject accurate volume.
Glabellar facial lines arise from the activity of corrugator muscle and orbicularis oculi muscle. These muscles move the brow medially, and the procerus muscle and depressor supercilii muscle pull the brow inferiorly. This creates a frown or “furrowed brow”. The location, size, and use of the muscles vary markedly among individuals. An effective dose for facial lines is determined by gross observation of the patient’s ability to activate the superficial muscles injected.
Each treatment lasts approximately three to four months. More frequent injection of this product is not recommended because the safety and efficacy are not established.
Dilution Technique: Prior to injection, reconstitute freeze-dried Botulax inj. 100 units with sterile normal saline without a preservative, 0.9% Sodium Chloride Injection is the recommended diluent. Draw up the proper amount of diluent in the appropriate size syringe. Since the drug is denatured by bubbling or similar violent agitation, the diluent should be injected gently into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Record the date and time of reconstitution on the space on the label. Botulax inj. 100 units should be administered within four hours after reconstitution. During this time period, reconstituted Botulax inj. 100 units should be stored in a refrigerator (2-8°C). Reconstituted Botulax inj. 100 units should be clear, colorless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Because the drug and diluent do not contain any preservative, one vial of Botulax inj. 100 units should be used for a single patient.
Note: According to jabhealthlimited.com these dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in dose is also possible by administering a smaller or larger injection volume-from 0.05 mL (50% decrease in dose) to 0.15 mL (50% increase in dose).
According to jabhealthlimited.com signs and symptoms of overdose are not apparent immediately post-injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for up to several weeks for signs or symptoms of systemic weakness or muscle paralysis.
An antitoxin is available in the event of immediate knowledge of an overdose or misinjection. The antitoxin will not reverse any botulinum toxin induced muscle weakness effects already appeared by the time of antitoxin administration.
Botulax inj. 100 units should not be administered when; The patients have known hypersensitivity to any ingredient in the formulation of Botulax inj. 100 units.
The patients have neuromuscular junctional disorders (e.g., myasthenia gravis, Lambert-Eaton syndrome or amyotrophic laternal sclerosis), (The diseases may be exacerbated due to the muscle relaxation activity of the drug).
The drug is used for the treatment of cervical dystonia in the patients with severe respiratory disorder.
The patients are pregnant women, women of childbearing potential, or mothers under lactation.
According to jabhealthlimited.com since the active constituent in this drug is Clostridium botulinum toxin type A neurotoxin which is derived from Clostridium botulinum, the recommended dosages and frequency of administration should be observed with a full understanding of the precautions in use. Physicians administering the drug must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. An understanding of standard electromyographic techniques is also required for the administration of the drug. The recommended dosage and frequency of administration for Botulax inj. 100 units should not be exceeded.
Spread of Toxin Effect: The effects of botulinum toxin products may spread from the area of injection and produce negative symptoms. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses.
Hypersensitivity reactions: Serious and/or immediate hypersensitivity reactions have been rarely reported with other botulinum toxin injections. These reactions include anaphylaxis, urticaria, soft tissue edema and dyspnea. One fetal case of anaphylaxis has been reported in which lidocaine was used as a diluent but the causal agent cannot be reliably determined. If such a reaction occurs, further injection of the drug should be discontinued and appropriate medical therapy should be immediately instituted.
Pre-existing neuromuscular disorders: Individuals with peripheral motor neuropathic diseases (e.g., amyotrophic laternal sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of botulinum toxin injection. Published medical literature with other botulinum toxin injection has reported rare cases of administration of a botulinum toxin to patients with known or unrecognized neuromuscular disorders where the patients have shown extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases, dysphagia has lasted several months and required placement of a gastric feeding tube.
Dysphagia: Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients with all botulinum toxins, in these patients, there are reports of rare cases of dysphagia severe enough to warrant the insertion of a gastric feeding tube. There are also rare case reports where subsequent to the finding of dysphagia a patient developed aspiration pneumonia and died.
There have also been rare reports of adverse events with other botulinum toxin injection involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease.
Lack of Interchangeability between Botulinum Toxin Products: They are not interchangeable with other preparations of botulinum toxin products. Therefore, units of biological activity of botulinum toxin cannot be compared or converted into units of any other botulinum toxin products assessed with any other specific assay method.
Botulax inj. 100 units should be administered with caution in: Patients under treatment by other muscle relaxants (e.g., tubocurarine chloride, dantrolene sodium, etc.). (Muscle relaxation may be potentiated or risks of dysphagia may be increased).
Patients under treatments by drugs with muscle relaxing activity, e.g., spectinomycin HCl, aminoglycoside antibiotics (gentamicin sulfate, neomycin sulfate, etc.), polypeptide antibiotics (polymixin B sulfate, etc.), tetracycline antibiotics, lincomycin antibiotics (lincosamides), muscle relaxants (baclofen etc.), anti-cholinergic agents (scopolamine butylbromide, trihexylphenidil HCl, etc.), benzodiazepine and the similar drugs (diazepam, etizolam, etc.), benzamide drugs (thiapride HCl, sulpiride, etc.). [Muscle relaxation may be potentiated or risks of dysphagia may be increased].
General Precautions: This drug contains albumin, a derivative of human blood. When a medicinal product derived from human blood or serum is administered in human body, the potential of infectious diseases by transmissible agents cannot be completely excluded. It may include any pathogenic agent that is still unknown. In order to decrease the risks of infection by transmissible agents, particular cares including appropriate assay methods are given to the controls of the donors and donation site, to the manufacturing process and to the virus removal/inactivation process.
Due to the nature of the disease being treated, the effects of the drug on the ability to drive or to operate machines cannot be predicted.
During the administration of other botulinum toxin injection for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit. It is recommended that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. An ophthalmoscope to diagnose this condition should be available. Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. Covering the affected eye may alleviate these symptoms.
Blepharospasm: Reduced blinking from botulinum toxin injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. One case of other botulinum toxin injection corneal perforation in an aphakic eye requiring corneal grafting has occurred because of this effect. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.
Carcinogenesis, mutagenesis, impairment of fertility: Long term studies in animals have not been performed to evaluate carcinogenic potential of botumum toxin.
Use in Children: Safety and effectiveness in children and adolescents below the age of 18 have not been established.
Use In Pregnancy & Lactation
Safety in pregnant women and nursing mothers has not been established in this drug. Other botulinum toxin injection has been shown to produce abortions and effects at daily doses of 0.1-25 U/kg/day and at 2 U/kg and higher in rabbits; whereas in rats and mice, no abortions or effects were observed when up to 4 U/kg of botulinum toxin were injected. Doses of 8 and 16 U/kg in rats and mice have been shown to be associated with reduced fetal body weight and/or delayed ossification of the hyoid bone, which may be reversible. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Botulax inj. 100 units is administered to a nursing woman. Botulax inj. 100 units is contraindicated in pregnancy and lactation.
BOTULAX SIDE EFFECTS
There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin.
There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established.
The following events have been reported since the drug has been marketed and a causal relationship to the botulinum toxin injected is unknown: skin rash (including erythema multiforme, urticaria and psoriasiform eruption), pruritus, and allergic reaction.
In general, adverse events occur within the first week following injection of Botulinum Toxin Type A and while generally transient may have a duration of several months. Localized pain, tenderness, and/or bruising may be associated with the injection. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of adjacent muscles may also occur due to spread of toxin.
In cervical dystonia patients evaluated for safety in double-blind and open-label studies following injection of Botulinum Toxin Type A, the most frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).7
Other events reported in 2-10% of patients in any one study in decreasing order of incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported rarely.
Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of Botulinum Toxin Type A resulting from the spread of the toxin outside the injected muscles.
The most common severe adverse event associated with the use of Botulinum Toxin Type A injection in patients with cervical dystonia is dysphagia with about 20% of these cases also reporting dyspnea. Most dysphagia is reported as mild or moderate in severity. However, it may rarely be associated with more severe signs and symptoms.
Additionally, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection of 120 Units of Botulinum Toxin Type A for the treatment of cervical dystonia, and reports of dysphonia in patients who have been treated for cervical dystonia.
Primary Axillary Hyperhidrosis
The most frequently reported adverse events (3 – 10% of patients) following injection of Botulinum Toxin Type A in double-blind studies included injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety.
The data reflect 346 patients exposed to Botulinum Toxin Type A 50 Units and 110 patients exposed to Botulinum Toxin Type A 75 Units in each axilla.
Because clinical trials are conducted under widely varying conditions, adverse events observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not be predictive of rates observed in practice.
In a study of blepharospasm patients who received an average dose per eye of 33 Units (injected at 3 to 5 sites) of the currently manufactured Botulinum Toxin Type A, the most frequently reported treatmentrelated adverse reactions were ptosis (20.8%), superficial punctate keratitis (6.3%) and eye dryness (6.3%).8
In this study, the rate for ptosis in the current Botulinum Toxin Type A treated group (20.8% of patients) was significantly higher than the original Botulinum Toxin Type A treated group (4.0% of patients) (p=0.014%). All of these events were mild or moderate except for one case of ptosis which was rated severe.
Other events reported in prior clinical studies in decreasing order of incidence include: irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia and entropion, diffuse skin rash and local swelling of the eyelid skin lasting for several days following eyelid injection.
In two cases of VII nerve disorder (one case of an aphakic eye), reduced blinking from Botulinum Toxin Type A injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, and corneal ulceration. Perforation occurred in the aphakic eye and required corneal grafting.
A report of acute angle closure glaucoma one day after receiving an injection of botulinum toxin for blepharospasm was received, with recovery four months later after laser iridotomy and trabeculectomy. Focal facial paralysis, syncope and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm.
Extraocular muscles adjacent to the injection site can be affected, causing ptosis or vertical deviation, especially with higher doses of Botulinum Toxin Type A. The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus are 15.7% and 16.9%, respectively.4
Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision, or past-pointing. Covering the affected eye may alleviate these symptoms.
The incidence of ptosis was 0.9% after inferior rectus injection and 37.7% after superior rectus injection.
Ptosis (0.3%) and vertical deviation greater than two prism diopters (2.1%) were reported to persist for over six months in a larger series of 5587 injections of horizontal muscles in 3104 patients.
In these patients, the injection procedure itself caused nine scleral perforations. A vitreous hemorrhage occurred in one case and later cleared. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar hemorrhages occurred without visual loss. Decompression of the orbit after five minutes was done to restore retinal circulation in one case. Five eyes had pupillary change consistent with ciliary ganglion damage (Adie’s pupil).
One patient developed anterior segment ischemia after receiving Botulinum Toxin Type A injection into the medial rectus muscle under direct visualization for esotropia.
Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of Botulinum Toxin Type A treatment by inactivating the biological activity of the toxin. The rate of formation of neutralizing antibodies in patients receiving Botulinum Toxin Type A has not been well studied.
In the phase 3 cervical dystonia study1 that enrolled only patients with a history of receiving Botulinum Toxin Type A for multiple treatment sessions, at study entry there were 192 patients with antibody assay results, of whom 33 (17%) had a positive assay for neutralizing activity. There were 96 patients in the randomized period of the phase 3 study with valid assays at both study entry and end and who were neutralizing activity negative at entry. Of these 96, 2 patients (2%) converted to positive for neutralizing activity. Both of these converting patients were among the 52 who had received two Botulinum Toxin Type A treatments between the two assays; none were in the group randomized to placebo in the controlled comparison period of the study.
In the randomized period of the cervical dystonia study, patients in the Botulinum Toxin Type A group whose baseline assays were neutralizing antibody negative showed improvements on CDSS (n=64, mean CDSS change -2.1) while patients whose baseline assays were neutralizing antibody positive did not (n=14, mean CDSS change +1.1). However, in uncontrolled studies there are also individual patients who are perceived as continuing to respond to treatments despite the presence of neutralizing activity. Not all patients who become non-responsive to Botulinum Toxin Type A after an initial period of clinical response have demonstrable levels of neutralizing activity.
One patient among the 445 hyperhidrosis patients with analyzed specimens showed the presence of neutralizing antibodies.
The data reflect the patients whose test results were considered positive or negative for neutralizing activity to Botulinum Toxin Type A in a mouse protection assay. The results of these tests are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, concomitant medications and underlying disease. For these reasons, comparison of the incidence of neutralizing activity to Botulinum Toxin Type A with the incidence reported to other products may be misleading.
The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that Botulinum Toxin Type A injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.
The effect of other botulinum toxin may be potentiated by aminoglycoside antibiotics or other drugs that interfere with neuromuscular transmission e.g. tubocurarine-type muscle relaxants. Concomitant use of Botulax inj. 100 units with aminoglycosides or spectinomycin is contraindicated. Polymyxins, tetracyclines and lincomycin should be used with caution in the Botulax inj 100 units-treated patient.
The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.
Caution For Usage
Unopened vials of Botulax inj. 100 units should be stored under refrigeration (2-8°C). After reconstitution, Botulax inj. 100 units should be stored in a refrigerator (2-8°C) for up to 4 hours prior to use. For safe disposal, unused vials should be sterilized after melting it with a little amount of water. Equipment used with the drug (such as syringes) should also be sterilized.
The residual Botulax inj. 100 units should be inactivated using dilute hypochlorite solution (0.5%).
The unopened lyophilized vial should be stored in a refrigerator (2-8°C).
Patient Counseling Information
Botulax inj. 100 units may cause serious side effects that can be life threatening. Call the physician or get immediate medical help if the patient experiences any negative symptoms after the treatment with Botulax inj. 100 units. Problems of swallowing, speaking, breathing, or muscle weakness could happen hours to weeks after the injection of Botulax inj. 100 units.
Patients with blepharospasm may have been extremely sedentary for a long time. Such patients should be cautioned to resume activity slowly and carefully after the administration of Botulax inj. 100 units. Botulax inj. 100 units blocks neuromuscular transmission binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, Botulax inj. 100 units produces partial chemical denervation of the muscle resulting in a localized muscle activity reduction. In addition, the muscle may atrophy, axonal sprouting may occur, and extra junctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by Botulax inj. 100 units.
The paralysis activity of botulinum toxin is effective for the relief of excessive abnormal contraction associated with blepharospasm.
When injected into neck muscles, other botulinum toxin injection acts to provide relief from both objective signs and subjective symptoms of spasmodic torticollis (cervical dystonia). These improvements may include reduced pain/discomfort, reduced head rotation, reduced shoulder elevation, decreased size and strength of hypertrophic muscles.
The efficacy of another botulinum toxin product in deviations over 50 prism diopters, in restrictive strabismus, in Duane’s syndrome with lateral rectus weakness, and in secondary strabismus caused by prior surgical over-recession of the antagonist has not been established or repeated injections may be required for the treatment.
Botulinum toxin is ineffective in chronic paralytic strabismus and only surgical repair is effective to reduce antagonist contracture.
Presence of antibodies to botulinum toxin type A may reduce the effectiveness of botulinum toxin therapy. In clinical studies, reduction in effectiveness due to antibody production has occurred in one patient with blepharospasm receiving 3 doses of botulinum toxin over a 6 week period totaling 92 U, and in several patients with torticollis who received multiple doses experimentally, totaling over 300 U in a one month period. For this reason, the dose of Botulax inj. 100 units for blepharospasm should be kept in any case below 200 U in one month period.
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