BOTOX®
Allergan
Botulinum Toxin Type A
Neuromuscular Paralytic Agent
Action And Clinical Pharmacology: Botulinum toxin type A blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When injected i.m. at therapeutic doses, botulinum toxin type A produces a partial chemical denervation of the muscle resulting in localized muscle paralysis.
When chemically denervated, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus reversing muscle weakness produced by localized injection of botulinum toxin type A.
When injected into neck muscles, botulinum toxin type A reduces both objective signs and subjective symptoms of cervical dystonia (spasmodic torticollis). These improvements include reduced angle of head turning, reduced shoulder elevation, decreased size and strength of hypertrophic muscles, and decreased pain. Based on the results of well-controlled studies, 40 to 58% of patients with cervical dystonia would be expected to have a significant improvement in their symptoms.
The paralytic effect on muscles injected with botulinum toxin type A reduces the excessive, abnormal contractions of blepharospasm associated with dystonia.
When used for the treatment of strabismus, it has been postulated that the administration of botulinum toxin type A affects muscle pairs by inducing an atrophic lengthening of the injected muscle and a corresponding shortening of the antagonist muscle.
Following injection of botulinum toxin type A some distant muscles have shown increased electrophysiologic neuromuscular jitter. This effect is not associated with other types of electrophysiologic abnormalities, or with clinical signs of weakness or symptoms regarding either safety or efficacy.
Indications And Clinical Uses: To reduce the subjective symptoms and objective signs of cervical dystonia (spasmodic torticollis) in adults.
For the treatment of blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age or older.
For the treatment of strabismus in patients 12 years of age or older. Botulinum toxin type A is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair.
Contra-Indications: In the presence of infection at the proposed injection site(s). In individuals with known hypersensitivity to any ingredient in the formulation.
Manufacturers’ Warnings In Clinical States: The recommended dosages and frequencies of administration for botulinum toxin type A should not be exceeded.
The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or spectinomycin, or other drugs that interfere with neruromuscular transmission (e.g., tubocuraine-type muscle relaxants). Caution should be exercised when botulinum toxin type A is used with aminoglycosides (e.g., streptomycin, tobramycin, neomycin, gentamicin, netilmicin, kanamycin, amikacin), spectinomycin, polymyxins, tetracyclines, lincomycin or any other drugs that interfere with neuromuscular transmission. Caution should also be exercised when botulinum toxin type A is utilized for treatment of patients with myasthenia gravis, Eaton Lambert Syndrome, or other disorders that produce a depletion of acetylcholine.
Precautions: General: The safe and effective use of botulinum toxin type A depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering botulinum toxin type A should be familiar with the relevant 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 treatment of strabismus and may be useful for the treatment of cervical dystonia and blepharospasm.
As with all biologic products, an anaphylactic reaction may occur. Necessary precautions should be taken and epinephrine should be available.
Caution should be used when botulinum toxin type A is used in the presence of inflammation at the proposed injection site(s).
Cervical Dystonia (Spasmodic Torticollis): Botulinum toxin type A when injected for cervical dystonia may cause dysphagia ranging in severity from very mild to severe, with potential for aspiration, and in rare instances may require medical intervention (nasogastric tube feeding).
In one study, dysphagia appeared to be dose-related, occurring at frequencies of 8, 21 and 35% with mean dosages of 66, 129 and 253 U respectively. Dysphagia has been reported in clinical trials to occur less frequently with total doses below 200 U in one treatment session. Limiting the dose injected into the sternocleidomastoid to less than 100 U may decrease the occurrence of dysphagia. Patients with smaller neck muscle mass, or patients who require bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia. Dysphagia may be attributable to distribution of the pharmacological effect of botulinum toxin type A resulting from spread of the toxin in the vicinity of the injection site.
Blepharospasm: Reduced blinking from botulinum toxin type A when injected into the orbicularis oculi muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with VII nerve disorders. Careful testing of previously operated eyes for corneal sensation, 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.
Strabismus: The efficacy of botulinum toxin type A 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 is doubtful. In order to enhance efficacy, multiple injections over time may be required.
During the administration of botulinum toxin type A 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.
Drug Interactions: The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics, spectinomycin, or any other drugs that interfere with neuromuscular transmission. Caution should be exercised when botulinum toxin type A is used in patients taking any of these drugs (see Warnings).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies in animals have not been performed to evaluate the carcinogenic potential of botulinum toxin type A. Botulinum toxin type A was not mutagenic in in vitro and in vivo mutagenicity studies. A fertility and reproductive toxicity study following i.m. injection of botulinum toxin type A in rats indicated the ‘no observable effect level’ (NOEL) on reproduction was at dosages of 4 U/kg (approximately 2/3 of the maximum recommended human dose) in male rats and at dosages of 8 U/kg in female rats.
Pregnancy: Pregnancy Category C: Teratogenic Effects: The teratogenic effects of botulinum toxin type A were evaluated in mice, rats and rabbits. No teratogenic effects were observed when presumed pregnant mice were injected i.m. with doses of 4 U/kg (approximately 2/3 of the maximum recommended human dose) and 8 U/kg on days 5 and 13 of gestation; however, dosages of 16 U/kg induced a slightly lower fetal body weight. No teratogenic effects were observed in rats when injected i.m. with doses of 16 U/kg on days 6 and 13 of gestation, and 2 U/kg/day on days 6 through 15 of gestation. In rabbits, daily injections at dosages of 0.5 U/kg/day (days 6 through 18 of gestation) and 4 and 6 U/kg (days 6 and 13 of gestation) caused death and abortions among surviving animals. External malformations were observed in the fetus in one 0.125 U/kg/day and one 2 U/kg dosage. The rabbit appears to be a more sensitive species to botulinum toxin type A.
Reproductive and Developmental Effects: The reproductive and developmental effects of botulinum toxin type A were evaluated in rats at dose levels of 4, 8 and 16 U/kg. Muscle atrophy at the injected site, reduced body weight gains and reduced absolute feed consumption were observed following i.m. injection of botulinum toxin type A at dosages of 4 U/kg and higher on days 5 and 13 of presumed gestation, and day 7 of lactation. No effects on maternal reproductive performance were observed at the highest dose tested, 16 U/kg (approximately 3 times the maximum recommended human dose). No adverse effects on development of the pups was observed at 4 U/kg; however, higher dosages were associated with reduced pup body weight and/or pup viability at birth.
There are no adequate and well-controlled studies of botulinum toxin type A administration in pregnant women. Because animal reproduction studies are not always predictive of human response, botulinum toxin type A should be administered during pregnancy only if the potential benefit justifes the potential risk to the fetus.
Lactation: 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 botulinum toxin type A is administered to a nursing woman.
Children: Safety and effectiveness in children below the age of 12 years have not been established.
Information for the Patient: Patients with cervical dystonia (spasmodic torticollis) should be informed of the possibility of experiencing dysphagia which may persist for 2 to 3 weeks after injection, but has been reported in one case of lasting 5 months post-injection. Patients should also be advised of the potential for experiencing malaise lasting up to 6 weeks after injection with botulinum toxic type A. Patients who are sedentary should be cautioned to resume activity gradually following the administration of botulinum toxin type A.
As with any treatment with the potential to allow previously sedentary patients to resume activities, the sedentary patient should be cautioned to resume activity gradually following the administration of botulinum toxin type A.
Adverse Reactions: Cervical Dystonia: The safety of botulinum toxin type A used for the treatment of cervical dystonia was evaluated in 710 patients. The most frequently reported adverse reactions were dysphagia, pain, soreness and bruising at the injection site, local weakness, symptomatic general weakness, malaise and nausea.
Dysphagia may be attributable to spread of the botulinum toxin type A in the vicinity of the site of injection and into surrounding muscles. Local weakness represents the expected pharmacological action of botulinum toxin. In general, adverse reactions occur within the first few days following injection and last approximately 2 weeks.
Other adverse reactions during clinical trials which were reported rarely (1%) with botulinum toxin type A injection for cervical dystonia include drowsiness, numbness, stiffness, diplopia, ptosis, headache, dyspnea, fever, and flu syndrome. A female patient developed brachial plexopathy 2 days after injection of 120 units of botulinum toxin type A for cervical dystonia, with recovery after 5 months.
Blepharospasm: In clinical studies, there were reports of 7 cases of diffuse skin rash and 2 cases of local swelling of the eyelid skin lasting for several days following eyelid injection.
In clinical studies of 1 684 patients who received 4 258 treatments (involving multiple injections) for blepharospasm, reported incidence rates of adverse reactions per treated eye are as listed: ptosis 11%; irritation/tearing (includes dry eye, lagophthalmos, and photophobia) 10%; ectropion, keratitis, diplopia and entropion were reported rarely (incidence less than 1%).
Ecchymosis may occur and can be prevented by applying pressure at the injection site immediately after the injection.
In 2 cases of VII nerve disorder (1 case of an aphakic eye), reduced blinking from botulinum toxin type A when injected into the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, and corneal ulceration. Perforation requiring corneal grafting occurred in one case, an aphakic eye.
A patient suffered an attack of acute angle closure glaucoma one day after receiving an injection of botulinum toxin for blepharospasm, with recovery 4 months later after laser iridotomy and trabeculectomy.
Strabismus: Inducing paralysis in 1 or more extraocular muscles may produce spatial disorientation, double vision, or past-pointing. Covering the affected eye may alleviate these symptoms. 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 2 058 adults who received 3 650 injections for horizontal strabismus are: ptosis 15.7%; vertical deviation 16.9%.
The incidence of ptosis was 0.9% after inferior rectus injection and 37.7% after superior rectus injection.
The incidence rates of these adverse events persisting for over 6 months in a large series of 5 587 injections of horizontal muscles in 3 104 patients are: ptosis lasting over 180 days 0.3%; vertical deviation greater than 2 prism diopters lasting over 180 days 2.1%.
In these patients, the injection procedure itself caused nine scleral perforations. A vitreous hemorrhage occurred and later cleared in one case. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar hemorrhages occurred without visual loss. Decompression of the orbit after 5 minutes was done to restore retinal circulation in 1 case. Five eyes had pupillary change consistent with ciliary ganglion damage (Adies pupil).
A patient developed anterior segment ischemia after receiving botulinum toxin type A into the medial rectus muscle under direct visualization for esotropia.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdosage or injection error, additional information may be obtained by contacting Allergan, Inc. at (800) 433-8871.
No cases of systemic toxicity have been reported following accidental injection or oral ingestion of botulinum toxin type A. Should accidental injection or oral ingestion occur, the patient should be monitored for approximately 1 week for signs or symptoms of systemic weakness or muscle paralysis.
Dosage And Administration: General: For i.m. use only.
The use of 1 vial for more than 1 patient is not recommended because the product and diluent do not contain a preservative. Do not freeze reconstituted botulinum toxin type A. Once opened and reconstituted, use within 4 hours and discard remaining solution.
An injection of botulinum toxin type A is prepared by drawing into a sterile 1 mL tuberculin syringe an amount of the properly diluted toxin slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe may be attached to the electromyographic injection needle, preferably a 1.5 inch, 27 gauge needle. Injection volume in excess of the intended dose is expelled through the needle into an appropriate waste container to assure patency of the needle and to confirm that there is no syringe-needle leakage. A new sterile needle and syringe should be used to enter the vial on each occasion for dilution or removal of botulinum toxin type A.
Cervical Dystonia (Spasmodic Torticollis): Several dosing regimens have been used in clinical trials for treatment of cervical dystonia with botulinum toxin type A. Dosing must be tailored to the individual patient based on the patient’s head and neck position, localization of pain and muscle hypertrophy, patient’s body weight, and patient response. In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of diluted botulinum toxin type A ranged from 140 to 280 U. However, in clinical practice a range of 200 to 360 U have been used effectively. In general, a total dose of 6 U/kg every 2 months should not be exceeded for treatment of cervical dystonia.
A 25, 27 or 30 gauge needle may be used for superficial muscles, and a 22 gauge needle may be used for deeper musculature. For cervical dystonia, localization of the involved muscles with electromyographic guidance may be useful.
Multiple injection sites allow botulinum toxin type A to have more uniform contact with the innervation areas of the dystonic muscle, and are especially useful in larger muscles. The optimal number of injection sites is dependent upon the size of the muscle to be chemically denervated.
Clinical improvement generally occurs within the first 2 weeks after injection. The maximum clinical benefit generally occurs approximately 6 weeks postinjection. Repeat doses should be administered when the clinical effect of a previous injection diminishes, but not more frequently than every 2 months. The interval between injections reported in the clinical trials showed substantial variation (from 2 to 32 weeks), with a typical duration of approximately 12 to 16 weeks, depending on patient’s individual symptoms and responses.
This information is provided as guidance for the initial injection. The extent of muscle hypertrophy and the muscle groups involved in the dystonic posture may change with time necessitating alterations in the dose of toxin and muscles to be injected. The exact dosage and sites injected must be individualized for each patient.
Blepharospasm: For blepharospasm, diluted botulinum toxin type A is injected using a sterile, 27 to 30 gauge needle without electromyographic guidance. The initial recommended dose is 1.25 to 2.5 U (0.05 to 0.1 mL volume at each site) injected into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid.
In general, the initial effect of the injections is seen within 3 days and reaches a peak at 1 to 2 weeks post-treatment. Treatment effects last approximately 3 months, following which the procedure can be repeated indefinitely.
At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient (i.e., defined as an effect that lasts no longer than 2 months). However there appears to be little benefit obtainable from injecting more than 5 units per site. Some tolerance may be found when botulinum toxin type A is used in treating blepharospasm if treatments are given more frequently than every 3 months, and it is rare to have the effect be permanent.
The cumulative dose of botulinum toxin type A for treatment of blepharospasm in a 2-month period should not exceed 200 U.
Strabismus: Botulinum toxin type A is intended for injection into extraocular muscles utilizing the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure or electromyographic guidance should not be attempted. Physicians should be familiar with electromyographic techniques.
To prepare the eye for botulinum toxin type A injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection.
Note: The recommended volume of botulinum toxin type A injected for treatment of strabismus is 0.05 to 0.15 mL per muscle.
The initial listed doses of the diluted botulinum toxin type A typically create paralysis of injected muscles beginning 1 to 2 days after injection and increasing in intensity during the first week. The paralysis lasts for 2 to 6 weeks and gradually resolves over a similar time period. Overcorrections lasting over 6 months have been rare. About one-half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose, or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilize the alignment.
I. Initial doses in units (abbreviated as U). Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.
A. For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1.25 to 2.5 U in any one muscle.
B. For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2.5 to 5.0 U in any one muscle.
C. For persistent VI nerve palsy of 1 month or longer duration: 1.25 to 2.5 U in the medial rectus muscle.
II. Subsequent doses for residual or recurrent strabismus.
A. It is recommended that patients be re-examined 7 to 14 days after each injection to assess the effect of that dose.
B. Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
C. Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to 2-fold compared to the previously administered dose.
D. Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.
E. The maximum recommended dose as a single injection for any one muscle is 25 U.
Lack of Response: There are several explanations for a lack or diminished response to an individual treatment with botulinum toxin type A. These may include inadequate dose selection, selection of inappropriate muscles for injection, muscles inaccessible to injection, underlying structural abnormalities such as muscle contractures or bone disorders, change in pattern of muscle involvement, patient perception of benefit compared with initial results, inappropriate storage or reconstitution, as well as neutralizing antibodies to botulinum toxin. A neutralizing antibody is defined as an antibody that inactivates the biological activity of the toxin. However, the proportion of patients that lose their response to botulinum toxin therapy and have demonstrable levels of neutralizing antibodies is small.
The reported incidence of neutralizing antibody measured by the mouse bioassay in patients treated with botulinum toxin, is estimated to be less than 5%. However, there were patients who continued to respond to therapy and demonstrated presence of neutralizing antibodies. For example, many cervical dystonia patients were injected with botulinum toxin at 2- to 3-week intervals with doses exceeding 300 units in a 30-day period.
The critical factors for neutralizing antibody production are the frequency and dose of injection. To reduce the potential for neutralizing antibody formation, it is recommended that injection intervals should be no more frequent than 2 months. The dose should not exceed 360 U in any 2-month period.
A suggested course of action when patients do not respond to botulinum toxin type A injections is: 1) wait the usual treatment interval; 2) consider reasons for lack of response listed above; 3) more than 1 treatment course should be considered before classification of a patient as a nonresponder; 4) test patient serum for neutralizing antibody presence.
Reconstituted Solutions: To reconstitute vacuum-dried botulinum toxin type A, use 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 product is denatured by bubbling or similar violent agitation, inject the diluent into the vial gently. 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. It should be administered within 4 hours after reconstitution.
During this time period, reconstituted botulinum toxin type A should be stored in a refrigerator (2 to 8°C). Reconstituted botulinum toxin type A should be clear, colorless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit.
Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the botulinum toxin type A dose is also possible by administering a smaller or larger injection volume (i.e., 0.05 mL [50% decrease in dose] to 0.15 mL [50% increase in dose]).
Availability And Storage: Each vial contains: Clostridium botulinum toxin type A 100 units (U), albumin (human) 0.5 mg and sodium chloride 0.9 mg in a sterile, vacuum-dried form without a preservative. One unit (U) corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice using reconstituted botulinum toxin type A and injected intraperitoneally.
Store the vacuum-dried product in a freezer at or below -5°C. Administer within 4 hours after the vial is removed from the freezer and reconstituted. During these 4 hours, reconstituted botulinum toxin type A should be stored in a refrigerator (2 to 8°C). Reconstituted botulinum toxin type A should be clear, colorless and free of particulate matter.
All vials, including expired vials or equipment used with the drug should be disposed of carefully as is done with all medical waste.
BOTOX® Allergan Botulinum Toxin Type A Neuromuscular Paralytic Agent
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