BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex is a sterile, vacuum-dried form of purified botulinum toxin type A, produced from a culture of the Hall strain of Clostridium botulinum grown in a medium containing N-Z amine and yeast extract. It is purified from the culture solution by a series of acid precipitations to a crystalline complex consisting of the active high molecular weight toxin protein and an associated hemagglutinin protein. The crystalline complex is re-dissolved in a solution containing saline and albumin and sterile filtered (0.2 microns) prior to vacuum-drying. BOTOX® is to be reconstituted with sterile non-preserved saline prior to intramuscular injection.
Each vial of BOTOX® Purified Neurotoxin Complex contains 100 units (U) of Clostridium botulinum toxin type A, 0.5 milligrams of albumin (human), and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative. One unit (U) corresponds to the calculatedmedian lethal intraperitoneal dose (LD/50) in mice of thereconstituted BOTOX® injected
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, BOTOX® produces a localized chemical denervation muscle paralysis. When the muscle is chemically denervated, it atrophies and may develop extrajunctional acetylcholine receptors. There is evidence that the nerve can sprout and reinnervate the muscle, with the weakness thus being reversible.
The paralytic effect on muscles injected with BOTOX® Purified Neurotoxin Complex is useful in reducing the excessive, abnormal contractions associated with blepharospasm. When used for the treatment of strabismus, it is postulated that the administration of BOTOX® affects muscle pairs by inducing an atrophic lengthening of the injected muscle and a corresponding shortening of the muscle' antagonist. Following peri-ocular injection of BOTOX®, distant muscles show electrophysiologic changes but no clinical weakness or other clinical change for a period of several weeks or months, parallel to the duration of local clinical paralysis.
In one study, botulinum toxin was evaluated in 27 patients with essential blepharospasm. Twenty-six of the patients had previously undergone drug treatment utilizing benztropine mesylate, clonazepam and/or baclofen without adequate clinical results. Three of these patients then underwent muscle stripping surgery still without an adequate outcome. One patient of the 27 was previously untreated. Upon using botulinum toxin, 25 of the 27 patients reported improvement within 48 hours. One of the other patients was later controlled with a higher dosage. The remaining patient reported only mild improvement but remained functionally impaired.
In another study, 12 patients with blepharospasm were evaluated in a double-blind, placebo-controlled study. All patients receiving botulinum toxin (n=8) were improved compared with no improvements in the placebo group (n=4). The mean dystonia score improved by 72%, the self-assessment score rating improved by 61%, and a videotape evaluation rating improved by 39%. The effects of the treatment lasted a mean of 12.5 weeks.
One thousand six hundred eighty-four patients with blepharospasm evaluated in an open trial showed clinical improvement lasting an average of 12.5 weeks prior to the need for re-treatment.
Six hundred seventy-seven patients with strabismus treated with one or more injections of BOTOX® Purified Neurotoxin Complex were evaluated in an open trial. Fifty-five percent of these patients were improved to an alignment of 10 prism diopters or less when evaluated six months or more following injection. These results are consistent with results from additional open label trials which were conducted for this indication.
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex is indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.
The efficacy of BOTOX® Purified Neurotoxin Complex in deviations over 50 prism diopters, in restrictive strabismus, in Duane' syndrome with lateral rectus weakness, and in secondary strabismus caused by prior surgical over-recession of the antagonist is doubtful, or multiple injections over time may be required. BOTOX® is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair.
Presence of antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX® Purified Neurotoxin Complex therapy. In clinical studies, reduction in effectiveness due to antibody production has occurred in one patient with blepharospasm receiving three doses of BOTOX® over a six week period totalling 92 U, and in several patients with torticollis who received multiple doses experimentally, totalling over 300 U in a one-month period. For this reason, the dose of BOTOX® for strabismus and blepharospasm should be kept below 200 U in a one month period.
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex is contraindicated in individuals with known hypersensitivity to any ingredient in the formulation.
The recommended dosages and frequencies of administration for BOTOX® Purified Neurotoxin Complex should not be exceeded. There have not been any reported instances of systemic toxicity resulting from accidental injection or oral ingestion of BOTOX® . Should accidental injection or oral ingestion occur, the person should be medically supervised for several days on an office or outpatient basis for signs or symptoms of systemic weakness or muscle paralysis. The entire contents of a vial is below the estimated dose for systemic toxicity in humans weighing 6 kg. or greater.
In the event of overdosage or injection into the wrong muscle, additional information may be obtained by contacting Allergan, Inc. at (800) 433-8871 from 8:00 a.m. to 4:00 p.m. Pacific Time, or at (714) 246-5954 for a recorded message at other times.
The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or any other drugs that interfere with neuromuscular transmission. Caution should be exercised when BOTOX® Purified Neurotoxin Complex is used in patients taking any of these drugs. This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
General: The safe and effective use of BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering BOTOX® must understand the relevant neuromuscular and orbital anatomy and any alterations to the anatomy due to prior surgical procedures, and standard electromyographic techniques.
As with all biologic products, epinephrine and other precautions as necessary should be available should an anaphylactic reaction occur.
During the administration of BOTOX® Purified Neurotoxin Complex 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.
Reduced blinking from BOTOX® Purified Neurotoxin Complex 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 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.
Information for Patients: Patients with blepharospasm may have been extremely sedentary for a long time. Sedentary patients should be cautioned to resume activity slowly and carefully following the administration of BOTOX® Purified Neurotoxin Complex.
Drug Interactions: The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or any other drugs that interfere with neuromuscular transmission. Caution should be exercised when BOTOX® Purified Neurotoxin Complex is used in patients taking any of these drugs. (See ).
Pregnancy: Pregnancy Category C: Animal reproduction studies have not been conducted with BOTOX® Purified Neurotoxin Complex. It is also not known whether BOTOX® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BOTOX® should be administered to pregnant women only if clearly needed.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term studies in animals have not been performed to evaluate carcinogenic potential of BOTOX® Purified Neurotoxin Complex.
Nursing Mothers: 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 BOTOX® Purified Neurotoxin Complex is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.
There have been reports of seven cases of diffuse skin rash and two cases of local swelling of the eyelid skin lasting for several days following eyelid injection.
Strabismus: 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. Extraocular muscles adjacent to the injection site are often affected, causing ptosis or vertical deviation, especially with higher doses of BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex. The incidence rates of these side effects in 2058 adults who received 3650 injections for horizontal strabismus are listed below:
Ptosis 15.7%
Vertical deviation 16.9%
The incidence of ptosis was much less after inferior rectus injection (0.9%) and much greater after superior rectus injection (37.7%).
The incidence rates of these side effects persisting for over six months in an enlarged series of 5587 injections of horizontal muscles in 3104 patients are listed below:
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. Decompression of the orbit after five minutes was done to restore retinal circulation in one case. No eye lost vision from retrobulbar hemorrhage. Five eyes had pupillary change consistent with ciliary ganglion damage (Adies pupil).
Blepharospasm: In 1684 patients who received 4258 treatments (involving multiple injections) for blepharospasm, the incidence rates of adverse reactions per treated eye are listed below:
Ptosis 11.0%
Irritation/Tearing 10.0%
(includes dry eye, lagophthalmos, and photophobia)
Ectropion, keratitis, diplopia and entropion were reported rarely (incidence less than 1%)
Ecchymosis occurs easily in the soft eyelid tissues. This can be prevented by applying pressure at the injection site immediately after the injection.
In two cases of VII nerve disorder (one case of an aphakic eye) reduced blinking from BOTOX® Purified Neurotoxin Complex injection of 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. Avoidance of injection into the lower lid area to avoid ectropion may reduce this hazard. Vigorous treatment of any corneal 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.
Two patients previously incapacitated by blepharospasm experienced cardiac collapse attributed to over-exertion within three weeks following BOTOX® Purified Neurotoxin Complex therapy. Sedentary patients should be cautioned to resume activity slowly and carefully following the administration of BOTOX® .
In the event of overdosage or injection into the wrong muscle, additional information may be obtained by contacting Allergan, Inc. at (800) 433-8871 from 8:00 a.m. to 4:00 p.m. Pacific Time, or at (714) 246-5954 for a recorded message at other times.
Strabismus: BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 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 technique.
An injection of BOTOX® Purified Neurotoxin Complex is prepared by drawing into a sterile 1.0 mL tuberculin syringe an amount of the properly diluted toxin (see Dilution Table ) slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is 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 BOTOX® .
To prepare the eye for BOTOX® Purified Neurotoxin Complex injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection.
Note: The volume of BOTOX® Purified Neurotoxin Complex injected for treatment of strabismus should be between 0.05 mL to 0.15 mL per muscle.
Strabismus dosage: The initial listed doses of the diluted BOTOX® Purified Neurotoxin Complex (see Dilution Table below) typically create paralysis of injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2-6 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.
Blepharospasm: For blepharospasm, diluted BOTOX® Purified Neurotoxin Complex (see Dilution Table ) is injected using a sterile, 27-30 gauge needle without electromyographic guidance. 1.25 U to 2.5 U (0.05 mL to 0.1 mL volume at each site) injected into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid is the initial recommended dose. 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 indefinitely. 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 BOTOX® is used in treating blepharospasm if treatments are given any more frequently than every three months, and it is rare to have the effect be permanent.
The cumulative dose of BOTOX® Purified Neurotoxin Complex in a 30-day period should not exceed 200 U.
To reconstitute vacuum-dried BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex, 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 BOTOX® 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. BOTOX® should be administered within 4 hours after reconstitution.
During this time period, reconstituted BOTOX® Purified Neurotoxin Complex should be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX® 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. The use of one vial for more than one patient is not recommended because the product and diluent do not contain a preservative.
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Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the BOTOX® Purified Neurotoxin Complex 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).
Each vial contains 100 U of vacuum-dried Clostridium botulinum toxin type A. NDC 0023-1145-01.
Rx only
Store the vacuum-dried product in a freezer at or below -5°C. Administer BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex within four hours after the vial is removed from the freezer and reconstituted. During these four hours, reconstituted BOTOX® should be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX® 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.
September 1999