Botox

Botox

Manufacturer:

Allergan

Distributor:

DKSH
Full Prescribing Info
Contents
Clostridium botulinum toxin type A.
Description
Each vial of BOTOX 100 Units contains 100 Units of Clostridium botulinum type A neurotoxin complex 900kD, 0.5 mg of human albumin and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.
A sterile white vacuum dried powder in a clear glass vial, for use in a single patient. One unit corresponds to the median lethal dose (LD50) when reconstituted BOTOX is injected intraperitoneally into mice under defined conditions.
Action
Pharmacology: BOTOX blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering the nerve terminal and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, BOTOX produces a localised muscular paralysis by means of chemodenervation. When the muscle is chemically denervated, it atrophies and may develop extrajunctional acetylcholine receptors. There is evidence that the nerve can sprout and re-innervate the muscle, with the weakness thus being reversible.
BOTOX's ability to reduce muscle activity is useful in reducing the excessive, abnormal contractions associated with blepharospasm. When injected into neck muscles, BOTOX provides relief from both objective signs and subjective symptoms of spasmodic torticollis (cervical dystonia) resulting in reduced angle of head turning, reduced shoulder elevation, decreased size and strength of hypertrophic muscles and decreased pain.
Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. In sensory neurons, BOTOX inhibits the release of sensory neurotransmitters (e.g., Substance P, CGRP) and downregulates the expression of cell surface receptors (e.g., TRPV1). BOTOX also prevents and reverses sensitization in nociceptive sensory neurons.198
Pharmacokinetics: General characteristics of the active substance: Distribution studies in rats indicate minimal muscular diffusion of 125l-botulinum neurotoxin A complex in the gastrocnemius muscle after injection, followed by rapid systemic metabolism and urinary excretion. The amount of radiolabeled material in the muscle declined at a half-life of approximately 10 hours. At the injection site the radioactive material was mainly in the form of large macromolecules, whereas very little of the radioactivity reaching the systemic circulation was TCA-precipitable, suggesting a minimal systemic exposure of toxin following gastrocnemius muscle injection of 125I-botulinum neurotoxin A complex. Within 24 hours of dosing, 60% of the radioactivity was excreted in the urine. The toxin is probably metabolised by proteases and the molecular components cycled through normal metabolic pathways.
Classical absorption, distribution, biotransformation and elimination studies on the active substance have not been performed due to the nature of this product.
Characteristics in patients: It is believed that little systemic distribution of therapeutic doses of BOTOX occurs. BOTOX is not expected to be presented in the peripheral blood at measurable levels following IM or intradermal injection at the recommended doses. The recommended quantities of neurotoxin administered at each treatment session are not expected to result in systemic, overt distant clinical effects, i.e. muscle weakness, in patients without other neuromuscular dysfunction. However, clinical studies using single fibre electromyographic techniques have shown subtle electrophysiologic findings consistent with neuromuscular inhibition (i.e. "jitter") in muscles distant to the injection site, but these were unaccompanied by any clinical signs or symptoms of neuromuscular inhibition from the effects of botulinum toxin.
Indications/Uses
BOTOX (botullinum toxin type A) purified neurotoxin complex is indicated for the following therapeutic indications: BOTOX is indicated for the treatment of bleopharospasm associated with dystonia, including benign essential blepharospasm, hemifacial spasm and VIIth nerve disorders in patients 12 years or older.
BOTOX is indicated for the correction of strabismus in patients 12 years of age or older.
BOTOX is indicated for the treatment of spasmodic torticollis (cervical dystonia) in adults.
BOTOX is indicated for the treatment of dynamic equinus foot deformity due to spasticity in paediatric cerebral palsy patients, two years of age and older.
BOTOX is indicated in the management of focal spasticity: including wrist and hand disability due to upper limb spasticity associated with stroke in adults.
Including ankle and foot disability due to lower lim spasticity associated with stroke in adults.
BOTOX is indicated for the management of severe hyperhidrosis of the axillae which does not respond to tropical treatment with antiperspirant or antihidrotics.
BOTOX is indicated for the prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine).
BOTOX is indicated for the treatment of urinary incontinence due to neurogenic detrusor overactivity (NDO) associated with Multiple Sclerosis or Spinal Cord Injury in adults who had an inadequate response to or are intolerant of an anticholinergic medication.
BOTOX is indicated for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and frequency, in adult patients who have an inadequate response to or are intolerant of an anticholinergic medication.
BOTOX (botulinum toxin type A) purified neurotoxin complex is indicated for the following cosmetic indications: BOTOX is indicated for the temporary improvement in the appearance of upper facial rhytides (glabellar lines, crow's feet and forehead lines) in adults.
BOTOX is indicated for the temporary treatment of glabellar lines associated with corrugator and/or procerus muscle activity in adult patients below 65 years of age.
Dosage/Direction for Use
General: The use of one vial for more than one patient is not recommended because the product and diluent do not contain a preservative. Once opened and reconstituted, store in a refrigerator and use within twenty-four hours. Discard any remaining solution. Do not freeze reconstituted BOTOX.
Reconstituted BOTOX is injected with the purpose of reaching the motor endplate region of the muscle to be treated.
BOTOX should only be given by physicians with the appropriate qualifications and experience in the treatment of patients and the use of required equipment. The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and injection into vulnerable anatomic structures must be avoided.
Route of administration: Intramuscular injection. May be subcutaneous injection for blepharospasm. Intradermal for primary hyperhidrosis of axillae. Intradetrusor use of bladder dysfunction only.
Reconstitution of vial: Dilution Technique: Prior to injection, reconstitute vacuum-dried BOTOX with sterile normal saline without a preservative; 0.9% Sodium Chloride is the recommended diluent.
It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage. Remove the flip-off plastic seal from the BOTOX vial. An appropriate amount of diluent (see dilution table as follows, or for specific instructions for intradetrusor injections for neurogenic detrusor activity, see Neurogenic Detrusor Overactivity as follows) is drawn up into a syringe. The exposed portion of the rubber septum of the vials is cleaned with alcohol (70%) prior to insertion of the needle. Draw up the proper amount of diluent in the appropriate size syringe, and slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix BOTOX with the saline by rotating the vial. Record the date and time of reconstitution on the space on the label. BOTOX should be administered within twenty-four hours after reconstitution.
During this time period, reconstituted BOTOX should be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX should be clear, colourless 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. (See Table 1.)

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A decrease or increase in the BOTOX dose is possible by administering a smaller or larger injection volume.
The "unit" by which the potency of preparations of BOTOX is measured should be used to calculate dosages of BOTOX only and is not transferable to other preparations of botulinum toxin.
Doses recommended for BOTOX are not interchangeable with other preparations of botulinum toxin.
Lack of Response: There are several potential explanations for a diminished or absent response to an individual treatment with BOTOX. 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; neutralising antibodies to botulinum toxin.
A neutralising antibody is defined as an antibody that inactivates the biological activity of the toxin. In general, the proportion of patients who lose their response to botulinum toxin therapy and have demonstrable levels of neutralising antibodies is less than 5%, though in a long-term juvenile cerebral palsy study, of 117 patients treated with BOTOX, antibodies were detected in 33/117 (28%) at either 27 or 39 months. Thirty-one of these 33 had been responders, 19/31 (6%) continued to respond, with 7/31 (2%) becoming non-responders, and no data available for 5/31.
The critical factors for neutralising antibody production are the frequency and dose of injection. Tolerance may be observed in some patients treated more frequently than every three months. The potential for neutralising antibody formation may be minimised by injecting with the lowest effective dose given at the longest feasible intervals between injections (injection intervals should typically be no more frequent than three months). The dose should not exceed 360 U in any two month period for adult spasticity patients and patients with cervical dystonia. The total dose of BOTOX in any three month period should not exceed 8 U/kg or 300 U (whichever is the lesser amount) when used in children for the treatment of equinus foot deformity. When patients do not respond to BOTOX injections a suggested course of action is: wait the usual treatment interval; consider reasons for lack of response listed previously; test the patient's serum for neutralising antibody presence. More than one ineffective treatment course should occur before classification of a patient as a non-responder, because there are patients who continue to respond to therapy despite the presence of neutralising antibodies.
Blepharospasm: For blepharospasm, reconstituted BOTOX (see Table 1) is injected using a sterile, 27 - 30 gauge needle with or without electromyographic guidance. The initial recommended dose is 1.25 - 2.5 U in (0.05 - 0.1 mL volume at each site) injected into the medial and lateral orbicularis oculi of the upper lid and into the lateral orbicularis oculi of the lower lid.
Injection placement may vary based on the patient's presentation. Avoiding injection near the levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. Ecchymosis occurs easily in the soft eyelid tissues. This can be prevented by applying pressure at the injection site immediately after the injection. The hazard of ectropion may be reduced by avoiding injection into the lower lid area.
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. The initial dose should not exceed 25 U per eye. Normally no additional benefit is conferred by treating more frequently than every three months. It is rare for the effect to be permanent.
In the management of blepharospasm total dosing should not exceed 100 U every 12 weeks.
Hemifacial Spasm: Patients with hemifacial spasm or VIIth nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles each being injected as needed. Further injections may be necessary into the corrugator, zygomaticus major, orbicularis oris and/or other facial muscles according to the extent of the spasm. Electromyographic control may be necessary to identify affected small circumoral muscles.
The cumulative dose of BOTOX for the treatment of hemifacial spasm in a 2 month period should not exceed 200 U.
Strabismus: BOTOX 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.
BOTOX is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair. The efficacy of BOTOX 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.
To prepare the eye for BOTOX injection, it is recommended that several drops of a local anaesthetic and an ocular decongestant be given several minutes prior to injection. Note: The recommended volume of BOTOX injected for treatment of strabismus is 0.05 mL to 0.15 mL per muscle.
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: For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1.25 U to 2.5 U in any one muscle.
For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2.5 U to 5.0 U in any one muscle.
For persistent VIIth nerve palsy of one month or longer duration: 1.25 U to 2.5 U in the medial rectus muscle.
Subsequent doses for residual or recurrent strabismus: It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose.
Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to two-fold compared to the previously administered dose.
Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidence by substantial function in the injected and adjacent muscles.
The maximum recommended dose as a single injection for any one muscle is 25 U.
The initial listed doses of the reconstituted BOTOX (see Table 1) 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 to 6 weeks and gradually resolves over a similar time period. Over-corrections lasting over six 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 stabilise the alignment.
Spasmodic Torticollis (Cervical Dystonia): Dosing must be tailored to the individual patient based on the patient's head and neck position, localization of pain, muscle hypertrophy, patient's bodyweight, and patient response. 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, localisation of the involved muscles with electromyographic guidance may be useful.
In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of reconstituted BOTOX ranged from 140 to 280 U. In more recent studies, the doses have ranged from 95 to 360 U (with an approximate mean of 240 U). As with any drug treatment, initial dosing in a naive patient should begin at the lowest effective dose.
The treatment of cervical dystonia typically may include, but is not limited to, injection of BOTOX into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, and/or the trapezius muscle(s). In general, a total dose of 6 U/kg every two months should not be exceeded for treatment of cervical dystonia.
Diluted BOTOX is injected using an appropriately sized needle (usually 25, 27 or 30 gauge). The table as follows is intended to give dosing guidelines for injection of BOTOX in the treatment of cervical dystonia: (see Table 2).

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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 individualised for each patient.
In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance. No more than 50 U should be given at any one site. Limiting the dose injected into the sternocleidomastoid muscle to less than 100 U may decrease the occurence of dysphagia. (see Precautions.) To minimise the incidence of dysphagia, the sternocleidomastoid should not be injected bilaterally. The concentrations of reconstituted material needed are 5 U/ 0.1ml and 10 U/0.1ml to allow reasonable injection volumes.
The tables as follows shows the median dose of BOTOX injected per muscle in a clinical study in which dose was determined by the practitioner based on the presentation of the individual cervical dystonia patient. (See Table 3.)

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Multiple injection sites allow BOTOX 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 two weeks after injection. The maximum clinical benefit generally occurs approximately six weeks post-injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes. The duration of therapeutic effect 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 the patient's individual disease and response. "Booster" injections are not recommended. Dosing intervals should not be more often than every two months.
Paediatric Cerebral Palsy: For the treatment of equinus due to spasticity in paediatric cerebral palsy, diluted BOTOX is injected using a sterile 23-26 gauge needle. In clinical trials, doses of 4 U/kg were administered by injecting BOTOX into each of two sites in the medial and lateral heads of the gastrocnemius muscle of the affected lower limb(s).
Following initial injection to the gastrocnemius muscle, further involvement of the anterior or posterior tibialis may need to be considered for additional improvement in the foot position at heel strike and during standing.
Clinical gait improvement generally begins within the first two weeks after injection, with further improvement over the next several weeks. Repeat doses should be administered when the clinical effect of a previous injection diminishes but not more frequently than every two months. The average duration of the therapeutic effect reported in an open-label clinical trial of 207 patients was 3.1 to 3.6 months. In this study, the dose was 4 U/kg, up to a maximum of 200 U at any single treatment session.
Focal Spasticity in Adults: The exact dosage and number of injection sites should be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, presence of local muscle weakness, and the patient response to previous treatment.
The recommended dilution is 200 Units/4mL or 100 Units/2mL with preservative-free 0.9% Sodium Chloride injection (see Table 1). A 25, 27 or 30 gauge needle may be used for superficial muscles, and a 22-gauge needle may be used for deeper musculature. Localisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful.
Multiple injection sites allow BOTOX to have more uniform contact with the innervation areas of the muscle and are especially useful in larger muscles.
If it is deemed appropriate by the treating physician, repeat BOTOX treatment may be administered when the effect of a previous injection has diminished, but generally no sooner than 12 weeks after the previous injection. The degree of muscle spasticity at the time of reinjection may necessitate alterations in the dose of BOTOX and muscles to be injected.
In clinical trials, the doses did not exceed 360 U divided among selected muscles (typically in the flexor muscles of the elbow, wrist and fingers) at any treatment session. Clinical improvement in muscle tone generally occurs within two weeks following treatment with the peak effect seen four to six weeks following treatment. In clinical studies, patients were injected at 12 to 16 week intervals. The degree of muscle spasticity at the time of reinjection may necessitate alterations in the dose of BOTOX and muscles to be injected.
Upper Limb Spasticity: In clinical trials, the doses did not exceed 360 U divided among selected muscles (typically in the flexor muscles of the elbow, wrist and fingers) at any treatment session. Clinical improvement in muscle tone generally occurs within two weeks following treatment with the peak effect seen four to six weeks following treatment. In clinical studies, patients were reinjected at 12 to 16 week intervals.
The table as follows is intended to give dosing guidelines for injection of BOTOX in the treatment of upper limb spasticity associated with stroke. (See Table 4.)

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Lower Limb Spasticity: The recommended dose for treating lower limb spasticity involving the ankle and foot is 300 Units to 400 Units divided among up to 6 muscles (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus, flexor digitorum longus and flexor digitorum brevis) (see Table 5 below).

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Upper Facial Lines (Glabellar Lines, Crow's Feet and Forehead Lines): As optimum dose levels and number of injection sites per muscle may vary among patients, individual dosing regimens should be drawn up. The recommended injection volume per injection site is 0.1 mL.
Glabellar Lines: BOTOX is reconstituted with 0.9% sterile non-preserved saline (100 U in 2.5 mL or injected as 4 U/0.1 mL) and 0.1 mL is administered using a 30 gauge needle in each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose 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. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.
In controlled clinical trials, improvement of severity of glabellar lines generally occurred within one week after treatment and the effect was demonstrated for up to 4 months. Typically the initial doses of reconstituted BOTOX induce chemical denervation of the injected muscles one to two days after injection, increasing in intensity during the first week.
Injection intervals should be no more frequent than every 3 months and should be performed using the lowest effective dose.
Treatment with BOTOX for cosmetic purposes may result in the formation of antibodies that may reduce the effectiveness of subsequent treatments with BOTOX for glabellar lines or for other indications.
Crow's Feet: BOTOX should be injected bilaterally at 3 sites in the lateral aspect of the orbicularis oculi (i.e. total of 6 injections), where most lines are seen when a smile is forced. In general, 2-6 U is recommended per injection site at a 2-3 mm depth, for a total dose of 6-18 U per side.
Injections should be at least 1 cm outside the bony orbit, not medial to the vertical line through the lateral canthus and not close to the inferior margin of the zygoma.
Crow's feet are well established, deep, radiating, horizontal and oblique furrows at the temporal aspect of each eye and are the direct result of the contraction of the lateral fibres of the orbicularis oculi muscles. In controlled clinical trials, injections of BOTOX into the lateral orbital area resulted in rapid onset of action (effect of BOTOX was apparent at the first assessment timepoint of 7 days) and reduced the severity of wrinkling in this are for up to 17 weeks.
Forehead Lines: BOTOX should be injected intramuscularly at each of 4 injection sites in the frontalis muscle. In general, 2-6 U is recommended per injection site every 1-2 cm along either side of a deep forehead crease, for a total dose of 8-24 U.
Injections should be at least 2-3 cm above the eyebrow to reduce the risk of brow ptosis.
Horizontal forehead lines are associated with chronic functional activity of the frontalis muscle. At two weeks post-injection, 84-95% of BOTOX - treated patients were considered by investigators as treatment responders; 75-80% of patients felt they had improvement (16 or 24 U at four sites in the frontalis muscle). Higher doses of BOTOX resulted in greater efficacy and longer duration of effect. Injections of BOTOX reduced the severity of horizontal forehead lines for up to 24 weeks as determined by a trained observer.
Hyperhidrosis of The Axilla: The hyperhidrotic area to be injected may be defined using standard staining techniques, e.g. Minor's iodine-starch test. BOTOX is reconstituted with 0.9% non-preserved sterile saline (100 U/4.0 mL). Using a 30 gauge needle, 50 U of BOTOX (2.0 mL) is injected intradermally, to each axilla evenly distributed in multiple sites approximately 1-2 cm apart.
At week 1 BOTOX treated patients demonstrated 95% treatment responder rate based on gravimetric assessment. At 16 weeks 82% of BOTOX treated patients were responding to treatment. Approximately 40% of patients received only 1 treatment with BOTOX and had duration of effect for over 1 year (median time 68 weeks). When patients received at least 2 consecutive treatments with BOTOX the mean time to re-treatment following their first treatment was 33 weeks (range 15 to 51 weeks). Repeat injections for axillary hyperhidrosis should be administered when effects from previous injections subside but usually not more frequently than every two months.
Chronic Migraine: The recommended dilution is 100 U/2mL, with a final concentration of 5 U per 0.1 mL. The recommended dose for treating chronic migraine is 155 U to 195 U administered intramuscularly (IM) using a sterile 30-gauge, 0.5 inch needle as 0.1 ml (5 U) injections per each site. Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams and table as follows. A 1 inch needle may be needed in the neck region for patients with thick neck muscles. With the exception of the procerus muscle, which should be injected at 1 site (midline), all muscles should be injected bilaterally with the minimum dose per muscle as indicated as follows, with half the number of injection sites administered to the left, and half to the right side of the head and neck. The recommended re-treatment schedule is every 12 weeks. If there is a predominant pain location(s), additional injections to one or both sides may be administered in up to 3 specific muscle groups (occipitalis, temporalis, and trapezius), up to the maximum dose per muscle as indicated in the table as follows. (See Table 6).

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Bladder Dysfunction (Neurogenic Detrusor Overactivity and Overactive Bladder): Patients should not have a urinary tract infection prior to treatment. Prophylactic antibiotics should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post treatment.
It is generally recommended that patients discontinue anti-platelet therapy at least three days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding.
Neurogenic Detrusor Overactivity: An intravesical instillation of diluted local anaesthetic with or without sedation, or general anaesthesia may be used prior to injection, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is 200 U of BOTOX.
Reconstitute two 100 Unit vials of BOTOX, each with 6 mL of 0.9% non-preserved saline solution and mix the vials gently. Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe. Complete the reconstitution by adding 6 mL of 0.9% non-preserved saline solution into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 U in each), for a total of 200 U of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.
Reconstitute a 200 Unit vial of BOTOX with 6 mL of 0.9% non-preserved saline solution and mix the vials gently. Draw 2 mL from the vial into each of three 10 mL syringes. Complete the reconstitution by adding 8 mL of 0.9% non-preserved saline solution into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 U in each), for a total of 200 U of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.
Reconstituted BOTOX (200 U/30 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL prior to the start of injections (depending on the needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1mL each (total volume of 30 mL) should be spaced approximately 1 cm apart. For the final injection, approximately 1 mL of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post-injection.
Clinical improvement may occur within 2 weeks. Patients should be considered for reinjection when the clinical effect of the previous injection diminished (median duration in phase 3 clinical studies was 256-295 days (36-42 weeks) for BOTOX 200 U), but no sooner than 3 months from the prior bladder injection. Based on patients who received treatments with only BOTOX 200 Units from the pivotal studies through the open label extension study (N=174), the overall median duration of response was 253 days (~36 weeks).
In the pivotal studies (300 Units and 200 units), none of the 475 neurogenic detrusor overactivity patients with analysed specimens developed the presence of neutralizing antibodies. In patients with analysed specimens in the drug development program (including the open-label extension study), neutralizing antibodies developed in 3 of 300 patients (1.0%) after receiving only Botox 200 unit doses and 5 of 258 patients (1.9%) after receiving at least one 300 Unit dose. Four of these eight patients continued to experience clinical benefit.
Overactive Bladder: An intravesical instillation of diluted local anaesthetic with or without sedation may be used prior to injection, per local site practice. If a local anaesthetic installation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is 100 U of BOTOX. The recommended dilution is 100 U/10 mL with 0.9% non-preserved saline solution (see Table 1). Dispose of any unused saline.
Reconstituted BOTOX (100 U/10 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart. For the final injection, approximately 1 mL of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualization should not be drained so that patients can demonstrate their ability to void prior to leaving the clinic. The patient should be observed for at least 30 minutes post-injection and until a spontaneous void has occurred.
Clinical improvement may occur within 2 weeks. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median duration in phase 3 clinical studies was 166 days [~24 weeks]), but no sooner than 3 months from the prior bladder injection. Based on patients who received treatments with only BOTOX 100 Units from the pivotal studies through the open label extension study (N=438), the overall median duration of response was ~212 days (~30 weeks).
In the pivotal studies, none of the 615 (0%) patients with analysed specimens developed the presence of serum neutralizing antibodies to Botox. In patients with patients with analyzed specimens from the pivotal phase 3 and the open-label extension studies, neutralizing antibodies developed in 0 of 954 patients (0.0%) while receiving Botox 100 Unit doses and 3 of 260 patients (1.2%) after subsequently receiving at least one 150 Unit dose. One of these three patients continued to experience clinical benefit.
Overdosage
Patients with botulism may present with symptoms of ptosis, diplopia, dysphagia, dysarthria, swallowing and speech disorders, cranial nerve findings, generalised weakness or paresis of the respiratory muscles. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalisation. If the musculature of the oropharynx and oesophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralysed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care.
Overdose of BOTOX is a relative term and depends upon dose, site of injection and underlying tissue properties. Signs and symptoms of overdose are likely not to be apparent immediately post-injection. Excessive doses may produce local, or distant, generalised and profound neuromuscular paralysis. Local weakness is usually well tolerated and resolves spontaneously without intervention. However, dysphagia may result in loss of airway protection and aspiration pneumonia. Patients or caregivers should be advised to seek immediate medical consultation if swallowing, speech or respiratory disorders arise.
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 or overdose be suspected, the patients should be medically supervised for up to several weeks for progressive signs or symptoms of systemic muscular weakness which could be local or distant from the site of injection which may include ptosis, diplopia, dysphagia, dysarthria, generalized weakness or respiratory failure. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization.
The entire contents of a vial is below the estimated dose (from primate studies) for toxicity in humans weighing 6kg or greater.
Contraindications
BOTOX is contra-indicated, in individuals with a known hypersensitivity to botulinum toxin type A or any constituent of the formulation; in patients with myasthenia gravis or Lambert-Eaton Syndrome.
BOTOX is contraindicated in the presence of infection at the proposed injection site(s). The recommended dosages and frequencies of administration of BOTOX should not be exceeded.
BOTOX for treatment of bladder dysfunction is also contraindicated: in patients who have a urinary tract infection;
in patients with acute urinary retention who are not routinely performing clean intermittent self-catheterisation (CIC);
in patients who are not willing and/or able to initiate catheterisation post-treatment if required.
Warnings
Distant Spread of Toxin Effect: Postmarketing safety data from BOTOX and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms that are consistent with the mechanism of action of botulinum toxin have been reported hours to weeks after injection, and may include muscular weakness, ptosis, diplopia, blurred vision, facial weakness, swallowing and speech disorders, constipation, aspiration pneumonia, difficulty breathing and respiratory depression. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in patients who have underlying conditions and comorbidities that would predispose them to these symptoms including adults treated for spasticity and other conditions, and are treated with high doses. Swallowing and breathing difficulties can be life threatening and death has been reported, although a definitive causal association to BOTOX has not been established.
The term "unit" upon which dosing is based, is a specific measurement of toxin activity that is unique to Allergan's formulation of botulinum toxin type A. Therefore, the "units" used to describe BOTOX activity are different from those used to describe that of other botulinum toxin preparations and the units representing BOTOX activity are not interchangeable with other products.
BOTOX should only be given by physicians with the appropriate qualifications and experience in the treatment of patients and the use of required equipment. The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and injection into vulnerable anatomic structures must be avoided.
Special Precautions
General: The safe and effective use of BOTOX depends upon proper storage of the product, selection of the correct dose and proper reconstitution and administration techniques. The relevant anatomy and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and care should be taken when injecting in or near vulnerable anatomic structures. Serious adverse events including fatal outcomes have been reported in patients who had received BOTOX injected directly into salivary glands, the oro-lingual-pharyngeal region, oesophagus and stomach. Some patients had pre-existing dysphagia or significant debility. Pneumothorax associated with injection procedure has been reported following the administration of BOTOX near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices.
An understanding of standard electromyographic techniques is also required for treatment of strabismus and may be useful for the treatment of cervical dystonia and hemifacial spasm and for the treatment of focal spasticity associated with stroke or paediatric cerebral palsy.
Caution should be used when BOTOX is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle(s).
Caution should also be exercised when BOTOX is utilised for treatment of patients with amyotrophic lateral sclerosis, or disorders that produce peripheral neuromuscular dysfunction.
No cases of systemic toxicity have been reported following accidental injection or oral ingestion of BOTOX. Signs of overdose are not apparent immediately post injection. Should accidental or oral ingestion occur, the patient should be medically supervised for several days on an office or outpatient basis for signs or symptoms of systemic weakness or muscle paralysis.
Anaphylactic reactions to botulinum toxin type A have not been reported so far, but as with all biological products, necessary precautions should be taken, adrenaline (epinephrine) and other anaphylactic measures should be available.
There are no known sedative effects of botulinum toxin. Its effects on the neuromuscular junction with consequent effects of muscle activity need to be taken into consideration together with an appraisal of the underlying disease when advising patients on their suitability to drive or to operate machinery.
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.
As is expected for any injection procedure, localized pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythaema, localised infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope.
Hypersensitivity Reactions: Serious and/or immediate hypersensitivity reactions such as anaphylaxis and serum sickness have been rarely reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue oedema, and dyspnoea. Some of these reactions have been reported following the use of BOTOX either alone or in conjunction with other products associated with similar reactions. If such a reaction occurs, further injection should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which the patient died after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine. The causal role of BOTOX, lidocaine, or both cannot be reliably determined.
Pre-Existing Neurologic Disorders: Patients with neuromuscular junction disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX. There have been rare cases of administration of botulinum toxin to patients with known or unrecognised neuromuscular junction 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. When exposed to very high doses, patients with neurologic disorders, e.g. paediatric cerebral palsy or adult spasticity, may also be at increased risk of clinically significant systemic effects.
Adverse Effects Distant From The Site Of Injection: Post-marketing safety data from BOTOX and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms that are consistent with the mechanism of action of botulinum toxin have been reported hours to weeks after injection, and may include muscular weakness, ptosis, diplopia, blurred vision, facial weakness, swallowing and speech disorders, constipation, aspiration pneumonia, difficulty breathing and respiratory depression. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in patients who have underlying conditions and comorbidities that would predispose them to these symptoms including adults treated for spasticity and other conditions, and are treated with high doses. Swallowing and breathing difficulties can be life threatening and death has been reported, although a definitive causal association to BOTOX has not been established.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Cardiovascular System: There have been reports of adverse events following administration of BOTOX involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. The exact relationship of these events to BOTOX is unknown.
Seizures: New onset or recurrent seizures have been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to the BOTOX injection has not been established. The reports in children were predominantly from cerebral palsy patients treated for spasticity.
Immunogenicity: Formation of neutralising antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin. The critical factors for neutralising antibody formation have not been well characterised. The potential for antibody formation may be minimised by injecting with the lowest effective dose given at the longest feasible intervals between injections.
Blepharospasm: Reduced blinking following the use of BOTOX injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with cranial nerve VII 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 medial 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 closures of the eye by patching or other means.
Because of the anticholinergic activity of botulinum toxin, caution should be exercised when treating patients at risk for angle closure glaucoma, including patients with anatomically narrow angles. Acute angle glaucoma has been reported very rarely following periorbital injections of botulinum toxin.
Strabismus: BOTOX is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair. The efficacy of BOTOX 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 BOTOX for the treatment of strabismus, retrobulbar haemorrhages 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.
Cervical Dystonia: The most frequently reported severe adverse event associated with the use of botulinum toxin type A in patients with cervical dystonia is dysphagia, with dyspnoea also being reported on occasion. On rare occasions the dysphagia has been severe enough to warrant the insertion of a gastric feeding tube. Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be mild, but could be severe. Dysphagia may persist for two to three weeks after injection, but infrequently has been reported to last five months post-injection. There have also been at least two reported incidents where subsequent to the finding of dysphagia, patients developed aspiration pneumonia and died.
Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia. Dysphagia has contributed to decreased food and water intake resulting in weight loss and dehydration. Patients with subclinical dysphagia may be at increased risk of experiencing more severe dysphagia following a BOTOX injection.
Limiting the dose injected into the sternocleidomastoid muscle 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 the localised diffusion of the toxin to the esophageal musculature. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Cerebral Palsy and Focal Spasticity in Adults: BOTOX is a treatment of focal spasticity that has been studied in association with usual standard of care regimens and is not intended as a replacement for these treatment modalities. BOTOX is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.
BOTOX should not be used for the treatment of focal limb spasticity in adult post-stroke patients if muscle tone reduction is not expected to result in improved function (e.g., improvement in gait), or improved symptoms (e.g. reduction in pain), or to facilitate care.
Caution should be exercised when treating adult patients with post-stroke spasticity who may be at increased risk of fall.
BOTOX should be used with caution for the treatment of focal lower limb spasticity in elderly post-stroke patients with significant co-morbidity and treatment should only be initiated if the benefit of treatment is considered to outweigh the potential risk.
There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. Caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease.
Hyperhidrosis: Patients should be evaluated for potential causes of secondary hyperhidrosis (e.g. hyperthyroidism, pheochromocytoma) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease.
Chronic Migraine: Refer to preceding Precautions, including specific information for Cervical Dystonia, Blepharospasm, and Strabismus, due to similar injection sites. Efficacy has not been established for BOTOX for prophylaxis of episodic migraine (headaches on <15 days per month).
Bladder Dysfunction (Neurogenic Detrusor Overactivity and Overactive Bladder): Appropriate medical caution should be exercised for performing a cystoscopy.
In patients who are not catheterising, post-void residual urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Patients should be instructed to contact their physician if they experience difficulties in voiding as catheterisation may be required.
Due to the risk of urinary retention, only patients who are willing and/or able to initiate catheterisation post-treatment, if required, should be considered for treatment.
Neurogenic Detrusor Overactivity: In patients with neurogenic detrusor overactivity, autonomic dysreflexia associated with the procedure could occur, which may require prompt medical therapy.
Upper Facial Rhytides (Glabellar Lines, Crow's Feet and Forehead Lines): Reduced blinking from BOTOX injection of the orbicularis oculi muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with cranial nerve VII disorders. Caution should be used when BOTOX treatment is used in patients who have an inflammation at the injection site, marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin or the inability to substantially lessen glabellar lines by physically spreading them apart.
Effects on the Ability to Drive and Use Machines: Asthenia, muscle weakness, dizziness and visual disturbance have been reported after treatment of BOTOX and could make driving or using machines dangerous.
Use in Children: There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. A causal association to BOTOX has not been established in these cases. Post-marketing reports of possible distant effects from the site of injection have been very rarely reported in paediatric patients with co-morbidities, predominately with cerebral palsy who received >8 U/kg. Extreme caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease.
The safety and effectiveness of BOTOX have not been established in children below the age of 2 years for cerebral palsy. In the treatment of blepharospasm, hemifacial spasm, associated focal dystonia and strabismus, in children below 12 years of age have not been demonstrated. The safety and effectiveness of BOTOX in the treatment of neurogenic detrusor overactivity and overactive bladder in patients below 18 years of age have not been demonstrated.
Use in Elderly: Clinical studies of BOTOX did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.
Of 1242 patients in placebo-controlled clinical studies of BOTOX, 41.4% (n=514) were 65 years of age or older, and 14.7% (n=182) were 75 years of age or older. No overall difference in the safety profile following BOTOX treatment was observed between patients aged 65 years and older compared to younger patients in these studies, with the exception of urinary tract infection where the incidence was higher in patients 65 years of age or older in both the placebo and BOTOX groups compared to the younger patients. Similarly, no overall difference in effectiveness was observed between these age groups in placebo-controlled pivotal clinical studies.
Use In Pregnancy & Lactation
There are no adequate and well-controlled studies of BOTOX administration in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Because animal reproductive studies are not always predictive of human response, BOTOX should be administered during pregnancy only if the potential benefit justifies the potential risk to the foetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks, including abortion or foetal malformations which have been observed in rabbits. There is no information on whether BOTOX is excreted in human milk. The use of BOTOX during lactation is not recommended.
Adverse Reactions
General: In general, adverse events occur within the first few days following injection of BOTOX and, while generally transient, may have a duration of several months, or in rare cases, longer. As is expected for any injection procedure, localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope. Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue. However, weakness of adjacent muscles and/or muscle remote from the site of injection has been reported.
The following events have been reported rarely since the drug has been marketed: skin rash (including erythema multiforme, urticaria and psoriasiform eruption), pruritus and allergic reaction.
There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia and or other significant debility, after treatment with botulinum toxin type A. There have also been 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 BOTOX is unknown.
Blepharospasm: In a 98 patient study of BOTOX, blepharospasm patients received an average dose per eye of 33 U injected at 3 to 15 sites. The most frequently reported treatment-related adverse events were eyelid ptosis (20.8%), superficial punctate keratitis and eye dryness (6.3% each).
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. During market use, angle closure glaucoma, visual disturbance, and facial weakness have also been reported.
In two cases of VIIth nerve disorder (one case of an aphakic eye), reduced blinking from BOTOX 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. 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.
Hemifacial Spasm: Adverse events reported after injection of BOTOX have included blurring of vision, facial droop, dizziness, and tiredness, in addition to those listed as previously mentioned under blepharospasm treatment.
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 can be affected, causing ptosis or vertical deviation, especially with higher doses of BOTOX. The incidence rates of these adverse effects in 2058 adults who received 3650 injections for horizontal strabismus are listed as follows: (see Table 7).

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The incidence of eyelid ptsosis was 0.9% after inferior rectus injection and 37.7% after superior rectus injection.
The incidence rates of these side effects persisting for over 6 months in an enlarged series of 5587 injections of horizontal muscles in 3104 patients are listed as follows: (see Table 8).

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In these patients, the injection procedure itself caused nine scleral perforations. A vitreous haemorrhage occurred in one case and later cleared. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar haemorrhages 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).
Cervical Dystonia: The following adverse events were reported with at least 2% greater incidence in BOTOX-treated patients compared with placebo-treated patients and are listed in descending order of incidence: pain (32%), focal weakness (17%), and dysphagia (13%) being the most common; then soreness, malaise, general weakness, upper respiratory infection, nausea, headache, drowsiness, musculoskeletal stiffness, dry mouth, dizziness, rhinitis, and hypertonia, all reported in 2 to 10% of patients.
Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX resulting from the spread of the toxin outside the injected muscles. Dysphagia is usually reported as mild to moderate severity in most patients. However, in an occasional patient it may be associated with more severe problems (See Warnings). Other treatment-related adverse events include numbness, diplopia, eyelid ptosis, dyspnoea, fever, and flu syndrome.
Cerebral Palsy: The safety of BOTOX used for the treatment of dynamic foot deformity due to spasticity in paediatric patients was evaluated. As is expected for any intramuscular injection procedure, localised pain was associated with the injection in these patients.
The adverse reactions most frequently reported as related to treatment include falling, leg pain, leg (local) weakness. The percentage of patients who experienced these events at least once during the study are summarized as follows: (see Table 9).

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Falling may be attributed to a change in the ankle position and gait and/or local weakness. Local weakness represents the expected pharmacological action of botulinum toxin.
Adverse events with >3 % difference between treatment groups regardless of treatment relationship, for 180 patients enrolled into two double-blind, randomised, placebo controlled studies included: ear infection, viral infection, rash and myalgia. Treatment-related adverse reactions reported in >1% of patients were leg cramps, fever, knee pain, ankle pain, pain at the injection site post-treatment asthenia, lethargy, malaise, muscle weakness, pain in extremity, gait abnormality, somnolence, tingling, and urinary incontinence. All treatment-related adverse events were mild to moderate in severity.
Upper Limb Spasticity In Adults: The safety of BOTOX was evaluated in 339 unique patients who received treatment for upper limb spasticity associated with stroke in double-blind and open label studies. In general, the majority of adverse events reported were mild to moderate in severity and were typically self-limiting.
The following events were reported as treatment related in 1-4% of patients and are listed in decreasing order of incidence: ecchymosis, arm pain, muscle weakness, hypertonia, and injection site pain.
The following events were reported as treatment related in less than 1% of patients and are listed in decreasing order of incidence: hypoaesthesia, arthralgia, asthenia, pain, bursitis, dermatitis, headache, injection site hypersensitivity, malaise, nausea, pareasthesia, postural hypotension, pruritus, and rash.
Fever and flu syndrome were also reported in approximately 1% of patients.
Lower Limb Spasticity in Adults: The safety of BOTOX was evaluated in 538 unique patients who received treatment for lower limb spasticity in double-blind, placebo-controlled studies. The most frequently reported adverse reactions reported by ≥1% of BOTOX treated patients and mor frequent than in placebo-treated patients in adult lower limb spasticity double-blind, placebo-controlled clinical trials are peripheral oedema (2.4%) and arthralgia (3.5%).
No change was observed in the overall safety profile with repeated dosing.
Glabellar Lines: Safety was evaluated in two multicentre, double-blind, placebo-controlled, parallel group studies of identical design (N=535; 405 in the BOTOX-treated group and 130 in the placebo-treated group). The most frequently reported treatment-related adverse events were headache (9.4% in the BOTOX-treated group and 15.4% in the placebo-treated group) and blepharoptosis (3.2% in the BOTOX-treated group and 0% in the placebo-treated group). Blepharoptosis is consistent with the pharmacologic action of BOTOX, and may be technique related.
Adverse events that were reported as treatment-related and were reported in 1-3% of BOTOX-treated patients are listed in decreasing order of incidence: injection site pain/burning/stinging (2.5%), face pain (2.2%), erythema (1.7%), local muscle weakness (1.7%), injection site oedema (1.5%), ecchymosis (1.0%), skin tightness (1.0%), paraesthesia (1.0%) and nausea (1.0%). Most adverse events reported were of mild-to-moderate severity and all were transient.
Crow's Feet: The safety of BOTOX for the treatment of crow's feet was evaluated in two multicentre, double-blind, placebo-controlled, parallel group studies (246 in the BOTOX-treated groups (6 U to 18 U/side) and 80 in the placebo-treated group). Most adverse events reported were of mild to moderate severity and all were transient. The most frequently reported treatment-related adverse events were injection site haemorrhage i.e. bruising at the injection site (8.1% in the BOTOX 6 U to 18 U/side groups and 10.0% in the placebo group) and headache (3.7% in the BOTOX 6 U to 18 U/side groups and 2.5% in the placebo group). Flu syndrome was reported in 1.6% of BOTOX-treated patients (6 U to 18 U/side) and in none of the placebo-treated patients. All other adverse events reported as treatment-related in the BOTOX groups were reported in less than 1% of patients.
Other studies have reported the incidence of injection site bruising to be between 4-25% of BOTOX-treated patients, with similar rates noted for placebo. Other adverse events related to BOTOX treatment included temporary droop of the lateral portion of the lower eyelid (5%), which is consistent with the pharmacologic action of BOTOX and may be injection technique-related.
Forehead Lines: In a clinical study where BOTOX was administered to 59 patients with horizontal forehead lines (8 U to 24 U into frontalis), the following treatment related adverse events were reported: headache (22.0%), bruising (10.2%), eyebrow ptosis (10.2%), eyelid swelling (20.3%), aching/itching forehead (5.1%), nausea (3.4%), feeling of tension (1.7%), flu-like symptoms/cold (1.7%) and other (6.8%). All adverse events were mild or moderate in severity and no serious adverse events were reported.
Hyperhidrosis Of The Axilla: The safety of BOTOX was evaluated in 287 patients who received at least 1 treatment exposure for focal hyperhidrosis of the axilla in double-blind and open-label studies. Adverse events reported as treatment related in greater than 1% of BOTOX treated patients are listed in decreasing order of incidence: perceived increase in non-axillary sweating (4.5%), injection site pain (1.7%), pain (1.4%) and vasodilation (hot flushes) (1.0%).
Chronic Migraine: For this indication the frequency of adverse reactions arising from clinical experience is defined as follows: Very Common (≥ 1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very Rare (<1/10,000).
Safety data were compiled from two double-blind, placebo-controlled studies involving 687 patients treated with 155 U - 195 U of BOTOX. The following adverse reactions were reported: Nervous system disorders: Common: Headache, migraine, facial paresis.
Eye disorders: Common: Eyelid ptosis.
Gastrointestinal disorders: Uncommon: Dysphagia.
General disorders and administration site conditions: Common: Injection site pain.
Skin and subcutaneous tissue disorders: Common: Pruritus, rash. Uncommon: Pain of skin.
Musculoskeletal and connective tissue disorders: Common: Neck pain, musculoskeletal stiffness, muscular weakness, myalgia, musculoskeletal pain, muscle spasms, muscle tightness. Uncommon: Pain in jaw.
Migraine, including worsening migraine, was reported in 3.8% of BOTOX and 2.6% of placebo patients, typically occurring within the first month after treatment. These reactions did not consistently reoccur with subsequent treatment cycles, and the overall incidence decreased with repeated treatments.
The discontinuation rate due to adverse events in these phase 3 trials was 3.8% for BOTOX vs. 1.2% for placebo.
Neurogenic Detrusor Overactivity: The table as follows presents the most frequently reported adverse reactions in double-blind studies within 12 weeks of injection for neurogenic detrusor overactivity. (See Table 10.)

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The following rates with BOTOX 200 Units were reported during the complete treatment cycle (median duration of 44 weeks of exposure): urinary tract infections (49.2%), urinary retention (17.2%), fatigue (6.1%), and insomnia (3.1%). In these neurogenic patients, the following additional adverse reactions were reported during the complete treatment cycle: constipation (4.2%), muscular weakness (3.8%), fall (3.1%), gait disturbance (2.7%), muscle spasm (2.3%), and bladder diverticulum (1.1%). Procedure-related events in the 200 Unit BOTOX group included: haematuria (3.8%), dysuria (2.3%), and autonomic dysreflexia (1.5%).
No change was observed in the overall safety profile with repeat dosing.
No difference on the MS exacerbation annualized rate (i.e., number of MS exacerbation events per patient-year) was observed (BOTOX=0.23, placebo=0.20) in the MS patients enrolled in the pivotal studies.
Among patients who were not catheterising at baseline prior to treatment, catheterisation was initiated in 38.9% following treatment with BOTOX 200 Units versus 17.3% on placebo.
Post Approval Study: A placebo controlled, double-blind post-approval study with BOTOX 100 Units (Study 3) was conducted in Multiple Sclerosis (MS) patients with urinary incontinence due to neurogenic detrusor overactivity. These patients were not adequately managed with at least one anticholinergic agent and not catheterizing at baseline. The table as follows presents the most frequently reported adverse reactions within 12 weeks of injection. (See Table 11).

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During the complete treatment cycle (median duration of 51 weeks of exposure), the following adverse events were reported with BOTOX 100 Units: urinary tract infections (39.4%), bacteriuria (18.2%), urinary retention (16.7%), residual urine volume* (16.7%), and dysuria (9.1%).
Procedure-related events included: dysuria (4.5%) and hematuria (3.0%).
No difference on the MS exacerbation annualized rate (i.e., number of MS exacerbation events per patient-year) was observed (BOTOX=0, placebo=0.07).
Catheterization was initiated in 15.2% of patients following treatment with BOTOX 100 Units versus 2.6% on placebo.
Overactive Bladder: The table as follows presents the most frequently reported adverse reactions in double-blind, placebo-controlled, pivotal Phase 3 studies within 12 weeks of injection for overactive bladder. (See Table 12).

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During the complete treatment cycle, the following adverse reactions with BOTOX 100 Units were reported: urinary tract infections (25.5%), dysuria (10.9%), bacteriuria (8.0%), urinary retention (5.8%), residual urine volume (3.4%), and pollakiuria (2.0%).
Events considered to be procedure-related by the investigator reported at any time following initial injection were dysuria (5.8%) and haematuria (2.2%).
Catheterisation was initiated in 6.5% following treatment with BOTOX 100 Units versus 0.4% in the placebo group.
No change was observed in the overall safety profile with repeat dosing.
Post-Post-Marketing Experience: There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility, after treatment with BOTOX.
Serious and/or immediate hypersensitivity reactions such as anaphylaxis and serum sickness have been rarely reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue oedema, and dyspnoea. Some of these reactions have been reported following the use of BOTOX either alone or in conjunction with other products associated with similar reactions. One fatal case of anaphylaxis has been reported in which the patient died after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine. The causal role of BOTOX, lidocaine, or both cannot be reliably determined.
There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes following BOTOX treatment. Some of these patients had risk factors including cardiovascular disease.
New onset or recurrent seizures have also been reported following BOTOX treatment, typically in patients who are predisposed to experiencing these events.
Angle closure glaucoma has been reported very rarely following BOTOX treatment for blepharospasm.
Lagophthalmos has been reported following BOTOX injection into the glabellar lines or crow's feet lines.
The following list includes adverse drug reactions or other medically relevant adverse events that have been reported since the drug has been marketed, regardless of indication, and may be in addition to those cited in Precautions, and Adverse Reactions: denervation/muscle atrophy; respiratory depression and/or respiratory failure; dyspnoea; aspiration pneumonia; dysarthria; dysphonia; dry mouth; strabismus; peripheral neuropathy, abdominal pain; diarrhoea; nausea; vomitting; pyrexia; anorexia; vision blurred; visual disturbance; hypoacusis; tinnitus; vertigo; facial palsy, facial paresis; brachial plexopathy; radiculopathy; syncope; hypoaesthesia; malaise; myalgia; myasthenia gravis; paraesthesia; rash; erythema multiforme; pruritus; dermatitis psoriasiform; hyperhidrosis; dry eye, localized muscle twitching/involuntary muscle contractions and alopecia, including madarosis.
Drug Interactions
Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics, or spectinomycin, or other drugs that interfere with neuromuscular transmission e.g. turbocurarine-type muscle relaxants. Other muscle relaxants should also be used with caution, perhaps reducing the starting dose of relaxant, or using an intermediate-action drug, such as vecuronium or atracurium, rather than those with longer lasting effects.
No specific tests have been carried out to establish the possibility of clinical interaction with other medicinal products. No drug interactions of clinical significance have been reported.
The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive 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
Incompatibilities: In the absence of incompatibility studies, this medicinal product should not be mixed with other medicinal products.
For safe disposal, unused vials should be reconstituted with a small amount of water then autoclaved. Any unused vials, syringes and spillages, etc., should be autoclaved, or the residual BOTOX inactivated using dilute hypochlorite solution (0.5%).
Information for Patients: 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 BOTOX. Patients should also be advised of the potential for experiencing malaise lasting up to six weeks after injection.
After bladder injections for urinary incontinence, patients should be instructed to contact their physician if they experience difficulties in voiding.
Storage
Unopened vials should be stored in a refrigerator (2°- 8°C). After reconstitution BOTOX may be stored in a refrigerator (2°- 8°C) for up to 24 hours prior to use.
Shelf-Life: The shelf life of BOTOX is three years.
ATC Classification
M03AX01 - botulinum toxin ; Belongs to the class of other agents used as peripherally-acting muscle relaxants.
Presentation/Packing
Powd for inj 100 U (a sterile white vacuum dried powder in a clear glass vial) x 1's.
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