Data Sheet
BOTOX®
botulinum toxin type A 100 units/vial
Presentation
BOTOX® (botulinum toxin type A) purified neurotoxin complex is a sterile, vacuum-dried injection of purified botulinum toxin type A, produced from a culture of the Hall strain of Clostridium botulinum grown in a medium containing casein hydrolysate, glucose and yeast extract. It is purified from the culture solution by a series of acid precipitations to a crystalline complex consisting of the haemagglutinin protein and the active high molecular weight toxin protein. The complex is re-dissolved in a solution containing sodium chloride and human 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® contains 100 units (U) of botulinum toxin, type A, as a haemagglutinin complex, 0.5 milligrams of human albumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried preparation without a preservative. One unit corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice of the reconstituted BOTOX® injected. The units by which the potency of the preparation of BOTOX® purified neurotoxin complex are measured are not interchangeable with other commercial preparations of botulinum toxin.
Uses
Actions
Therapeutic class: neuromuscular blocking agent
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 localised chemical denervation of the muscle, resulting in localised 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.
Blepharospasm
The paralytic effect on muscles injected with BOTOX® is useful in reducing the excessive, abnormal contractions associated with blepharospasm. Typically, patients with blepharospasm show improvement lasting an average of 12.5 weeks prior to the need for re-treatment.
Strabismus
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's antagonist.
Cervical Dystonia (spasmodic torticollis)
When injected into neck muscles BOTOX® acts to provide relief from both objective signs and subjective symptoms of cervical dystonia (spasmodic torticollis). These improvements may include reduced pain/discomfort, reduced head rotation, reduced shoulder elevation, decreased size and strength of hypertrophic muscles and functional disability improvement. Based on the results of early publications in naïve patients, 40 to 58% of patients with cervical dystonia respond with a significant improvement in their symptoms after initial treatment with BOTOX®. Among patients who have previously benefited from BOTOX® injection for cervical dystonia, approximately 91% can expect improvement for any given treatment period based on patient withdrawal data in a recent trial.
Focal Spasticity in adults and children two years and older
BOTOX® treatment reduces both the objective signs and subjective symptoms of spasticity. Improvements include reduction in muscle tone, increase in range of motion, reduction in pain and a reduction of spasticity related functional disability.
Primary Hyperhidrosis of the Axillae
The proposed mechanism of action of BOTOX® in hyperhidrosis is the inhibition of cholinergically driven excessive sweating, by locally blocking the autonomic sympathetic cholinergic nerve fibres innervating sweat glands. This is achieved by injecting the toxin in the vicinity of the sweat glands, which are located within the dermis of the skin. Injections for this indication must therefore be given intradermally. Hyperhidrosis is typically treated by multiple intradermal injections given in a grid-like pattern over the affected area.
In a double-blind placebo controlled clinical trial of 320 patients, the responder rate was 95% at week 1 and 93.8% at the primary endpoint of week 4, as assessed by the objective gravimetric evaluations.
The objective of treatment is to reduce sweating to a physiologically normal level which patients find tolerable. Anhidrosis is not the target.
Glabellar Lines
When injected into the corrugator and/or procerus muscles, BOTOX® weakens the overactive underlying muscle contraction, decreasing the severity of the glabellar lines and improving appearance. In controlled clinical trials, onset of action was rapid and lasted at least 4 months for many subjects.
Crow's Feet
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 fibers 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 area for up to 17 weeks.
Forehead Lines
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.
Pharmacokinetics
Pharmacokinetic studies in humans are not practicable with BOTOX®.
Distribution studies in rats indicate slow muscular diffusion of botulinum neurotoxin A complex in the gastrocnemius muscle after injection, followed by rapid systemic metabolism and urinary excretion. The amount of radiolabelled material in the muscle declined at a half-life of approximately 10 hours. At the injection site the radioactivity was bound to large protein molecules, whereas in plasma it was mostly bound to small molecules, suggesting rapid systemic metabolism of the substrate. Within 24 hours of dosing, 60% of the radioactivity was excreted in the urine. Autoradiographic results after intramuscular injection of 125I-botulinum neurotoxin A complex into the proximal inner surface of the upper eyelids of rabbits also indicate slow muscular diffusion.
In vitro studies of isolated rat synaptosome fragments indicated that botulinum toxin has a high affinity for cholinergic terminals where it binds to the pre-synaptic membrane
Indications
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 VIIth nerve disorders in patients 12 years of age and above
- to reduce the subjective symptoms and objective signs of spasmodic torticollis (cervical dystonia) in adults
- treatment of focal spasticity in children two years and older
- for the treatment of primary hyperhidrosis of the axillae
- for the treatment of focal spasticity in adults.
- for the treatment of upper facial rhytides, including forehead, crow's feet and glabellar lines
Dosage and Administration
Route of Administration
Intramuscular injection. Reconstituted BOTOX® is injected with the purpose of reaching the motor endplate region of the muscle to be treated. May be subcutaneous for blepharospasm. Intradermal for hyperhidrosis.
General
The product and recommended diluent do not contain a preservative and are for single use only. Once opened and reconstituted, store in the refrigerator and use within twenty four hours (this shelf life is when reconstitution is using the recommended diluent, sterile normal saline without preservative). Discard any remaining solution. Do not freeze reconstituted BOTOX®.
In general, dosing of BOTOX® should be individualised for each patient and always start with the minimal effective dose. The dosing interval should typically not be more frequent than every three months.
Cervical Dystonia (spasmodic torticollis)
Dosing must be tailored to the individual patient based on the patient's head and neck position, localisation of pain, muscle hypertrophy, patient's bodyweight, and patient response.
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. 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).
A 25, 27 or 30 gauge needle should be used for superficial muscles, and a needle of appropriate length may be used for deeper musculature. For cervical dystonia, localisation of the involved muscles with electromyographic guidance may be useful.
The table below is intended to give dosing guidelines for injection of BOTOX® in the treatment of cervical dystonia.
Dosage Guide
| Classification of Cervical Dystonia | Muscle Groupings | Total Dosage; Number of Sites |
|---|---|---|
| Sternocleidomastoid | 50-100 U; at least 2 sites | |
| Levator scapulae | 50 U; 1-2 sites | |
| Scalene | 25-50 U; 1-2 sites | |
| Splenius capitis | 25-75 U; 1-3 sites | |
| Trapezius | 25-100 U; 1-8 sites | |
| Type II Head rotation only |
Sternocleidomastoid | 25-100 U; at least 2 sites if >25 U given |
| Type III Head tilted toward side of shoulder elevation |
Sternocleidomastoid | 25-100 U; at posterior border; at least 2 sites if >25 U given |
| Levator scapulae | 25-100 U; at least 2 sites | |
| Scalene | 25-75 U; at least 2 sites | |
| Trapezius | 25-100 U; 1-8 sites | |
| Type IV Bilateral posterior cervical muscle spasm with elevation of the face |
Splenius capitis and cervicis | 50-200 U; 2-8 sites, treat bilaterally |
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.
The table below 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.
| Muscle(s) | Range of Medians* (U) |
Minimum-Maximum Dose, U/muscle** |
|---|---|---|
| Sternocleidomastoid | 50 | 15-190 |
| Trapezius | 50-60 | 5-200 |
| Levator scapulae | 50 | 10-180 |
| Splenius capitis/cervicis | 90 | 10-240 |
| Scalene | 40 | 5-90 |
* Two medians were given: for those patients who received one injection cycle
(n = 121) and for those patients who received two injection cycles (n = 90).
When only one number is given, the medians were the same for both groups of
patients.
** Limiting the dose injected into the sternocleidomastoid muscle to less than 100 U may decrease the occurrence of dysphagia. (See Precautions.)
In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of 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 medicinal treatment, initial dosing should begin at the lowest effective dose.
In general, a total dose of 360 U every two months should not be exceeded for the treatment of cervical dystonia. The time-to-retreatment will vary between patients, however data from controlled clinical studies indicates that symptoms may start to re-emerge at approximately 8-10 weeks post-injection. Clinical improvement generally occurs within the first two weeks after injection. The maximum clinical benefit generally occurs approximately six weeks post-injection. 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.
Repeat doses should be administered when the clinical effect of a previous injection diminishes, though usually not more frequently than every two months. "Booster" injections are not recommended.
Strabismus
BOTOX® (botulinum toxin type A) purified neurotoxin complex is intended for injection into extraocular muscles utilising 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® is prepared by drawing into a sterile 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 one and a half 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® injection, it is recommended that several drops of a local anaesthetic and an ocular decongestant be given several minutes prior to injection.
NOTE: The volume of BOTOX® injected for treatment of strabismus should be between 0.05 mL to 0.15 mL per muscle.
Strabismus dosage: The initial doses of the diluted BOTOX® (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 because of mechanical factors such as large deviations or restrictions, or because of lack of binocular motor fusion to stabilize the alignment.
- 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 VIth 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 maybe increased up to twice the size of the previously administered dose.
- Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.
- The maximum recommended dose as a single injection for any one muscle is 25 U.
Blepharospasm
An injection of BOTOX® (botulinum toxin type A) 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. A new, sterile needle and syringe should be used to enter the vial on each occasion for dilution or removal of BOTOX®.
For blepharospasm, diluted BOTOX® (see Dilution Table) is injected using a sterile, 27-30 gauge needle with or 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. Pre-tarsal injections are often appropriate and may vary based on the patient's presentation. In the upper lid, maximising the distance of the injection from 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.
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 units 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. The effect is rarely permanent.
The cumulative dose of BOTOX® in a two month period should not exceed 200 U.
VIIth Nerve Disorders
Patients with hemifacial spasm or VIIth nerve disorder should be treated as for unilateral blepharospasm. Further injections may be necessary into the corrugator, zygomaticus major, orbicularis oris and/or other facial muscles according to the extent of the spasm. Electromyographical control may be useful to identify small circumoral muscles.
The cumulative dose of BOTOX® in a two month period should not exceed 200 U.
Focal spasticity in children two years and older
The exact dosage and number of injection sites should be tailored to the child's needs 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. In clinical trials the dose per muscle ranged from 0.5-2.0 U/kg body weight in the upper limb and 2.0 -4.0 U/kg/body weight in the lower limb per treatment session. For the treatment of equinus foot deformity the total dose is up to 4 U/kg or 200 U (whichever is the lesser amount) divided into two sites in each medial and lateral head of the gastrocnemius muscle. In other muscles the dose per muscle ranged from 3.0-8.0 U/kg body weight and did not exceed 300U divided among selected muscles at any treatment session. 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.
A 27 or 30 gauge needle should be used with an appropriate needle length to reach the targeted muscles. For focal spasticity, localisation techniques include electromyography, muscle ultrasound or electrical stimulation.
Clinical improvement generally occurs within the first two weeks after injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes, but typically not more frequently than every three months. The maximum degree of muscle spasticity at the time of reinjection may necessitate alterations in the dose of BOTOX® and muscles to be injected.
The table below is intended to give dosing guidelines for injection of BOTOX® in the treatment of focal spasticity in children aged 2 years and older. The maximum total dose is 8.0 units/kg body weight and 300 units divided among selected muscles at any treatment session:
| Muscles in upper limb | Dosage in U/kg/muscle |
|---|---|
| Biceps brachii | 0.5 - 2.0 U |
| Brachialis | 0.5 - 2.0 U |
| Brachioradialis | 0.5 - 2.0 U |
| Flexor carpi ulnaris | 0.5 - 2.0 U |
| Flexor carpi radialis | 0.5 - 2.0 U |
| Pronator teres | 0.5 - 2.0 U |
| Pronator quadratus | 0.5 - 2.0 U |
| Flexor digitorum profundus | 0.5 - 2.0 U |
| Flexor digitorum sublimis | 0.5 - 2.0 U |
| Flexor pollicis longus | 0.5- 2.0 U |
| Flexor pollicis brevis | 0.5 - 2.0 U |
| Opponens pollicis | 0.5 - 2.0 U |
| Adductor pollicis | 0.5 - 2.0 U |
| Muscles in lower limb | Dosage in U/kg/muscle |
|---|---|
| Hip adductor group (adductor longus, adductor brevis, adductor magnus, medial hamstrings) | 4.0 U |
| Gastrocnemius | 2.0-4.0 U |
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. 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 degree of muscle spasticity at the time of reinjection may necessitate alterations in the dose of BOTOX® and muscles to be injected.
The table below is intended to give dosing guidelines for injection of BOTOX® in the treatment of focal spasticity.
| Muscle | Total Dosage; Number of Sites |
|---|---|
| Biceps brachii | 100 - 200 U; up to 4 sites |
| Flexor digitorum profundus | 15 - 50 U; 1-2 sites |
| Flexor digitorum sublimis | 15 - 50 U; 1-2 sites |
| Flexor carpi radialis | 15 - 60 U; 1-2 sites |
| Flexor carpi ulnaris | 10 - 50 U; 1-2 sites |
| Adductor pollicis | 20 U; 1-2 sites |
| Flexor pollicis longus | 20 U; 1-2 sites |
| Posterior tibialis | 70 - 100 U; 1-2 sites |
| Soleus | 80 - 125 U; 1-2 sites |
| Flexor digitorum longus/brevis | 50 - 100 U; 2-4 sites |
| Gastrocnemius medial/lateral | 50 - 200 U; 2-4 sites |
A 25, 27 or 30 gauge needle should be used with an appropriate needle length
to reach the targeted muscles. For focal spasticity, localisation techniques
include electromyography, muscle ultrasound or electrical stimulation.
Multiple injection sites may allow BOTOX® to have more uniform contact with the innervation areas of the muscle and may be especially useful in larger muscles.
Primary Hyperhidrosis of the Axillae
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.
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 regimes should be drawn up. The recommended injection volume per injection site is 0.1 mL.
Glabellar Lines
BOTOX® should be reconstituted with 0.9% sterile non-preserved saline (100 U/2.5 mL) and injected using a sterile 30 gauge needle. 0.1 mL (4 U) is administered in each of 5 injection 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, injection near the levator palpebrae superioris should be avoided, particularly in patients with larger brow-depressor complexes. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.
Improvement of severity of glabellar lines generally occurs within one week after treatment. The effect was demonstrated for up to 4 months.
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.
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.
Dilution Technique
To reconstitute vacuum-dried BOTOX® injection, 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 24 hours after reconstitution.
During this time period, reconstituted BOTOX® should be stored in a refrigerator (2°C to 8°C). Reconstituted BOTOX® should be clear, colourless and free of particulate matter. Parenteral medicines should be inspected visually for particulate matter and discolouration prior to administration and whenever the solution and the container permit. The product and recommended diluent do not contain a preservative and are for single use only.
Dilution Table:
Diluent added Resulting dose in (0.9% sodiumU/ 0.1 mL chloride injection)
1.0 mL 10.0 U
2.0 mL 5.0 U
4.0 mL 2.5 U
8.0 mL 1.25 U
NOTE: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the BOTOX® 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).
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, and inappropriate storage or reconstitution and 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 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 previously been responders; 19 continued to respond, 7 became clinical non-responders and no further data is available in 5 patients.
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 be no more than frequent than two months). The adult 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 300U (whichever is the lesser amount) when used in children for equinus foot deformity.
When patients do not respond to BOTOX® injections a suggested course of action is: (1) wait the usual treatment interval; (2) consider reasons for lack of response listed above; (3) 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.
Children
Safety and effectiveness in children below the age of 12 has not been established for the indications of blepharospasm, strabismus, VIIth nerve disorder, cervical dystonia, upper facial lines (forehead, crow's feet and glabellar lines) or primary hyperhidrosis of the axillae, nor in children below 2 years of age for cerebral palsy.
Elderly
Refer Adult dosage.
Contraindications
BOTOX® (botulinum toxin type A) purified neurotoxin complex, is contraindicated in individuals with known hypersensitivity to any ingredient in the formulation.
BOTOX® is contraindicated in patients with myasthenia gravis or Eaton Lambert Syndrome.
BOTOX® is contraindicated in the presence of infection at the proposed injection site(s).
Warnings and Precautions
General
The recommended dosages and frequencies of administration for BOTOX® (botulinum toxin type A) purified neurotoxin complex should not be exceeded.
One case of peripheral neuropathy has been reported in an adult male weighing 126 kg who received a total cumulative dose of 1800 U of BOTOX® intramuscularly over an 11 week period. This exceeded the approved dose.
In clinical use, there have been reports of events such as generalised weakness and myalgia which may possibly have been related to systemic absorption and systemic effects of BOTOX®.
There have not been any reported instances of systemic toxicity resulting from accidental injection or oral ingestion of BOTOX®. However, should accidental injection or oral ingestion occur the person should be medically supervised for several days up to six weeks, in an office or outpatient basis for signs and 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.
Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or spectinomycin, or any other medicines that interfere with neuromuscular transmission (e.g. tubocurarine-type muscle relaxants). Caution should be exercised when BOTOX® is used with aminoglycosides (e.g. streptomycin, tobramycin, neomycin, gentamycin, netilmycin, kanamycin, amikacin), spectinomycin, polymyxins, tetracyclines, lincomycin or any other medicines which interfere with neuromuscular transmission.
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® injection.
Individuals with peripheral motor neuropathic diseases (e.g., amotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should only receive BOTOX® with caution: Patients with neuromuscular disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX®. Published medical literature has reported rare cases of administration of a botulinum toxin to patients with known or unrecognized neuromuscular disorders where the patients have shown extreme sensitivity to the products. In some cases, dysphagia has lasted several months and required placement of a gastric feeding tube.
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® should be familiar with the relevant anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. An understanding of standard electromyographic techniques may be useful for the treatment of hemifacial spasm, cervical dystonia (spasmodic torticollis) and for the treatment of dynamic equinus foot deformity due to spasticity in juvenile cerebral palsy patients.
Serious and/or immediate hypersensitivity reactions have been rarely reported. As with all biological products, adrenaline and other precautions as necessary should be available should an anaphylactic reaction occur.
Caution should be used when BOTOX® is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness is present in the target muscles.
As with any injection, procedure-related injury could occur. An injection could result in localized infection, pain, inflammation, paresthesia, hypesthesia, tenderness, swelling, erythema, and/or bleeding/bruising. Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc. Care should be taken when injecting near vulnerable anatomic structures.
DUE TO THE LACK OF AN INTERNATIONAL UNIT, BOTOX® IS NOT THERAPEUTICALLY EQUIVALENT TO THE OTHER BOTULINUM TOXIN TYPE A PREPARATION CURRENTLY AVAILABLE ON THE NEW ZEALAND MARKET. THE POTENCIES OF BOTOX® AND THE OTHER BOTULINUM TOXIN TYPE A PREPARATION ARE BASED ON DIFFERENT ASSAY METHODS. IN VIEW OF THIS LACK OF HARMONISATION OF UNIT SYSTEMS FOR THE BOTULINUM TOXINS TYPE A ON THE MARKET, EXTREME CAUTION IS REQUIRED IF IT SHOULD PROVE NECESSARY TO SUBSTITUTE THE BOTULINUM TYPE A TOXIN OF ONE PHARMACEUTICAL COMPANY BY ANOTHER. THE EFFECT OF ADMINISTERING DIFFERENT BOTULINUM NEUROTOXIN SEROTYPES AT THE SAME TIME OR WITHIN SEVERAL MONTHS OF EACH OTHER IS UNKNOWN. EXCESSIVE NEUROMUSCULAR WEAKNESS MAY BE EXACERBATED BY ADMINISTRATION OF ANOTHER BOTULINUM TOXIN PRIOR TO THE RESOLUTION OF THE EFFECTS OF A PREVIOUSLY ADMINISTERED BOTULINUM TOXIN.
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 viral diseases or CJD have ever been identified for albumin.
Strabismus
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 musles may produce spatial disorientation, double vision or past pointing. Covering the affected eye may alleviate these symptoms.
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.
Blepharospasm
Reduced blinking from BOTOX® injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VIIth 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.
As a result 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 closure glaucoma has been reported very rarely following periorbital injections of botulinum toxin.
Cervical Dystonia (spasmodic torticollis)
The most frequently reported severe adverse event associated with the use of botulinum toxin type A in patients with cervical dystonia is dysphagia, with dyspnea also being reported on occasion. On rare occasions the dysphagia has been severe enough to warrant the insertion of a gastric feeding tube. 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.
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. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia. Dysphagia may be attributable to distribution of the pharmacological effect of BOTOX® injection resulting from spread of the toxin in the vicinity of the injection site.
Spasticity
BOTOX® is a treatment of focal spasticity that has only been studied in association with usual standard of care regimens. BOTOX® treatment is not likely to be effective in improving range of motion at a joint affected by a known fixed contracture. Identification of the goals for which BOTOX® treatment is being instituted must be undertaken prior to injection. Clinical examination to identify the specific muscles causing spasticity is necessary, and use of electromyography, muscle ultrasound or electrical stimulation may facilitate the accuracy of the BOTOX® injections.
Primary Hyperhidrosis of the Axillae
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.
Pregnancy: Pregnancy Category B3.
When pregnant mice and rats were injected intramuscularly during the period of organogenesis, at 4 U/kg there was reduced weight gain compared with controls and reduced fetal ossification at a single site. Higher doses (8 or 16 U/kg) were associated with reductions in fetal body weights and/or delayed ossification, but there was no evidence for teratogenicity.
Pregnant rabbits were particularly sensitive to BOTOX®. In a range-finding study, intramuscular administration twice during the period of organogenesis resulted in abortions (2 U/kg) and maternal deaths (4 and 6 U/kg). Daily intramuscular administration during the period of organogenesis resulted in reduced fetal weights (0.25 and 0.5 U/kg), increased resorptions (0.5 U/kg); the No-Observed-Effect-Level (NOEL) was 0.125 U/kg, although all doses produced maternal toxicity.
Intramuscular treatment of rats with a maternotoxic dose of BOTOX® (16 U/kg), twice during gestation and once during the lactation period, resulted in an increased post-implantation loss, and reduced pup weights, but post-weaning pup development was unaffected.
There are no adequate and well-controlled studies of the effects of BOTOX® in pregnant women, and its use in pregnancy should be avoided. If this drug is used during pregnancy, or if the patient becomes pregnant whilst taking this drug, the patient should be apprised of the potential risks, including abortion or fetal malformations.
Juvenile Use
Safety and efficacy have not been established in children below the age of 2 years for cerebral palsy, for those below the age of 12 years for blepharospasm, hemifacial spasm, strabismus and spasmodic dysphonia, for those below the age of 16 years for cervical dystonia, or for those below the age of 18 years for hyperhidrosis, and glabellar lines
There have been rare spontaneous reports of death in children after treatment with BOTOX®. Some of these patients had risk factors including significant neuromuscular debility, dysphagia, aspiration pneumonia, seizures and cardiovascular disease. Caution should be exercised when treating patients who are significantly debilitated such as those children who are quadriplegic, require a gastrointestinal feeding tube or have a history of aspiration pneumonia or lung disease.
New onset or recurrent seizures have also been reported, typically in children who are predisposed to experiencing these events. The exact relationship of these events to the BOTOX® injection has not been established.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals have not been performed to evaluate the carcinogenic potential of BOTOX® injection. BOTOX® is not structurally related to any known carcinogens. There has been no clinical evidence of cumulative adverse events following repeated injection of BOTOX®. BOTOX® was inactive in in vitro tests for gene mutation and in in vitro and in vivo tests for clastogenicity. Intramuscular BOTOX® doses of 4 U/kg (males) and 8 U/kg (females) did not affect rat fertility. Decreased fertility occurred with higher doses, but these also resulted in signs of toxicity.
Nursing Mothers
It is not known whether this medicine is excreted in human milk. Because many medicines are excreted in human milk, caution should be exercised when BOTOX® is administered to a nursing woman.
Adverse Effects
In general, adverse events occur within the first week following injection of BOTOX® and are transient. As is expected for any intramuscular injection procedure, localised pain, tenderness and/or bruising may be associated with the injection. Local weakness represents the expected pharmacological action of botulinum toxin.
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 or anaphylaxis, after treatment with botulinum toxin type A.
There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease.
New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established.
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 6 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 9 scleral perforations. A vitreous haemorrhage occurred and later cleared in one case. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar haemorrhages occurred. Decompression of the orbit after 5 minutes was necessary to restore retinal circulation in one case. There was no visual loss from retrobulbar haemorrhage in any of these cases but in five eyes there was pupillary change consistent with ciliary ganglion damage (Adies pupil).
Blepharospasm
In clinical studies of 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%
(including dry eye, lagophthalmos and photophobia)
Ectropion, keratitis, diplopia reported rarely and entropion 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 injection. Diffuse skin rash and local swelling of the eyelid skin lasting for several days following eyelid injection were reported infrequently in clinical studies.
In the 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 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® therapy. Sedentary patients should be cautioned to resume activity slowly and carefully following the administration of BOTOX®.
Acute angle closure glaucoma has been reported very rarely following periorbital injections of botulinum toxin (see Warnings and Precautions).
VIIth Nerve Disorders (hemifacial spasm)
Adverse effects reported after injection of BOTOX® have included blurring of vision, facial droop, dizziness and tiredness, in addition to those listed above for blepharospasm.
Cervical Dystonia (spasmodic torticollis)
The following adverse events were reported 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. Soreness, malaise, general weakness, upper respiratory infection, nausea, headache, drowsiness, stiffness, dry mouth, dizziness, rhinitis, flu syndrome, numbness and hypertonia were all reported in 2 to 10% of patients. Other treatment-related adverse events reported during clinical trials with BOTOX® injection for cervical dystonia included diplopia, ptosis, dyspnea, and fever.
| SAFETY DATA FROM PLACEBO-CONTROLLED, DOUBLE-BLIND CLINICAL TRIALS* | ||
|---|---|---|
Adverse Event |
BOTOX® (n = 231) |
PLACEBO (n = 224) |
| Pain† | 32% | 21% |
| Weakness, focal | 17% | 4% |
| Dysphagia | 13% | 3% |
| Soreness | 9% | 3% |
| Malaise | 6% | 2% |
| Weakness, general | 6% | 1% |
| Upper respiratory infection | 5% | 3% |
| Nausea | 5% | 1% |
| Headache | 5% | 3% |
| Drowsiness | 4% | 1% |
| Stiffness | 3% | 0% |
| Dry mouth | 3% | 0.4% |
| Dizziness | 3% | 1% |
| Rhinitis | 3% | 0% |
| Hypertonia | 2% | 0% |
| Flu syndrome | 3% | 4% |
| Numbness | 2% | 1% |
| Diplopia | 1% | 0% |
| Fever | 1% | 0% |
| Ptosis | 0.4% | 0% |
| Dyspnea | 0.4% | 0% |
| Voice alteration | 0.4% | 0% |
* these data were compiled from all reported adverse events in Allergan
placebo-controlled, double-blind studies including the meta-analysis of five
Oculinum studies completed prior to 1992.
† pain mainly represents local pain at injection site, but also includes neck pain, back pain and general muscle ache.
In an open label study, 18.6% (13/70) of patients reported dysphagia after treatment with a mean dose of 240.5 U BOTOX®. 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 and Precautions).
Dysphonia has also been reported in the literature in patients who have been treated for cervical dystonia. Rhinitis has also been reported.
Focal spasticity in children two years and older
The safety of BOTOX® used for the treatment of focal spasticity was evaluated, from clinical studies for the treatment of dynamic equinus foot deformity, upper limb spasticity and lower limb spasticity. As is expected for any intramuscular injection procedure, localised pain, discomfort, bruising and oedema was associated with the injection in these patients. All treatment related adverse events were mild to moderate in severity and were self-limiting.
In children treated for upper limb spasticity, the most frequently reported treatment related adverse events included local and general weakness, trigger finger, clumsiness, hypokinesia, falling and increased frequency of micturition, joint dislocation and muscle spasms. The percent of patients who experienced these events at least once during the study are summarised below:
| Botox® (n=74) | ||
|---|---|---|
| Muscular weakness, local | 5.4% | |
| Muscular weakness, general | 2.7% | |
| Trigger finger | 2.7% | |
| Clumsiness | 1.4% | |
| Falling | 1.4% | |
| Hypokinesia | 1.4% | |
| Increased frequency of micturition | 1.4% | |
| Joint dislocation | 1.4% | |
| Muscle spasms | 1.4% | |
Other adverse events reported commonly or very commonly in these studies were
convulsions, nasopharyngitis, pneumonia, vomiting and contusion.
In children treated for dynamic equinus foot deformity due to spasticity in juvenile cerebral palsy, The adverse events most frequently reported as treatment-related included falling, leg pain, leg (local) weakness and general weakness. The percentage of patients who experienced these events at least once during the study are summarised below:
| BOTOX® (n = 215) | |
|---|---|
| Falling | 9.3% |
| Leg pain | 2.3% |
| Weakness, local | 2.3% |
| Weakness, general | 2.3% |
Falling may be attributable to a change in ankle position and gait pattern
and/or local weakness. Local weakness represents the expected pharmacological
action of botulinum toxin.
Other treatment-related adverse reactions reported in 1% of patients were: leg cramps, fever, knee pain, ankle pain, pain at the injection site post-treatment and lethargy. Urinary incontinence has also been reported.
In children treated for spasticity of the hip adductor muscles, there were no adverse events reported in the studies evaluated.
Focal 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: arm pain and hypertonia.
Fever and flu syndrome were also reported in approximately 1% of patients. The following events were reported as treatment related in less than 1% of patients and are listed in decreasing order of incidence: hyperesthesia, arthralgia, asthenia, bursitis, dermatitis, headache, injection site hypersensitivity, malaise, nausea, paresthesia, postural hypotension and pruritus.
The safety of BOTOX® was evaluated in 82 patients who received a single treatment for lower limb spasticity associated with stroke in either a double blind or an open label study. The following treatment related adverse events were reported: accidental injury (1.2%), incoordination (1.2%) and paresthesia (1.2%). Adverse events reported were mild to moderate in severity.
Of the 56 patients who received BOTOX® in the double blind phase of the study, 44 went on to receive a second injection in the open label study. Additional treatment related adverse reactions reported were: hypertonia (4.5%), asthenia (2.3%), headache (2.3%) and hyperkinesia (2.3%).
Primary Hyperhidrosis of the Axillae
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%). Body odour has also been reported.
Glabellar Lines
Safety of BOTOX® for the treatment of glabellar lines was evaluated in two multicenter, double-blind, placebo-controlled, parallel group studies (n=535; 405 in the BOTOX®-treated group and 130 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 headache (9.4% in the BOTOX® group and 15.4% in the placebo group) and blepharoptosis (3.2% in the BOTOX® group). Blepharoptosis is consistent with the pharmacologic action of BOTOX® and may be injection technique related.
Adverse events reported as treatment related in 1-3% of BOTOX® treated patients, listed in decreasing order of incidence were: 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%), parethesia (1.0%) and nausea (1.0%).
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 (1-2). 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 (2).
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 (3).
Passive Adverse Event Surveillance
The following other adverse events have been reported since the drug has been marketed: abdominal pain; blurred vision; brachial plexopathy; decreased hearing; diarrhea; ear noise; erythema multiforme; fever; focal facial paralysis; localized numbness; loss of appetite; malaise; myalgia; myasthenia gravis; pruritus; psoriasiform eruption; radiculopathy; sweating; syncope; and vomiting and alopecia including madarosis.
Interactions
The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or any other medicines that interfere with neuromuscular transmission. Caution should be exercised when BOTOX® is used in patients taking any of these medicines. (See Warnings and Precautions)
Overdosage
Overdose of BOTOX® is a relative term and depends upon dose, site of injection, and underlying tissue properties. Local weakness is usually well tolerated and resolves spontaneously without intervention. However, dysphagia may result in loss of airway protection and aspiration pneumonia.
Patients with botulism may present with symptoms of ptosis, diplopia, swallowing and speech disorders, cranial nerve findings, generalised weakness, or paresis of the respiratory muscles. Should accidental injection or oral ingestion occur, the person should be medically supervised for several days up to six weeks 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 (from primate studies) for toxicity in humans weighing 6 kg or greater.
Patients or caregivers should be advised to seek immediate medical consultation if swallowing, speech or respiratory disorders arise.
In the event of overdosage, additional information may be obtained by contacting the Poisons Information Centre.
Pharmaceutical Precautions
BOTOX® (botulinum toxin type A) purified neurotoxin complex is a sterile, vacuum-dried preparation. It is supplied in a clear glass vial with a rubber stopper and tamper-proof aluminium seal, containing a white powder for reconstitution. Each vial contains 100 U of vacuum-dried Clostridium botulinum toxin type A. Refer to description for list of excipients.
STORE THE VACUUM-DRIED PRODUCT IN A REFRIGERATOR BETWEEN 2-8°C.
The shelf life of the packaged product is 36 months when stored at 2°C to 8°C.
Administer BOTOX® (botulinum toxin type A) purified neurotoxin complex within 24 hours after the vial is removed from the refrigerator and reconstituted. During these twenty four hours, reconstituted BOTOX® should be stored in a refrigerator. It should be clear, colourless and free of particulate matter. It is for single use only.
All vials, including expired vials, or equipment used with the medicine should be disposed of carefully as is done with all medical waste. Unused vials should be reconstituted with a small amount of water and then autoclaved. Any unused vials or equipment (such as syringes) should be autoclaved (120°C for 30 minutes), or the residual BOTOX® inactivated using dilute hypochlorite solution (0.5%) for 5 minutes.
Medicine Classification
Prescription Medicine
Package Quantities
Each vial contains 100 U of botulinum toxin type A, packaged individually.
Further Information
Nil
References
1 Lowe NJ et al. Bilateral, double-blind, randomized comparison of 3 doses of botulinum toxin type A and placebo in patients with crow's feet. J Am Aced Dermatol 2002; 47(6):834-40.
2. Keen M et al. Botulinum toxin A: A novel method to remove periorbital wrinkles. Facial Plast Surg 1994; 10(2):141-146.
3. Carruthers A et al. A prospective, double-blind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dermatol Surg 2003; 29(5):461-7.
Name and Address
Allergan New Zealand Limited
Cnr Manu Tapu Drive & Joseph Hammond Place
Auckland International Airport
Mangere, Auckland 1
NEW ZEALAND
Date of Preparation
January 2008