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.
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.
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.
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.
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.
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.
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.
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.
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.