Reconstituted Clostridium Botulinum Toxin Type A (see Table 1) is injected using a sterile, 27-30 gauge needle with or without electromyographic guidance.
Initial Recommended Dose: 1.25-2.5 units 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 3 days and reaches a peak at 1-2 weeks post-treatment. Each treatment lasts approximately 3 months, following which the procedure can be repeated indefinitely. At repeat-treatment sessions, the dose may be increased up to 2-fold if the response from the initial treatment is considered insufficient (usually defined as an effect that does not last longer than 2 months). However, there appears to be little benefit obtainable from injecting >5 units/site. The initial dose should not exceed 25 units/eye. Normally, no additional benefit is conferred by treating more frequently than every 3 months. It is rare for the effect to be permanent.
In the management of blepharospasm, total dosing should not exceed 100 units 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 botulinum toxin product for treatment of hemifacial spasm in a 2-month period should not exceed 200 units.
Botulinum toxin product 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.
Botulinum toxin product is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair. The efficacy of botulinum toxin product in deviations >50 prism diopters, in restrictive strabismus, Duane's syndrome with lateral rectus weakness and 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 Clostridium Botulinum Toxin Type A injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection.
Note: The recommended volume of Clostridium Botulinum Toxin Type A injected for treatment of strabismus is 0.05-0.15 mL per muscle.
I. Initial Doses in Units: Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.
a. For vertical muscles and for horizontal strabismus of <20 prism diopters: 1.25-2.5 units in any 1 muscle.
b. For horizontal strabismus of 20-50 prism diopters: 2.5-5 units in any 1 muscle.
c. For persistent VIIth
nerve palsy of 1 month or longer duration: 1.25-2.5 units in the medial rectus muscle.
II. Subsequent Doses for Residual or Recurrent Strabismus.
a. It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose.
b. Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
c. Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to 2-fold compared to the previously administered dose.
d. Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.
e. The maximum recommended dose as a single injection for any 1 muscle is 25 units.
The initial listed doses of the reconstituted Clostridium Botulinum Toxin Type A (see Table 1) typically create paralysis of injected muscles beginning 1-2 days after injection and increasing in intensity during the 1st week. The paralysis lasts for 2-6 weeks and gradually resolves over a similar time period. Over-corrections lasting over 6 months have been rare. About one-half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose or because of mechanical factors eg, large deviations or restrictions or because of the lack of binocular motor fusion to stabilize 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 body weight 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, localization of the involved muscles with electromyographic guidance may be useful.
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 Clostridium Botulinum Toxin Type A into the sternocleidomastoid, levator scapulae, scalene, splenius capitis and/or the trapezius muscle(s). In general, a total dose of 6 units/kg every 2 months should not be exceeded for treatment of cervical dystonia.
Diluted Clostridium Botulinum Toxin Type A is injected using an appropriately sized needle (usually 25, 27 or 30 gauge). Table 1 is intended to give dosing guidelines for injection of Clostridium Botulinum Toxin Type A in the treatment of cervical dystonia: See Table 1.
Click on icon to see table/diagram/image
Table 1 is provided as guidance for the initial injection. The extent of muscle hypertrophy and the muscle groups involved in the dystonic posture may change with time necessitating alterations in the dose of toxin and muscles to be injected. The exact dosage and sites injected must be individualized for each patient.
In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance. No more than 50 units should be given at any 1 site. Limiting the dose injected into the sternocleidomastoid muscle to <100 units may decrease the occurrence of dysphagia (see Precautions). To minimize the incidence of dysphagia, the sternocleidomastoid should not be injected bilaterally. The concentrations of reconstituted material needed are 5 and 10 units/0.1 mL to allow reasonable injection volumes.
Multiple injection sites allow botulinum toxin product to have more uniform contact with the innervation areas of the dystonic muscle and are especially useful in larger muscles. The optimal number of injection sites is dependent upon the size of the muscle to be chemically denervated.
Clinical improvement generally occurs within the first 2 weeks after injection. The maximum clinical benefit generally occurs approximately 6 weeks 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 2-32 weeks), with a typical duration of approximately 12-16 weeks, depending on the patient's individual disease and response. "Booster" injections are not recommended. Dosing intervals should not be more often than every 2 months.
Pediatric Cerebral Palsy:
For the treatment of equinus due to spasticity in pediatric cerebral palsy, diluted Clostridium Botulinum Toxin Type A is injected using a sterile 23-26 gauge needle.
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 2 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 3 months. The dose is recommended 4 units/kg, up to maximum of 200 units at any single treatment session.
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.
Clostridium Botulinum Toxin Type A is reconstituted with 0.9% sterile nonpreserved saline (100 units in 2.5 mL or injected as 4 units/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 units.
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.
Careful attention should be paid to avoid injection of this product into the blood vessel. The thumb or index finger should be placed firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be oriented superiorly and medially during the injection and careful attention should be paid to inject accurate volume.
Glabella facial lines arise from the activity of corrugator muscle and orbicularis oculi muscle. These muscles move the brow medially, and the procerus muscle and depressor supercilii muscle pull the brow inferiorly. This creates a frown or "furrowed brow". The location, size, and use of the muscles vary markedly among individuals. An effective dose for facial lines is determined by gross observation of the patient's ability to activate the superficial muscles injected. Each treatment lasts approximately for up to 4 months. More frequent injection of this product is not recommended because the safety and efficacy are not established.
Typically the initial doses of reconstituted Clostridium Botulinum Toxin Type A induce chemical denervation of the injected muscles 1-2 days after injection, increasing in intensity during the 1st week. Injection intervals should be no more frequent than every 3 months and should be performed using the lowest effective dose.
Treatment with Clostridium Botulinum Toxin Type A for cosmetic purposes may result in the formation of antibodies that may reduce the effectiveness of subsequent treatments with Clostridium Botulinum Toxin Type A for glabellar lines or for other indications.
Clostridium Botulinum Toxin Type A should be injected bilaterally at 3 sites in the lateral aspect of the orbicularis oculi (ie, total of 6 injections), where most lines are seen when a smile is forced. In general, 2-6 units is recommended per injection site at a 2-3 mm depth, for a total dose of 6-18 units per side.
Injection 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.
NABOTA should be injected IM at each of 4 injection sites in the frontalis muscle. In general, 2-6 units is recommended per injection site every 1-2 cm along either side of a deep forehead crease, for a total dose of 8-24 units.
Injections should be at least 2-3 cm above the eyebrow to reduce the risk of brow ptosis.
Focal Spasticity in Adults:
The exact dosage and number of injection sites may be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, the presence of local muscle weakness, and the patient response to previous treatment. Clinical improvement of spasticity was observed within the 4 weeks, and also assessed at 8 and 12 weeks after the injection. (See Table 2.)
Click on icon to see table/diagram/image
In the clinical study, the recommended dose was allowed up to 360 Units, and divided among selected muscles.
Sterile 24-30 gauge needle is recommended. Needle length should be determined based on muscle location and depth. Localisation of the involved muscles with techniques such as electromyographic guidance, or nerve stimulation is recommended.
(revision based on NABOTA's clinical result)
Hyperhidrosis of the Axilla:
The hyperhidrotic area to be injected may be defined using standard staining techniques eg, Minor's iodine-starch test. NABOTA is reconstituted with 0.9% nonpreserved sterile saline (100 units/4 mL). Using a 30 gauge needle, NABOTA 50 units (2 mL) is injected intradermally, to each axilla evenly distributed in multiple sites approximately 1-2 cm apart.
At week 1, botulinum toxin product-treated patients demonstrated 95% treatment responder rate based on gravimetric assessment. At 16 weeks, 82% of botulinum toxin product-treated patients were responding to treatment. Approximately 40% of patients received only 1 treatment with botulinum toxin product and had duration of effect for >1 year (median time 68 weeks). When patients received at least 2 consecutive treatments with botulinum toxin product, the mean time to re-treatment following their 1st treatment was 33 weeks (range 15-51 weeks). Repeat injections for axillary hyperhidrosis should be administered when effects from previous injections subside but usually not more frequently than every 2 months.
The recommended dilution is 100 units/2 mL, with a final concentration of 5 units/0.1 mL. Recommended Dose: 155-195 units administered IM using a sterile 30 gauge, 0.5 inch needle as 0.1 mL (5 units) injections should be divided across 7 specific head/neck muscle areas as specified in Table 3 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 muscle 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 the 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 Table 3. (See Table 3.)
Click on icon to see table/diagram/image
Neurogenic Detrusor Overactivity:
Patients should not have an acute 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 antiplatelet therapy at least 3 days before the injection procedure. Patients on the anticoagulant therapy need to be managed appropriately to decrease the risk of bleeding.
An intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is Clostridium Botulinum Toxin Type A 200 units.
Reconstitute two 100 units vials of NABOTA, each with 6 mL of 0.9% nonpreserved 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 3rd 10 mL syringe. Complete the reconstitution by adding 6 mL of 0.9 % nonpreserved 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 units in each), for a total of 200 units of reconstituted Clostridium Botulinum Toxin Type A. Use immediately after reconstitution in the syringe.
Dispose of any unused saline.
Reconstituted Clostridium Botulinum Toxin Type A (200 units/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 1 mL 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 min post-injection.
Based on the reported clinical result with other botulinum toxin products, when the clinical effect of the previous injection diminished, patients should be considered for reinjection, but no sooner than 3 months from the prior bladder injection.
General: The use of one vial for more than patient is not recommended because NABOTA and diluent do not contain a preservative. Once opened and reconstituted, store in a refrigerator and use within 24 hrs. Discard any remaining solution. Do not freeze reconstituted NABOTA.
Reconstituted NABOTA is injected with the purpose of reaching the motor endplate region of the muscle to be treated.
Route of Administration: IM injection. May be SC injection for blepharospasm.
Reconstitution of Vial: Dilution Technique: Prior to injection, reconstitute lyophilized-dried NABOTA 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 NABOTA vial. An appropriate amount of diluent (see Table 4 or for specific instructions for intradetrusor injections for neurogenic detrusor activity, refer to Neurogenic Detrusor Overactivity as previously mentioned) is drawn up into a syringe. The exposed portion of 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 syringe size and slowly inject the diluent into the vial.
Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix NABOTA with the saline by rotating the vial. Record the date and time of reconstitution on the space on the label. NABOTA should be administered within 24 hrs after reconstitution.
During this time period, reconstituted NABOTA should be stored in a refrigerator (2-8°C). Reconstituted NABOTA should be clear, colorless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit. (See Table 4.)
Click on icon to see table/diagram/image
A decrease or increase in NABOTA dose is possible by administering a smaller or larger injection volume. The "unit" by which the potency of preparations of NABOTA is measured should be used to calculate dosages of NABOTA only and is not transferable to other preparations of botulinum toxin.
Doses recommended for NABOTA are not interchangeable with other preparations of botulinum toxin.