Generic Name: botulinum toxin type A

Brand Names: Botox, Botox Cosmetic

Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Botulinum toxin type A (Botox^®, Botox^® Cosmetic) and type B (Myobloc^®) currently are commercially available in the US; types C and F reportedly under clinical investigation in other countries.

Cervical Dystonia

Management of cervical dystonia (also referred to as spasmodic torticollis) to decrease the severity of associated abnormal head position and neck pain; designated an orphan drug by FDA for this use.

Considered first-line therapy for cervical dystonia because of its efficacy, relatively low incidence of adverse effects, and temporary dose-related therapeutic effects (compared with surgery).

Comparative safety and efficacy of botulinum toxin types A and B in cervical dystonia have not been established.

Blepharospasm and Associated Facial Nerve Disorders

Management of blepharospasm associated with dystonia, including benign essential blepharospasm and seventh cranial (facial) nerve disorders; considered a first-line therapy.

Designated an orphan drug by FDA for treatment of blepharospasm associated with dystonia in adults and children ≥12 years of age.

Management of Meige’s syndrome† (idiopathic blepharospasm with facial and oromandibular dystonias).

Strabismus and Nystagmus

Management of dystonia-associated strabismus; designated an orphan drug by FDA for this use. An effective alternative or adjunct to surgery in selected adults and children with congenital or acquired strabismus.

Also has been used in vertical strabismus in dysthyroid ophthalmopathy for which surgery is inappropriate.

Safety and efficacy not established for treatment of ocular deviations >50 prism diopters†, restrictive strabismus†, or Duane’s syndrome with lateral rectus weakness†.

Has been used in surgically overcorrected or undercorrected strabismus; however, efficacy not established in strabismus secondary to prior surgical overrecession of the ocular antagonist muscle.

Not effective in chronic paralytic strabismus except as an adjunct to surgical repair to reduce ocular antagonist muscle contracture.

Spasmodic Dysphonia (Laryngeal Dystonia)

Treatment of choice for management of spasmodic dysphonia† (laryngeal dystonia) despite occasional complications and possible risk of reflex laryngeal stridor. Spasmodic dysphonia involving the adductor muscles appears to be more common; a limited number of patients with abductor muscle spasm have obtained some benefit from EMG-guided injections of the toxin into the posterior cricoarytenoid muscle.

Oromandibular Dystonias

Has been used successfully in the management of various oromandibular dystonias† (e.g., Meige’s syndrome†); considered a treatment of choice by some clinicians, although efficacy evidence from well-controlled studies is lacking.

Focal Limb Dystonias

Has been used for the management of focal limb dystonias (e.g., writer’s cramp†); considered first-line therapy.

Tremor

Has been used for the management of various types of tremor†, including hand tremor†.

Axillary Hyperhidrosis

Management of severe primary axillary hyperhidrosis that has not responded adequately to conservative treatments (e.g., topical antiperspirants).

Requires repeated treatment but avoids associated morbidity (e.g., pneumothorax, Horner’s syndrome, compensatory hyperhidrosis) of surgical procedures.

Gustatory Sweating

Used with good results in patients with gustatory sweating† (e.g., Frey syndrome, diabetic gustatory sweating); considered a treatment of choice by some clinicians, although efficacy data are limited.

Cosmesis of Glabellar Facial (“Frown”) Lines

Used for temporary improvement in the appearance of moderate to severe glabellar facial (“frown”) lines associated with corrugator and/or procerus muscle activity.

A treatment of choice in individuals wishing to avoid major procedure.

Cosmetic effects generally persist at least 4–6 months.

May not be appropriate when a wide range of facial expressions is required for professional or personal reasons.

Cosmesis of Lateral Canthal Wrinkles (“Crow’s Feet”)

Has been used for temporary improvement in the appearance of facial wrinkles associated with hyperactivity of the orbiculus oculi muscle† (lateral canthal wrinkles†, also known as “crow’s feet”†).

Cosmesis of Horizontal Forehead Lines

Has been used for temporary improvement in the appearance of hyperfunctional facial lines caused by frontalis muscle hyperactivity† (horizontal forehead lines).

Young individuals (usually females) with expressive horizontal forehead lines reportedly exhibit the best response.

Spasticity Associated with Cerebral Palsy

Has been used for the treatment of dynamic muscle contracture in pediatric patients with cerebral palsy†; designated an orphan drug by the FDA for this use. Some clinicians suggest conjunctive use of physical therapy and orthotics (e.g., casting).

Also has been used as an adjunct to analgesics for relief of postoperative pain secondary to muscle spasm associated with cerebral palsy† following orthopedic surgery.

Spasticity Associated with Stroke

Has been used to decrease spasticity, improve posture and range of motion, and relieve painful muscle spasms in patients with spasticity associated with stroke†.

Spasticity Associated with Multiple Sclerosis

Has been used for treatment of spasticity associated with multiple sclerosis† (e.g., hip adductor spasms†, spastic ankles†).

Anal Sphincter Disorders

Has been used effectively to treat uncomplicated cases of chronic anal fissure†; circumvents potential complications of surgery.

Has been used for pain reduction following hemorrhoidectomy†, presumably as a result of reducing spasm of the anal sphincter.

Neurogenic Voiding Dysfunction

Has been used for the treatment of detrusor-sphincter dyssynergia† (generally detrusor-external sphincter dyssynergia†) associated with spinal cord disease or injury.

Voiding Dysfunction Associated with Benign Prostatic Hyperplasia

Has been used to treat voiding dysfunction associated with benign prostatic hyperplasia† (benign prostatic hypertrophy, BPH).

Achalasia

Has been used successfully in a limited number of patients to relieve dysphagia, pain, and regurgitation associated with achalasia†; much less effective in achalasia secondary to gastroesophageal junction carcinoma or other malignancy than in idiopathic achalasia.

Musculoskeletal Pain Disorders

Has been used for pain relief in a variety of pain disorders of musculoskeletal origin, including myofascial pain syndrome†, chronic neck pain†, chronic lower back pain†, and whiplash-associated disorder†.

Has also been used for treatment of tennis elbow†.

Prophylaxis of Disabling Headache

Has been used to reduce the frequency of and/or pain associated with migraine headache† in certain patients who require an alternative to conventional drug therapies because of inefficacy, intolerance, contraindications, and/or poor compliance.

Has been used with relatively inconsistent benefit in post-whiplash (cervicogenic) headache†.

Dosage and Administration

General

• Adjust dosage carefully according to response and particular condition treated.
• Generally, the effective IM dose depends on muscle mass: the larger the muscle, the higher the required dose.
• Individual susceptibility to the toxin varies; and optimal dosages for a number of conditions have not been fully elucidated.
• Lower doses may be required in patients with preexisting weakness or when there is concern about weakness, in those with milder disease severity, and in women and patients with lower body weights.
• If a patient fails to respond, consider possibility of an inadequate drug dose, incorrectly reconstituted and/or improperly stored drug solution, and/or misinjection.
• Manufacturer recommends ≥12 weeks between treatment sessions for cosmesis.
• Some clinicians state strict adherence to recommended treatment interval of 12 weeks is not critical with low doses administered for cosmesis (e.g., 100 units total dose); such clinicians repeat injections after 2 weeks if desired results are not achieved after initial treatment.
• Some clinicians suggest a treatment interval ≥8–12 weeks for noncosmetic indications.

Administration

Administer by IM injection into affected muscles, intradermally, intracutaneously†, sub-Q†, or directly into affected glands†.

IM Administration

Administer by IM injection into affected muscles.

Just before administration, withdraw a volume of reconstituted drug slightly greater than the volume of the intended dose into an appropriately sized sterile syringe and expel any air bubbles in the syringe barrel; attach a new needle appropriate for the injection site to the syringe and confirm needle patency.

Reconstitution

Formulations of Botox^® and Botox^® Cosmetic of botulinum toxin type A are identical and are interchangeable provided the appropriate dilutions and administration techniques for a given indication are used.

For noncosmetic uses, reconstitute vial containing 100 units of vacuum-dried drug with 1, 2, 4, or 8 mL of 0.9% sodium chloride injection without preservatives to provide a solution containing 10, 5, 2.5, or 1.25 units per 0.1 mL, respectively.

For cosmetic uses, reconstitute 50- or 100-unit vials of vacuum-dried drug with 1.25 mL or 2.5 mL, respectively, of 0.9% sodium chloride injection without preservatives to provide solutions containing 4 units of botulinum toxin type A per 0.1 mL.

Use a new, sterile needle and syringe to enter the vial during reconstitution and for withdrawal of each dose.

To prevent possible toxin inactivation, allow stopper of vial to dry thoroughly after cleansing with alcohol before entering vial with a needle.

Vials may be reentered to treat the same patient within 4 hours of reconstitution; refrigerate during this time.

Direct 0.9% sodium chloride diluent toward side of vial using an appropriately sized syringe with a 21-gauge, 2.5-inch needle. Gently swirl to avoid excessive foaming of solution; do not shake.

Record date and time of reconstitution on drug vial.

Carefully dispose of all used vials, including expired vials and/or equipment used in preparation and administration, as medical waste.

Dilution

The optimum dilution to produce maximal effect not established; however, some clinicians state that use of concentrated solution (e.g., 100 units/mL) avoids many complications related to more extensive spread of toxin when less concentrated solutions (e.g., 10 units/mL) used.

Prepare desired dose for administration by using a fixed concentration of the drug (e.g., 20–100 units/mL) and varying the volume of the injection to obtain the appropriate dose (e.g., decrease administered injection volume from 0.1 mL to 0.05 mL per dose to decrease dose by 50%, or increase administered injection volume from 0.1 mL to 0.15 mL to increase dose by 50%) or by diluting the appropriate dose in a fixed volume (e.g., 2–4 mL) of diluent (e.g., 0.9% sodium chloride injection without preservatives).

Lidocaine reportedly used as diluent to reduce pain on injection†; however, manufacturer states that diluents other than 0.9% sodium chloride injection without preservatives are not recommended because of potential for unknown interactions or adverse effects of other components.

Bacteriostatic (i.e., preserved with benzyl alcohol) 0.9% sodium chloride injection used as a diluent† reportedly is associated with less pain upon injection. However, manufacturer states that diluents other than 0.9% sodium chloride injection without preservatives are not recommended.

IM Injection Techniques

Targeting injection to the appropriate muscle(s) may be facilitated by active electromyography (EMG), ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks (e.g., evidence of muscular hypertrophy, stiffness, tenderness, visible abnormal muscular activity).

EMG-guided injections often recommended to ensure optimal placement of toxin for efficacy, particularly in patients who have not responded adequately to previous injections, and to minimize adverse effects on nonaffected tissue.

EMG guidance may allow more accurate identification of neural motor end plate, facilitating more precise injection and improving effectiveness of lower doses.

Injection into the midbelly of larger muscles where the motor end plates are located may enhance benefit.

Cervical Dystonia

Total dose administered at each treatment session is given as several injections divided among affected muscles.

Identify affected muscles by careful clinical evaluation, including physical examination and palpation (e.g., for areas of hypertrophy, pain). Palpation of contracting muscles while the patient’s head is placed in the position most favored by dystonic pulling of the neck muscles reportedly is helpful.

EMG guidance also may be useful in delineating involved muscles for injection, particularly in obese patients or for muscles difficult to identify by palpation.

Blepharospasm and Hemifacial Spasm

For the treatment of blepharospasm, the initial recommended dose is injected at each site without EMG guidance into the medial and lateral pretarsal orbicularis oculi of the upper lid and into lateral pretarsal orbicularis oculi of the lower lid.

Reduce or prevent ecchymosis of adnexa by using very fine-gauge needles (e.g., 30- , 32-gauge), limiting repeat use of needles to ≤4 times, appropriate discontinuance of medications and supplements that affect platelet function (e.g., aspirin, vitamin E) prior to injection, and by applying pressure and/or ice to the injection site immediately post-injection.

Reduce risk of ptosis by avoiding injection near the levator palpebrae superioris.

Reduce risk of diplopia by avoiding medial lower lid injections, thereby reducing drug diffusion into the inferior oblique muscle.

Treatment of hemifacial spasm, which sometimes occurs in conjunction with blepharospasm, should be individualized. Initially inject only those muscles considered most disturbing to the patient, such as the orbicularis oculi (as for blepharospasm); affected muscles of the lower face may respond through drug diffusion or cessation of eyelid contractions that act as a trigger for spasm.

Strabismus

To ensure optimum placement of the needle within targeted extraocular muscles, injection with EMG guidance or into exposed muscles during surgery is recommended; however, some clinicians suggest that the drug can be safely administered by clinicians with sufficient experiential knowledge of orbital anatomy.

Spasmodic Dysphonia Involving the Adductor Muscles

Inject into the thyroarytenoid vocalis complex via the cricothyroid cartilage with EMG guidance; use a hollow, Teflon^®-coated needle.

Also has been given by indirect laryngeal endoscopy (without EMG guidance) in some (e.g., post-surgical) patients.

While injections have been given into both vocal cords, some clinicians prefer unilateral injections to minimize adverse effects; controversy exists regarding the optimal method.

Spasmodic Dysphonia Involving the Abductor Muscles

Inject into the posterior cricothyroid muscle using EMG guidance.

Injection of abductor muscles is technically complicated and has the potential to cause serious adverse effects such as bilateral abductor paralysis with airway obstruction.

Oromandibular Dystonia

Use EMG and/or palpation to select for injection the muscles responsible for the particular type of oromandibular dysfunction (e.g., jaw-closing, jaw-opening).

Spasticity Associated with Cerebral Palsy

Optimal treatment regimen, including optimal dose and number of injection sites, not determined.

Chronic Anal Fissure

Inject both lateral and distal to the fissure; local anesthesia before injection generally not necessary.

Inject internal or external anal sphincter; optimal injection site not determined. Some clinicians prefer injection of the internal sphincter because spasm of this muscle contributes to chronic anal fissure and because of its ease of palpation and injection.

Other clinicians prefer injection of the external sphincter because of concerns that inaccurate localization of the injection in the internal sphincter may result in fecal and/or flatulence incontinence attributable to drug diffusion into the intrasphincteric space.

Avoid deep injections that may enter the puborectalis muscle; such injections may be associated with a high risk of incontinence.

Neurogenic Voiding Dysfunction

May be administered by transperineal injection guided by EMG, transrectal ultrasound, or MRI or transurethral injection (generally into the external urethral sphincter) during cystoscopy.

Achalasia

Administer injections into the lower esophageal sphincter (LES) during endoscopy.

Optimum candidates include patients with symptomatic achalasia who have concomitant illness and/or who are at high risk for complications such as esophageal reflux or perforation (generally geriatric patients, who may be more likely to respond than younger patients), those who have not responded to prior myotomy, those who have had esophageal perforation associated with pneumatic dilatation, and those with an epiphrenic diverticulum.

Headache

Standardized doses and procedures for injection have not been established.

Fixed doses given at symmetrical injection sites recommended for patients with migraine or migrainous headache, while sites of injection for those with tension-type headache generally are determined by the location of pain (“follow the pain” approach); a combination of these techniques has been suggested for patients with coexisting migraine and tension-type headache.

Injection sites most commonly used for the treatment of headache include the glabellar and frontal regions, the temporalis and occipitalis muscles, and the cervical paraspinal region.

Administration Precautions for Facial Cosmesis

When used for facial cosmesis, ensure that the correct injection volume and concentration are administered.

Minimize the risk of ptosis by avoiding injections near the levator palpebrae superioris, especially in individuals with larger brow-depressor complexes.

Injections in the forehead area should always be made above the lowest fold produced when the individual is asked to elevate their forehead, or ≥2 cm above the brow.

In older individuals, do not inject the lower portion of the brow (this muscle is used to raise the eyebrows in order to see).

Do not treat entire forehead and glabellar lines during a single session; high risk of ptosis.

When injections in the midpupillary line are made in individuals with large brow-depressor complexes, inject 1 cm above the bony superior orbital margin; dose should not exceed 5 units.

Injection sites in the medial corrugator muscle should be ≥1 cm above the supraorbital ridge and should not be injected <1 cm above the central eyebrow.

Avoid eyelid ptosis by asking the individual to remain upright (e.g., avoid naps in the reclining position) for 4 hours following treatment, avoid rubbing or massaging the treated area for 4 hours (to prevent excess diffusion and possible weakness of adjacent muscles), and frown and smile repeatedly for at least ≥1–4 hours immediately following treatment.

Apply digital pressure at the border of the supraorbital ridge while injecting the corrugator muscle to minimize the potential for diffusion into the levator muscle and resultant weakening.

When injection sites are marked (e.g., with a ball-point pen) to ensure optimal targeting, avoid injecting directly into the marked areas to prevent tattooing of the skin.

Before injection, instruct the individual to accentuate specific facial lines to be treated by frowning (for glabellar lines), squinting (for lateral canthal wrinkles), or elevating the brow (for horizontal forehead lines).

When treating lateral canthal wrinkles (“crow’s feet”), avoid injecting too close to the eyelids to avoid delayed eye closure, decreased blinking, excessive tearing, and lateral rectus muscle weakness. Inject 1 cm outside the bony lateral orbital margin or 1.5 cm lateral to the lateral canthus to minimize risk of transient strabismus or diplopia. Avoid making injections below the zygomaticus muscle to avoid ptosis of the upper lip.

Inject as superficially as possible in a series of continuous blebs to avoid ecchymoses in the periorbital area, with each injection at the advancing border of the previous one to avoid hitting blood vessels.

Vary volume and concentration of injections according to the area being treated (e.g., lateral canthal wrinkles, glabellar lines, platysma). Low-volume, concentrated solutions are recommended to paralyze specific facial muscles; larger volumes of less-concentrated solutions may be used to smooth lateral canthal wrinkles (“crow’s feet”) or the brow area. However, larger, less-concentrated volumes of solution reported to result in unacceptably short durations of improvement and larger areas of undesired paralysis.

Cosmesis of Glabellar Facial Lines

Clinicians using a botulinum toxin for facial cosmesis should be thoroughly familiar with dynamic facial anatomy.

Inject affected facial muscles with a 30-gauge needle and tuberculin syringe.

EMG-guided injection has been recommended to more accurately target certain facial muscle(s) (e.g., platysma, in the lower face, or where there is facial asymmetry), but some clinicians suggest that EMG may be of limited benefit when muscles to be injected are difficult to identify by palpation and/or visualization.

Some clinicians suggest that toxin injected in the procerus muscle be massaged toward the depressor supercilii muscle following injection (i.e., to decrease activity of the depressor muscle and its contribution to facial lines).

Effects appear to last longer with repeated treatments in some individuals. Attributed to behavioral modification (i.e., avoiding certain facial movements that produce excessive pleating of facial skin) or to some degree of fibrosis or atrophy of injected muscles. No histologic evidence of permanent degeneration or atrophy to date.

Cosmesis of Horizontal Forehead Lines

Inject sites laterally in an arc away from the brow, with the most lateral injection placed vertically above the midpupil to retain some frontalis muscle function for facial expression.

A second treatment session may be needed for optimal results if several rows of deep hyperfunctional forehead lines are present.

Firmly massage sites laterally following injection.

Cosmesis of Lateral Canthal Wrinkles (“Crow’s Feet”)

Administer the toxin as the individual squints in an exaggerated manner at several sites located 1 cm lateral to the bony rim or 1.5 cm lateral to the lateral canthus at 1- to 1.5-cm intervals into the raised folds of skin in an arc from just beneath the lateral edge of the eyebrow down to the lateral infraorbital rim.

Controlling Injection Pain

Pretreatment with ice packs or topical or local anesthetics (e.g., lidocaine/prilocaine cream [EMLA] and an occlusive dressing, proparacaine hydrochloride ophthalmic drops) has been recommended prior to injection, particularly when preexisting muscle pain exists or when injecting extrinsic ocular muscles.

Other clinicians report topical or local anesthetics are not useful to prevent injection pain since they do not penetrate underlying muscles and/or require additional injections.

Dilution with 0.9% sodium chloride injection containing a preservative (benzyl alcohol) has been reported to reduce pain on injection; however, the manufacturer recommends use of 0.9% sodium chloride injection without preservatives for reconstitution and/or dilution.

IV sedation or general anesthesia may be needed prior to injection in some patients (e.g. those in considerable pain, those with urologic conditions, pediatric patients receiving multiple injections in the hand).

Intradermal Injection

Administer by intradermal injection for treatment of hyperhidrosis.

Hyperhidrosis

Use standard staining techniques (e.g., Minor’s iodine starch test) to identify axillary hyperhidrotic area for injection.

Consult manufacturer’s labeling or specialized references for instructions on how to perform Minor’s iodine starch test.

Make injections at a 45° angle to the skin surface and as superficially as possible to ensure intradermal administration, minimize leakage, and allow optimum diffusion into the eccrine gland.

If injection sites are marked with ink, avoid direct injection into marked areas to prevent permanent tattooing of the skin.

Carefully compress treated skin area to promote drug penetration.

Intraglandular Injection

Administer by injection directly into affected gland(s)†.

Voiding Dysfunction Associated with Benign Prostatic Hypertrophy

Injections into the prostate gland may be administered by transrectal ultrasonography (TRUS) guidance.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

All doses refer to units of Botox^® or Botox^® Cosmetic; these preparations have equivalent potency on a unit-for-unit basis.

Botox^® and Botox^® Cosmetic formulations are identical, and the manufacturer states that these preparations may be used interchangeably provided the appropriate dilutions and administration techniques for a given indication are used. (See Reconstitution under Dosage and Administration.)

Units of biologic activity for different serotypes or formulations of botulinum toxin cannot be compared with or converted to units of other botulinum toxins. Data on several different serotypes (e.g., botulinum toxin types A, B, C, F) and/or formulations of botulinum toxin have been reported; assay methods used to determine potency of these various toxins are specific to each individual manufacturer and/or formulation.

At least 2 different formulations and/or potencies of botulinum toxin type A have been used in clinical trials in the US and Europe (e.g., Botox^®, Dysport^®); Dysport^® currently is not commercially available in the US.

Differences in formulation and/or potency should be kept in mind when evaluating clinical trials involving different preparations of botulinum toxin.

Pediatric Patients

Blepharospasm and Associated Facial Nerve Disorders

Blepharospasm

IM

Initially, 1.25–2.5 units at each site injected with a sterile, 27- or 30-gauge needle without EMG guidance into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid.

This dose represents an injection volume of 0.05–0.1 mL at each injection site using a solution containing 25 units/mL.

Dose during subsequent treatment sessions may be increased by up to twofold if initial response is insufficient (e.g., the duration of effect is <2 months); however, little additional benefit from doses >5 units per site.

Tolerance may occur, especially if injections for blepharospasm are administered at <3-month intervals.

Alternatively, some clinicians recommend a dose of 15–20 units per eye divided among injection sites with a total cumulative dosage <100 units during any 30-day treatment period.

Manufacturer states that the total cumulative dosage should not exceed 200 units during any 30-day treatment period; some clinicians report routine use of considerably lower cumulative dosages (e.g., <100 units).

Initial effect generally occurs within 3 days of injection (range: 2–7 days), and maximal benefit occurs 1–2 weeks after treatment. The duration of effect is approximately 3 months and is rarely permanent.

Hemifacial Spasm

IM

Initial dose: 12–25 units administered into the inferior and superior orbicularis oculi, buccolabial, and/or platysma muscles.

Alternatively, 10–12.5 units injected into the orbicularis oculi and 2.5–5 units for most other affected facial muscles (e.g., 2 injections [2.5 units each] into the lower lid and 2 injections into the upper brow on the affected side with 1 additional injection of 2.5 units into the upper cheek for a total dose of 12.5 units) has been used.

Duration of response of hemifacial spasm may be somewhat longer compared with that in blepharospasm.

Strabismus

IM

Several minutes prior to injection, instill several drops of a topical ophthalmic anesthetic (e.g., 0.5% proparacaine hydrochloride) and an ocular decongestant (e.g., 2.5% phenylephrine hydrochloride) in the affected eye(s).

Strabismus involving vertical extraocular muscles or horizontal strabismus of <20 prism diopters: 1.25–2.5 units initially injected into any one muscle.

Horizontal strabismus of 20–50 prism diopters: 2.5–5 units initially into any one muscle; some clinicians suggest dividing this dose between the muscles of both affected eyes.

Persistent sixth-nerve palsy lasting ≥1 month: 1.25–2.5 units initially injected into the medial rectus muscle.

Use lower dose in each dose range for treatment of small deviations and larger doses only for large deviations.

The volume injected for the treatment of strabismus should be 0.05–0.15 mL per muscle.

Paralysis of injected muscles generally begins 1–2 days after injection and increases in intensity during the first week after injection. Paralysis generally lasts 2–6 weeks and gradually resolves over a similar time period.

Overcorrections exceeding 6 months in duration have been reported rarely.

Reexamine patients 7–14 days after each injection to evaluate response and to determine need for additional or larger doses.

Subsequent injections will be required in approximately 50% of patients because of inadequate initial response, mechanical factors (e.g., large deviations or restrictions), and/or lack of binocular motor fusion to stabilize the alignment.

If subsequent injections are required, administer a dose comparable to the initial dose in patients who experience adequate paralysis of the target muscle. For patients experiencing incomplete paralysis of the target muscle after the initial injection, increase dose up to twofold compared with the previously administered dose.

Do not be administer subsequent injections until the effects of the previous dose have dissipated as evidenced by substantial return of function in the injected and adjacent muscles.

Maximum dose as a single injection into any one muscle is 25 units.

Spasticity Associated with Cerebral Palsy

IM

Optimal treatment regimen, including optimal dose and number of injection sites, has not been determined.†

Base dose on the size of the muscles to be injected, the number of muscles to be injected concurrently, and the body weight of the patient; other factors used to determine the appropriate dose include general health of the patient, target muscle strength, antagonist muscle strength, potential number of neuromuscular junctions in the target muscle, degree of joint function and/or deformity, patient age, concern for excessive muscular weakness, anticipated duration of therapy, and previous response to therapy.†

Dose of 1–6 units/kg per muscle has been recommended based on clinical experience, with a maximum dose of 3–6 units/kg per treatment session for large muscles, a maximum dose of 1–2 units/kg per treatment session for small muscles, and a maximum dose of 50 units per injection site.†

Maximum recommended total dose administered during a single treatment session should not exceed 12 units/kg or 400 units, whichever is less.†

Alternatively, maximum dose of 6 units/kg per treatment session suggested by some clinicians.†

Largest total dose injected at one treatment session reportedly 29 units/kg, divided among several large muscles of the lower extremities.†

Maximum dose of 10–12 units/kg per treatment session has been recommended when only 1 or 2 muscles are injected.†

Onset of muscle weakness following injection generally occurs within 2–3 days and reaches a peak after about 3–4 weeks; reassess patients 6 weeks after initial treatment session. Muscle weakness generally wears off after 3 months; functional improvement may last considerably longer.†

Adults

Cervical Dystonia

IM

Titrate dose in initial and subsequent treatment sessions to patient’s previous response to the drug, history of adverse reactions, severity of dystonia based on head and neck position, localization of pain, muscular hypertrophy, mass of target muscles, and their proximity to critical toxin-sensitive anatomic structures (e.g., larynx, pharynx).

Initial dose for toxin-naive patients should be relatively small; adjust subsequent doses based on patient response and tolerance.

Median dose following adjustment according to initial response and tolerance in a clinical trial was 236 units (25th to 75th percentile range: 198–300 units) divided among affected muscles.

Alternatively, some clinicians suggest a dose of 25–75 units per affected muscle.

Onset of clinical improvement generally observed within 2 weeks of treatment and maximum benefit occurs approximately 6 weeks after treatment; most patients return to their pretreatment status after 3 months.

Blepharospasm and Associated Facial Nerve Disorders

Blepharospasm

IM

Initially, 1.25–2.5 units at each site injected with a sterile, 27- or 30-gauge needle without EMG guidance into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid.

This dose represents an injection volume of 0.05–0.1 mL at each injection site using a solution containing 25 units/mL.

Dose during subsequent treatment sessions may be increased by up to twofold if initial response is insufficient (e.g., the duration of effect is <2 months); however, little additional benefit from doses >5 units per site.

Tolerance may occur, especially if injections for blepharospasm are administered at <3-month intervals.

Alternatively, some clinicians recommend a dose of 15–20 units per eye divided among injection sites with a total cumulative dosage <100 units during any 30-day treatment period.

Manufacturer states that the total cumulative dosage should not exceed 200 units during any 30-day treatment period; some clinicians report routine use of considerably lower cumulative dosages (e.g., <100 units).

Initial effect generally occurs within 3 days of injection (range: 2–7 days), and maximal benefit occurs 1–2 weeks after treatment. The duration of effect is approximately 3 months and is rarely permanent.

Hemifacial Spasm

IM

Initial dose: 12–25 units administered into the inferior and superior orbicularis oculi, buccolabial, and/or platysma muscles.

Alternatively, 10–12.5 units injected into the orbicularis oculi and 2.5–5 units for most other affected facial muscles (e.g., 2 injections [2.5 units each] into the lower lid and 2 injections into the upper brow on the affected side with 1 additional injection of 2.5 units into the upper cheek for a total dose of 12.5 units) has been used.

Duration of response of hemifacial spasm may be somewhat longer compared that in blepharospasm.

Strabismus

IM

Several minutes prior to injections, instill several drops of a topical ophthalmic anesthetic (e.g., 0.5% proparacaine hydrochloride) and an ocular decongestant (e.g., 2.5% phenylephrine hydrochloride) in the affected eye(s).

Strabismus involving vertical extraocular muscles or horizontal strabismus of <20 prism diopters: 1.25–2.5 units initially injected into any one muscle.

Horizontal strabismus of 20–50 prism diopters: 2.5–5 units initially into any one muscle; some clinicians suggest dividing this dose between the muscles of both affected eyes.

Persistent sixth-nerve palsy lasting ≥1 month: 1.25–2.5 units initially injected into the medial rectus muscle.

Use lower dose in each dose range for treatment of small deviations and larger doses only for large deviations.

The volume injected for the treatment of strabismus should be 0.05–0.15 mL per muscle.

Paralysis of injected muscles generally begins 1–2 days after injection and increases in intensity during the first week after injection. Paralysis generally lasts 2–6 weeks and resolves gradually over a similar time period.

Overcorrections exceeding 6 months in duration have been reported rarely.

Reexamine patients 7–14 days after each injection to evaluate response and to determine need for additional or larger doses.

Subsequent injections will be required in approximately 50% of patients because of inadequate initial response, mechanical factors (e.g., large deviations or restrictions), and/or lack of binocular motor fusion to stabilize the alignment.

If subsequent injections are required, administer a dose comparable to the initial dose in patients who experience adequate paralysis of the target muscle. For patients experiencing incomplete paralysis of the target muscle after the initial injection, increase dose up to twofold compared with the previously administered dose.

Do not administer subsequent injections until the effects of the previous dose have dissipated as evidenced by substantial return of function in the injected and adjacent muscles.

Maximum dose as a single injection into any one muscle is 25 units.

Spasmodic Dysphonia (Laryngeal Dystonia)

Adductor Muscle Dysphonia

IM

Some clinicians have used small doses (e.g., 0.031–4 units) injected into both vocal cords to produce mild bilateral paralysis, while others have injected larger doses (5–30 units) into one vocalis complex to produce unilateral paralysis. Dosage can be adjusted based on the severity of glottal spasms and the response to previous injections.†

Improvement in voice fluency generally occurs within 24–72 hours and lasts for up to 3–6 months.†

Abductor Muscle Dysphonia

IM

Total doses of 1.25–5 units have been injected into the posterior cricothyroid muscle.†

Alternatively, some experts use total doses averaging less than 1 unit (range: 0.1–10 units) per vocal cord.†

Some clinicians recommend injection of only one side of the abductor muscle during any given treatment session with an additional dose on the same side 2 weeks later if abduction is still present, or injection of the contralateral side if the initial injection produced paralysis of the abductor but did not result in adequate voice improvement.†

Oromandibular Dystonia

IM

Wide range of doses has been used.†

Low doses may be used initially to produce gradual muscle weakening, with dose titration on repeat injections according to response.†

Jaw-closing oromandibular dystonias: 25–50 units into each masseter muscle suggested; if satisfactory results are not obtained, 5–40 units also may be injected into each temporalis muscle.†

Primary Axillary Hyperhidrosis

Intradermal

Total dose of 50 units per axilla injected with a 30-gauge needle. Administer dose in aliquots of 0.1–0.2 mL in multiple (10–15), evenly spaced sites (to minimize the area of no effect) approximately 1–2 cm apart.

Total doses of 50–60 units (e.g., 2.5–5 units/cm² of skin area) injected among 10–20 sites in the hyperhidrotic area of each axilla also have been used.

Unlike in other indications (e.g., cosmetic treatment of facial lines), the dose in hyperhidrosis is best determined by the surface area of involved skin rather than by muscle mass.

Total doses as low as 30 units in each axilla have been used.

Maximum total dose of 100 units per axilla in larger individuals recommended by some clinicians; doses of up to 200 units per axilla have been used in a limited number of patients to achieve a prolonged response (e.g., up to 19 months).

Anhidrosis generally occurs within 24 hours, reaches a peak at 1 week, and lasts 4–12 months; duration of response appears to be dose related. Repeat injections should be administered when the clinical effect of previous dose have diminished.

Cosmesis of Glabellar Facial (“Frown”) Lines

IM

Initially, some clinicians suggest intentionally underdosing until the individual’s response to the drug is ascertained.

Since the location, size, and use of the involved facial muscles vary markedly among individuals, dosage adjustment may be based on the effect of a given dose on facial line cosmesis determined by gross observation of the individual’s ability to activate the targeted superficial muscles 2–4 weeks after an injection.

Manufacturer recommends total dose of 20 units per treatment session administered by injecting 4 units (0.1 mL of a solution containing 40 units/mL) into each of 5 sites: 2 injections in each corrugator muscle and one in the procerus muscle.

A variety of other doses has been suggested.

Doses of 2–25 units per injection site or 0.5–1 unit/kg have been recommended for facial cosmesis

Minimum doses required for a demonstrable response: 5–12.5 units per session or 1–2.5 units per injection site.

Effective initial doses: 12.5–20 units per session or 2.5–5 units in each corrugator muscle and 2.5 units in the procerus muscle.

Larger doses may be required in men because of greater forehead muscle mass or in women who have more horizontal brows, deeper frown lines, or larger and stronger forehead muscles.

Initial injections generally induce chemical denervation of targeted muscles 24–48 hours after injection; paralytic effect may continue to increase in intensity for as long as 1 week after injection, and sometimes may not become evident for up to 14 days following injection.

Treatment sessions should be ≥3 months apart and lowest effective dose should be used. (See Antibody Formation and Tolerance, under Cautions.)

Cosmetic effects generally last approximately 3–4 months, although durations of up to 6 months have been reported.

Some clinicians repeat injections 2 weeks after initial treatment of hyperfunctional facial lines (e.g., glabellar region, forehead, lateral canthal wrinkles) if the individual is not pleased with the cosmetic results and suggest that the limitation on the injection interval is not crucial with the small doses (generally <100 units) used for most cosmetic indications.

Cosmesis of Lateral Canthal Wrinkles (“Crow’s Feet”)

IM

6–18 units (e.g., 2.5–3 units per injection) for each side has been used; higher doses necessary in some individuals.†

Alternatively, 8–10 units administered as 5 units in 2 sites on each side or as 8 units in 1 site on each side has been used.†

Cosmesis of Horizontal Forehead Lines

IM

Some clinicians recommend total doses of 5–35 units for the forehead area, administered as multiple injections of 2.5 or 5 units each about 1.5–2 cm apart in an evenly distributed grid pattern followed by firm massage laterally.†

Alternatively, administer 6 injections of 3 units each about 1.5–2 cm apart across the forehead.†

Alternatively, higher total doses of 25–60 units have been suggested.†

A second treatment session may be needed for optimal results if several rows of deep hyperfunctional forehead lines are present.†

Effects generally apparent within 3 days after injection; up to 14 days may be required for results to become evident.†

Maximal effects observed in 1–2 weeks and generally last 3–6 months; prolonged responses reported in some patients, allowing yearly reinjection intervals.†

Anal Sphincter Disorders

Chronic Anal Fissure

IM

5–20 units initially has generally been used.†

Healing rates may be higher with higher doses.†

Injections may be repeated using initial or higher dose in patients who fail to heal or who have relapses.†

Pain reduction occurs within 2 days and reduced sphincter tone maintained for ≥4 weeks.†

Neurogenic Voiding Dysfunction

IM

Neurogenic voiding dysfunction (e.g., chronic urinary retention, severe dysuria) associated with detrusor-sphincter dyssynergia, dysfunctional voiding, nonrelaxing urethral sphincter, cauda equina lesion, peripheral neuropathy, and idiopathic detrusor underactivity: 50 or 100 units administered as a single injection, generally into the external urethral sphincter, has been used.†

Detrusor-sphincter dysfunction associated with spinal cord injury or trauma: 80–100 units administered as a single injection.†

Onset of improvement in urinary symptoms has occurred about 7–15 days following injection; duration of benefit appears dose-related.†

Duration of response in patients receiving a single 100-unit injection for detrusor-sphincter dyssynergia is about 2–3 months; patients who received 100 units monthly for 3 months had improvement in vesicourethral function for 9–13 months.†

Achalasia

IM

Total doses of 80–100 units injected into the lower esophageal sphincter (LES) during endoscopy, generally as 4 injections of 20 units each (20 units/mL) into various quadrants of the LES.†

Headache

IM

Various types of headache†, including migraine†, cluster headache†, tension-type headache†, chronic daily headache†, and cervicogenic headache†: Total doses of 10–150 units IM given in multiple sites generally have been used.†

Total doses as high as 250 units reportedly have been used.†

Migraine: Some clinicians suggest that higher total doses (75–150 units) in multiple sites may be needed for more consistent efficacy.†

Maximum headache relief may require several weeks after injections.†

Evaluate patients 4–6 weeks after injection; repeat injections generally are needed after 3–4 months, although duration of response varies.†

Prescribing Limits

Pediatric Patients

Blepharospasm

IM

Total cumulative dosage should not exceed 200 units during any 30-day treatment period.

Doses >5 units per site provide little added benefit. Tolerance to therapy increased if injections are administered at <3-month intervals.

Strabismus

IM

Maximum dose: 25 units as a single injection into any one muscle.

Spasticity Associated with Cerebral Palsy

IM

Maximum recommended total dose administered during a single treatment session should not exceed 12 units/kg or 400 units, whichever is less.

Alternatively, maximum dose of 6 units/kg per treatment session suggested by some clinicians.

Largest total dose injected at one treatment session reportedly was 29 units/kg, divided among several large muscles of the lower extremities.

Maximum dose of 10–12 units/kg per treatment session has been recommended when only 1 or 2 muscles are injected.

Adults

Cervical Dystonia

IM

Some clinicians suggest total dose per treatment session should not exceed 200 units; however, doses as high as 300–400 units per treatment session reported.

Decrease risk of dysphagia by using multiple injection sites rather than a single site and by limiting the total dose injected into the sternocleidomastoid muscles to ≤100 units. (See Dysphagia under Cautions.)

Blepharospasm

IM

Total cumulative dosage should not exceed 200 units during any 30-day treatment period.

Doses exceeding 5 units per site provide little added benefit. Tolerance to therapy increased if injections are administered at <3-month intervals.

Strabismus

IM

Maximum dose: 25 units as a single injection into any one muscle.

Primary Axillary Hyperhidrosis

IM

Maximum total dose: 100 units per axilla in larger individuals recommended by some clinicians. Doses of up to 200 units per axilla have been used. The manufacturer-recommended dose is 50 units per axilla.

Cosmesis of Glabellar Facial Lines

IM

When injections in the midpupillary line are made in individuals with large brow-depressor complexes, inject 1 cm above the bony superior orbital margin; dose should not exceed 5 units.

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Cautions

Contraindications

• Hypersensitivity to botulinum toxin type A or any ingredient in the formulation.
• Infection at the proposed injection site(s).

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Botox^® Formulations

Formulations of Botox^® and Botox^® Cosmetic of botulinum toxin type A are identical; therefore, adverse effects observed with Botox^® also may occur with use of Botox^® Cosmetic.

Adherence to Recommended Dosage

Do not exceed recommended dosage and frequency of administration; safety and efficacy of higher dosages have not been evaluated. Severe adverse effects, including a botulism-like syndrome, have been reported with use of higher than recommended dosages of botulinum toxins and/or unlicensed preparations of botulinum toxins. Deaths reported rarely, sometimes associated with dysphagia, pneumonia, and/or other substantial debility or anaphylaxis.

Comorbid Disorders

Increased risk of serious adverse systemic effects, including severe dysphagia, muscle weakness, and/or respiratory compromise, with recommended doses in patients with underlying conditions such as peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junction disorders (e.g., myasthenia gravis, Lambert-Eaton syndrome); exercise caution when used in such patients. May be related to use of higher dosages in such patients.

Rarely, extreme sensitivity to systemic effects of usual clinical doses reported in patients with known or unrecognized neuromuscular disorders; some patients experienced several months of severe dysphagia and required a gastrostomy or nasogastric tube.

Some clinicians state that use for cosmetic treatment of neck wrinkles is contraindicated in patients with amyotrophic lateral sclerosis.

Serious systemic effects related to distant spread of botulinum toxin reported, more often and with greater severity in children with cerebral palsy receiving such therapy; hospitalizations and deaths have occurred.

Dysphagia

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Most common serious adverse effect reported in patients with cervical dystonia; also reported in patients receiving botulinum toxin type A for other conditions (e.g., torticollis, muscle spasticity associated with cerebral palsy). Results from diffusion of the toxin to tissues (e.g., posterior pharyngeal muscles) outside the injected muscles.

Rarely, fatal aspiration pneumonia or other serious debilities may develop subsequently.

Occurs most frequently following injection of one or both sternocleidomastoid or scalenus muscles; risk increased in patients with cervical dystonia and smaller neck muscle mass (e.g., female) receiving bilateral injections and/or relatively high doses into the sternocleidomastoid muscle. Also increased risk in cervical dystonia patients with subclinical dysphagia. Injections into the levator scapulae associated with an increased risk of dysphagia and upper respiratory infection.

Use lowest effective dose in high-risk muscles.

Average onset reportedly about 10 days, but can occur as early as day 1 or as late as several weeks following injection; average time to resolution about 3.5 weeks. Most cases are mild or moderate in severity, but some cases have required placement of gastric feeding tubes.

Reduce risk by decreasing dose or volume of injection (e.g., using multiple small injections) or by injecting ≥2 cm above belly of contralateral sternocleidomastoid muscle.

Transient dysphagia also reported in patients with spasmodic dysphonia (laryngeal dystonia), oromandibular dystonia, or spasticity associated with cerebral palsy.

Risk of Creutzfeldt-Jakob Disease

Formulation contains human albumin derived from blood. Theoretical but remote risk of transmission of Creutzfeldt-Jakob disease (CJD) via albumin component; however, no cases of CJD identified to date.

Sensitivity Reactions

Hypersensitivity Reactions

Serious and/or immediate hypersensitivity reactions (including anaphylaxis, urticaria, soft tissue edema, dyspnea) reported rarely. At least one fatal case of anaphylaxis reported; causal relationship not determined since lidocaine was used as diluent.

If anaphylaxis or other severe allergic reaction occurs, discontinue immediately and institute appropriate therapy (e.g., epinephrine) as indicated.

Major Toxicities

Systemic Toxicity (Botulism)

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Serious systemic toxicity, including respiratory compromise and death, reported during an ongoing FDA safety review of botulinum toxins type A and type B. More frequent and severe in children with limb spasticity associated with cerebral palsy. Causal relationship not established to date; FDA will review additional safety data from clinical studies, medical literature, and postmarketing adverse event reports to further evaluate risk of systemic toxicity. Botulism also possible after iatrogenic overdose or misinjection of botulinum toxin. Botulinum toxin generally not present in peripheral blood following IM injection of usual therapeutic doses and generally does not induce systemic effects (e.g., generalized or distant muscle weakness) in patients without predisposing neuromuscular dysfunction.

Precise risk of generalized muscle weakness after treatment not fully elucidated; however, generalized muscle weakness reported rarely following treatment of cervical dystonia. Generalized botulism-like syndrome, including respiratory arrest, reported rarely after IM injections of therapeutic doses.

Maximum safe dose that does not produce toxicity is not known; risk of acute botulism increased with single IM doses >500 units. Generalized botulism-like syndrome reported in at least one patient treated with cumulative IM dose of only 100 units. Serious systemic toxicity has been reported during postmarketing experience with doses of 6.25–32 units/kg in children and doses of 100–700 units in adults.

Manifestations of overdose (botulism) include diplopia, ptosis, blurred vision, photophobia, dry mouth, difficulty speaking and swallowing, autonomic dysfunction such as bowel stasis, and generalized muscle weakness that can progress to a symmetric, descending flaccid paralysis; manifestations not apparent immediately after the drug is injected.

If accidental injection or ingestion occurs, closely monitor patient for up to several weeks for manifestations of systemic weakness or muscle paralysis. Recovery occurs through neurogenesis of axonal sprouts and motor end plates; can require weeks or months.

In event of overdose or misinjection (i.e., wrong muscle), contact manufacturer immediately for additional information and state health department to obtain botulinum antitoxin through CDC; if state health department is not available, contact CDC by telephone at 404-639-2206 or 404-639-2888 (after hours). Antitoxin will not reverse botulinum toxin-induced muscle weakness already evident at the time of antitoxin administration but may stabilize the deficits.

Antitoxin to a given type of botulinum toxin does not neutralize other types (e.g., anti-A botulinum antitoxin does not neutralize botulinum toxin types B through G).

For information about overdosage, contact Allergan Pharmaceuticals at 800-433-8871 from 8:00–4:00 p.m. Pacific Time or at 714-246-5954 for a recorded message at other times.

General Precautions

Safe and Effective Use

Proper storage, deliberate dose selection, and proper reconstitution and administration practices critical for safe and effective use.

Experience of Clinician

Thorough knowledge of diagnosis, management, and regional anatomy of the treated disorder, careful dose selection, and accomplished injection techniques are critical in obtaining therapeutic benefit and minimizing adverse effects. Some experts recommend limiting use to clinicians with specialized training.

Working knowledge of EMG techniques required for treatment of strabismus; may be useful for accurate injection of target muscles in patients with cervical dystonia.

Systemic Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Local spread of toxin may result in weakness to adjacent muscles. Systemic spread of botulinum toxin also is possible and can cause a botulism-like syndrome (e.g., dysphagia, muscle weakness, ptosis, respiratory failure). Condition treated determines the muscles injected and therefore proximate muscles affected by infiltration and resultant undesired weakness.

Weakness of adjacent muscles commonly reported. Often occurs within first week of treatment and generally is transient but may persist for several months. Monitor patients for possible systemic effects including dysphagia, dysphonia, respiratory compromise, and generalized weakness following administration.

Excessive weakness of target muscles also may occur; neck weakness and dysphagia have been reported in cervical dystonia or cosmesis (e.g., age-related neck degeneration), ipsilateral upper-lip ptosis in cosmesis of lateral canthal wrinkles (“crow’s feet”), facial weakness in hemifacial spasm, and breathy voice in adductor spasmodic dysphonia.

When injections are made in laryngeal area, some experts recommend ready availability of equipment to establish an airway. Do not inject into laryngeal area just prior to surgery because weakness of vocalis muscles may create postoperative airway vulnerability.

Some clinicians state that in patients with cerebral palsy, excessive muscle weakness in agonist or antagonist muscles is a relative contraindication to treatment.

Some clinicians recommend that individuals receiving injections for facial cosmesis remain in an upright position ≥4 hours after treatment to minimize risk of eyelid ptosis.

Pre-existing Target Muscle Comorbidity

Use with caution in patients who have inflammation at the proposed injection site(s) or excessive weakness and/or atrophy of the target muscle(s).

Injection-related Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Injection-related injury is possible, resulting in localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding or bruising. Needle-related pain and/or anxiety may result in vasovagal reactions (e.g., syncope, hypotension).

Administer with caution to patients with thrombocytopenia or a bleeding disorder (e.g., hemophilia) or those receiving anticoagulant therapy.

Exercise caution when injecting near vulnerable adjacent structures; retrobulbar hemorrhage reported in patients receiving injections for strabismus and pneumothorax in patients receiving injections near lung or pleura.

Use in Hyperhidrosis

Evaluate for potential causes of secondary hyperhidrosis (e.g., hyperthyroidism) to avoid possibility of symptomatic treatment without diagnosis and/or treatment of the underlying disease.

Manufacturer states that safety and efficacy for hyperhidrosis in areas other than the axilla not established; hand muscle weakness or blepharoptosis may occur in patients treated for palmar or facial hyperhidrosis, respectively.

Use in Blepharospasm

Carefully evaluate for corneal sensation, especially those who had prior surgical intervention. To decrease the risk of ectropion, avoid injection of lower lid area.

Aggressively manage any epithelial defect that occurs with protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or by other clinically appropriate methods.

Corneal exposure, persistent epithelial defect, and corneal ulceration reported in patients receiving injections in the orbicularis muscle, especially those with facial nerve disorders and reduced blink response.

At least one patient with blepharospasm developed a decreased blink response that resulted in corneal perforation in an aphakic eye and subsequent corneal grafting.

At least one patient developed acute angle-closure glaucoma 1 day after injection.

Focal facial paralysis, syncope, and exacerbation of myasthenia gravis also have been reported.

Use in Strabismus

Retrobulbar hemorrhage due to needle penetration of the orbit and resultant compromised retinal circulation reported.

Because of possibility of needle penetrations of the ocular globe, an ophthalmoscope and appropriate instruments should be readily available to decompress the orbit in the event of retrobulbar hemorrhage.

If adverse effects such as spatial disorientation, double vision, and/or past pointing occur, these effects may be reduced by covering the affected eye.

Use in Laryngeal Dystonia

Limit use to clinicians experienced in treatment of diseases of the larynx; consider management under the care of a team composed of a neurologist, otolaryngologist, and speech pathologist.

Use in Oromandibular Dystonias

Consider a treatment team composed of a neurologist, otolaryngologist, and speech pathologist and a clinician experienced in regional EMG techniques.

Cosmetic Use

Safety and efficacy not evaluated in individuals with an inflammatory skin problem at the injection site, marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, or manually irreducible glabellar lines; use with caution in such individuals.

Manufacturer recommends injection intervals of ≥3 months and use of the lowest effective dose.

Antibody Formation and Tolerance

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Highly immunogenic (bacterial origin); possible formation of neutralizing antibodies resulting in reduced response to treatment. Long-term immunogenicity remains to be determined. Antibodies to the toxin do not appear to induce hypersensitivity responses.

Tolerance manifests as the absence of muscular paralysis, weakness, and/or atrophy after injection.

Patients who develop tolerance to botulinum toxin type A may respond to botulinum toxin type B or other botulinum toxin serotypes (e.g., botulinum toxin type F); however, long-term response to other serotypes in such patients not fully elucidated.

Administer lowest effective dose at the longest feasible treatment interval to minimize risk of antibody formation and tolerance. Manufacturer recommends ≥3-month interval between treatment sessions.

Risk of neutralizing antibodies and tolerance may be increased by increased frequency of injection sessions, increased duration of therapy, higher injected doses (e.g., >300 units), inadvertent injection into the systemic circulation, and/or the use of “booster” doses (i.e., additional injections of the drug 2 weeks after initial treatment into different muscles or at increased doses).

Not known if patients with neutralizing antibodies to botulinum toxin type A are at increased risk of developing tolerance to type B.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; abortion or fetal malformations observed in rabbits. If used during pregnancy or patient becomes pregnant while taking drug, apprise of potential hazard to fetus.

At least one woman treated during pregnancy reportedly gave birth prematurely; causal relationship considered unlikely.

Dosing Precautions

Ensure accuracy of dosing information; units of biologic activity for different serotypes or formulations of botulinum toxin cannot be compared with or converted to units of other botulinum toxins.

Dosing errors reported; use care in evaluating data in medical literature on different toxin serotypes (e.g., botulinum toxin types A, B, C, F) since assay methods used to determine potency of different serotypes are specific to each individual manufacturer and/or formulation.

Reporting Adverse Effects

Report adverse events to the Pharmacovigilance Division of Allergan Pharmaceuticals (800-433-8871, select option 2) or the US Department of Health and Human Services (DHHS) Adverse Event Reporting System (AERS) at 800-822-7967.

Specific Populations

Pregnancy

Category C.

Do not use for cosmesis during pregnancy.

Lactation

Not known whether distributed into human milk. Use with caution.

Pediatric Use

Safety and efficacy not established in children <12 years of age with blepharospasm or strabismus.

Safety and efficacy not established in children <16 years of age with cervical dystonia.

Safety and efficacy not established in children <18 years of age with hyperhidrosis.

Has been effective and well tolerated when used for treatment of strabismus in pediatric patients ≥2 months of age†.

Has been used generally without unusual adverse effects for the treatment of cerebral palsy in pediatric patients ≥18 months of age†.

Not recommended for cosmetic use in children <18 years of age.

Some clinicians state that use is contraindicated in children <18 months of age.

Serious systemic toxicity resembling botulism (e.g., dysphagia, respiratory failure) reported during postmarketing experience in children <16 years of age. Such effects were observed with botulinum toxin type A doses of 6.25–32 units/kg. Severe cases involving death or hospitalization or requiring use of gastric feeding tubes and/or mechanical ventilation have occurred, principally in children with cerebral palsy-associated limb spasticity. No deaths or serious complications requiring intubation or ventilatory support reported among such cases of botulism in adults.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

Less effective in clinical trials for cosmesis of glabellar-line appearance in adults >65 years of age than in younger individuals, possibly because of loss of dermal elasticity with increasing age.

Some clinicians suggest combined use with injectable dermal fillers (e.g., collagen) may improve cosmesis in geriatric individuals.

Safety and efficacy data in patients ≥75 years of age insufficient for any comparison to results in younger adults.

Common Adverse Effects

Treatment of cervical dystonia: Dysphagia (e.g., swallowing difficulty, choking sensation), upper respiratory infection, neck pain, headache.

Treatment of blepharospasm: Ptosis, keratitis (including filamentary keratitis), dry eye, blurred vision, diplopia, entropion, conjunctivitis, increased tearing.

Treatment of strabismus: Ptosis and/or vertical deviation.

Treatment of primary axillary hyperhidrosis: Injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, anxiety.

Cosmesis of glabellar lines: Headache, respiratory infection, flu syndrome, blepharoptosis, transient eyelid ptosis (blepharoptosis), nausea.

Injection-site reactions: Pain, infection, inflammation, tenderness, swelling, erythema, bleeding, bruising.

Interactions

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

Not detected in peripheral circulation following IM injection at recommended doses and systemic effects (e.g., generalized muscle weakness) generally do not occur; however, single-fiber electromyography (e.g., increased jitter) indicate subclinical effects in muscles distant from the injection site.

Subclinical effects may indicate toxin spread via circulation, retrograde or orthograde axonal transport, or some action of the toxin at a third, central, or unidentified site.

Onset

Following injection into a muscle, weakness ensues in approximately 2–4 days and total paralysis of the injected muscle occurs within 10 days; actively contracting muscles may internalize toxin more rapidly.

Duration

Extent of paralysis and atrophy of injected muscle correlates directly with the amount of toxin injected (i.e., concentration and volume of toxin solution).

Redevelopment of extrajunctional receptors and terminals limits the duration of activity to a few months; functional recovery develops in 3–6 months, but neurologic redevelopment may continue for as long as 3 years.

Response in autonomic disorders involving excessive glandular secretion (e.g., hyperhidrosis) may persist longer than in conditions involving overactivity of striated or smooth muscle; additional study needed.

For additional information regarding onset and duration of effect, see specific indication in Dosage under Dosage and Administration.

Stability

Storage

Parenteral

Powder for Injection (Botox^® and Botox^® Cosmetic)

2–8°C; do not use after expiration date marked on vial.

Following reconstitution in single-use vials with 0.9% sodium chloride injection without preservatives, store at 2–8°C and use within 4 hours; do not freeze.

Vials may be reentered to treat the same patient within 4 hours of reconstitution; store at 2–8°C during this time. Discard any remaining solution.

Actions

• Induces chemical denervation and flaccid paralysis by disruption of neurotransmission; inhibits release of acetylcholine at presynaptic cholinergic nerve terminals of the peripheral nervous system and at ganglionic nerve terminals of the autonomic nervous system.
• Inhibits sweat production by blocking release of acetylcholine, which mediates sympathetic neurotransmission in the eccrine glands.
• Induces neuromuscular blockade via a zinc-dependent endopeptidase, which blocks vesicles containing acetylcholine from fusing with the terminal membrane of the motor neuron.
• Without acetylcholine release, the muscle is unable to contract and flaccid paralysis ensues.
• At therapeutic doses, muscular paralysis limited to injected muscle; however, weakness or paralysis of adjacent muscles may occur as a result of local diffusion.
• Selective chemodenervation is reversible; although muscular atrophy occurs, regeneration of extrajunctional receptors and terminals limits the duration of activity to a few months.
• Recovery of neuromuscular activity occurs through neurogenesis of axonal sprouts and motor end plates.
• Functional recovery develops in 3–6 months, but sprouting and remodeling may continue for as long as 3 years.
• Response in autonomic disorders involving excessive glandular secretion (e.g., hyperhidrosis) may be longer than in conditions involving overactivity of striated or smooth muscle; additional study needed to elucidate mechanism in glandular and non-muscle tissue.

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

• Inform patients with cervical dystonia of possibility of dysphagia (typically mild to moderate); rarely, severe dysphagia occurs, sometimes associated with aspiration, dyspnea, pneumonia, and need to reestablish an airway.
• Importance of informing patients of possible systemic effects (e.g., weakness, shortness of breath, respiratory complications, swallowing difficulties) following local injection.
• Advise patients and/or caregivers to seek immediate medical attention if unexpected muscle weakness, swallowing, speech, or respiratory disorders occur.
• Advise previously sedentary patients to resume activity gradually following treatment.
• Advise women who become pregnant while receiving the drug of the potential risks to the fetus and that abortion and fetal malformations have been observed in animals given the drug during gestation.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., neuromuscular disorders).
• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

The FDA has determined that unlicensed botulinum toxin has been imported into the US without proper declaration of contents by sender; in some cases, unlicensed product has been shipped directly to physicians. Botulism has been reported in several individuals who received injections of unlicensed, highly concentrated botulinum toxin type A.

To facilitate identification, vials of Botox^® and Botox^® Cosmetic have holographic film on the label that contains the name “Allergan” within horizontal lines of rainbow color. To see the hologram, rotate vial back and forth between fingers under a desk lamp or fluorescent light. (The holographic film is absent in the date/batch area of label.) If the lines of rainbow color or the name “Allergan” cannot be seen on product label, do not use product and contact Allergan for additional information at 800-890-4345 between 8:00 a.m. and 4:00 p.m. (Pacific Time).

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions September 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.