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Botox Cosmetic

Last reviewed on RxList: 4/5/2017
Drug Description

BOTOX Cosmetic
(onabotulinumtoxinA) Injection

WARNING

DISTANT SPREAD OF TOXIN EFFECT

Postmarketing reports indicate that the effects of BOTOX Cosmetic and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and upper limb spasticity and at lower doses. [See WARNINGS AND PRECAUTIONS]

DESCRIPTION

BOTOX Cosmetic (onabotulinumtoxinA) for injection, is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A intended for intramuscular use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying.

The primary release procedure for BOTOX Cosmetic uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan's products BOTOX and BOTOX Cosmetic. One Unit of BOTOX Cosmetic corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice. Due to specific details of this assay such as the vehicle, dilution scheme and laboratory protocols, Units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. The specific activity of BOTOX Cosmetic is approximately 20 Units/nanogram of neurotoxin complex.

Each vial of BOTOX Cosmetic contains either 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride; or 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

For Consumers

What are the possible side effects of Botox (Botox, Botox Cosmetic)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

The botulinum toxin contained in Botox can spread to other body areas beyond where it was injected. This has caused serious life-threatening side effects in some people receiving botulism toxin injections, even for cosmetic purposes.

Call your doctor at once if you have any of these serious side effects, some of which can occur up to several weeks after an...

Indications & Dosage

INDICATIONS

Bladder Dysfunction

Overactive Bladder

BOTOX (onabotulinumtoxinA) for injection is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic me dication.

Detrusor Overactivity Associated With A Neurologic Condition

BOTOX is indicated for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e .g., SCI, MS) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.

Chronic Migraine

BOTOX is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).

Important Limitations

Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per mo nth) in seven placebo-controlled studies.

Spasticity

Upper Limb Spasticity

BOTOX is indicated for the treatment of upper limb spasticity in adult patients, to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris) , finger flexors (flexor digitorum profundus and flexor digitorum sublimis), and thumb flexors (adductor pollicis and flexor pollicis longus).

Lower Limb Spasticity

BOTOX is indicated for the treatment of lower limb spasticity in adult patients to decrease the severity of increased muscle tone in ankle and toe flexors (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus, and flexor digitorum longus).

Important Limitations

Safety and effectiveness of BOTOX have not been established for the treatment of other upper or lower limb muscle groups. Safety and effectiveness of BOTOX have not been established for the treatment of spasticity in pediatric patients under age 18 years. BOTOX has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture. Treatment with BOTOX is not intended to substitute for usual standard of care rehabilitation regimens.

Cervical Dystonia

BOTOX is indicated for the treatment of adults with cervical dystonia, to reduce the severity of abnormal head position and n eck pain associated with cervical dystonia.

Primary Axillary Hyperhidrosis

BOTOX is indicated for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents.

Important Limitations

The safety and effectiveness of BOTOX for hyperhidrosis in other body areas have not been established. Weakness of hand muscles and blepharoptosis may occur in patients who receive BOTOX for palmar hyperhidrosis and facial hyperhidrosis, respectively.

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

Safety and effectiveness of BOTOX have not been established for the treatment of axillary hyperhidrosis in pediatric patients under age 18.

Blepharospasm and Strabismus

BOTOX is indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.

DOSAGE AND ADMINISTRATION

Instructions For Safe Use

The potency Units of BOTOX (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see WARNINGS AND PRECAUTIONS and DESCRIPTION] .

Indication specific dosage and administration recommendations should be followed. When initiating treatment, the lowest recommended dose should be used. In treating adult patients for one or more indications, the maximum cumulative dose should n ot exceed 400 Units, in a 3 month interval.

The safe and effective use of BOTOX depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. An understanding of standard electromyographic techniques is also required for treatment of strabismus, upper or lower limb spasticity, and may be useful for the treatment of cervical dystonia. Physicians administering BOTOX must understand the relevant neuromuscular and structural anatomy of the area involved and any alteration s to the anatomy due to prior surgical procedures and disease, especially when injecting near the lungs.

Preparation And Dilution Technique

Prior to injection, reconstitute each vacuum-dried vial of BOTOX with only sterile, preservative-free 0.9% Sodium Chloride Injection USP. Draw up the proper amount of diluent in the appropriate size syringe (see Table 1, or for specific instructions for detr usor overactivity associated with a neurologic condition see Section 2.3), and slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix BOTOX with the saline by rotating the vial. Record the date and time of reconstitution on the space on the label. BOTOX should be administered within 24 hours after reconstitution. During this time period, reconstituted BOTOX should be stored in a refrigerator (2° to 8°C).

Table 1: Dilution Instructions for BOTOX Vials (50 Units, 100 Units and 200 Units)**

Diluent* Added to 50 Unit Vial Resulting Dose Units per 0.1 mL Diluent* Added to 100 Unit Vial Resulting Dose Units per 0.1 mL Diluent* Added to 200 Unit Vial Resulting Dose Units per 0.1 mL
1 mL 5 Units 1 mL 10 Units 1 mL 20 Units
2 mL 2.5 Units 2 mL 5 Units 2 mL 10 Units
4 mL 1.25 Units 4 mL 2.5 Units 4 mL 5 Units
    8 mL 1.25 Units 8 mL 2.5 Units
    10 mL 1 Unit 10 mL 2 Units
*Preservative-free 0.9% Sodium Chloride Injection, USP Only
**For Detrusor Overactivity associated with a Neurologic Condition Dilution see Section 2.3

Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the BOTOX dose is also possible by administering a smaller or larger injection volume -from 0.05 mL (50% decrease in dose) to 0.15 mL (50% increase in dose).

An injection of BOTOX is prepared by drawing into an appropriately sized sterile syringe an amount of the properly reconstituted toxin slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is attached to an appropriate injection needle. Patency of the needle should be confirmed. A new, sterile needle and syringe should be used to enter the vial on each occasion for removal of BOTOX.

Reconstituted BOTOX should be clear, colorless, and free of particulate matter. Parenteral drug produ cts should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit.

Bladder Dysfunction

General

Patients must not have a urinary tract infection (UTI) at the time of treatment. Prophylactic antibiotics, except aminoglycos ides, [see DRUG INTERACTIONS] should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the likelihood of procedure-related UTI.

Patients should discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding.

Appropriate caution should be exercised when performing a cystoscopy.

Overactive Bladder

An intravesical instillation of diluted local anesthetic with or without sedation may be used prior to injection, per local s ite practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.

The recommended dose is 100 Units of BOTOX, and is the maximum recommended dose. The recommended dilution is 100 Units/10 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1). Dispose of any unused saline.

Reconstituted BOTOX (100 Units/10 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the t rigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided.

The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injection s (depending on the needle length) to remove any air.

The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, patients shou ld demonstrate their ability to void prior to leaving the clinic. The patient should be obser ved for at least 30 minutes post-injection and until a spontaneous void has occurred.

Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median time until patients qualified for the second treatment of BOTOX in double-blind, placebo-controlled clinical studies was 169 days [~24 weeks]), but no sooner than 12 weeks from the prior bladder injection.

Figure 1: Injection Pattern for Intradetrusor Injections for Treatment of Overactive Bladder and Detrusor Overactivity associated with a Neurologic Condition

Injection Pattern for Intradetrusor Injections for Treatment of Overactive Bladder and Detrusor Overactivity associated with a Neurologic Condition - Illustration

Detrusor Overactivity Associated With A Neurologic Condition

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 st erile saline before injection.

The recommended dose is 200 Units of BOTOX per treatment, and should not be exceeded.

200 Unit Vial of BOTOX

  • Reconstitute a 200 Unit vial of BOTOX with 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently.
  • Draw 2 mL from the vial into each of three 10 mL syringes.
  • Complete the reconstitution by adding 8 mL of preservative-free 0.9% Sodium Chloride Injection, USP 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 BOTOX.
  • Use immediately after reconstitution in the syringe. Dispose of any unused saline.

100 Unit Vial of BOTOX

  • Reconstitute two 100 Unit vials of BOTOX, each with 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vials gently.
  • Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe for a total of 4 mL in each syringe.
  • Complete the reconstitution by adding 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP 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 BOTOX.
  • Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Reconstituted BOTOX (200 Units/30 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the t rigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over -distension should be avoided.

The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injection s (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 (~6.7 Units) each (total volume of 30 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of sterile normal s aline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post -injection.

Patients should be considered for re-injection when the clinical effect of the previous injection diminishes (median time to qualification for re-treatment in the double-blind, placebo-controlled clinical studies was 295-337 days [42-48 weeks] for BOTOX 200 Units), but no sooner than 12 weeks from the prior bladder injection.

Chronic Migraine

The recommended dilution is 200 Units/4 mL or 100 Units/2 mL, with a final concentration of 5 Units per 0.1 mL (see Table 1). The recommended dose for treating chronic migraine is 155 Units ad ministered intramuscularly using a sterile 30-gauge, 0.5 inch needle as 0.1 mL (5 Units) injections per each site. Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams and Table 2 below. A one 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 one site (midline), all muscles should be injected bilaterally 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.

Diagrams 1-4: Recommended Injection Sites (A through G) for Chronic Migraine

 Recommended Injection Sites (A through G) for Chronic Migraine - Illustration

Table 2: BOTOX Dosing by Muscle for Chronic Migraine

Head/Neck Area Recommended Dose (Number of Sitesa)
Frontalisb 20 Units divided in 4 sites
Corrugatorb 10 Units divided in 2 sites
Procerus 5 Units in 1 site
Occipitalisb 30 Units divided in 6 sites
Temporalisb 40 Units divided in 8 sites
Trapeziusb 30 Units divided in 6 sites
Cervical Paraspinal Muscle Groupb 20 Units divided in 4 sites
Total Dose: 155 Units divided in 31 sites
a Each IM injection site = 0.1 mL = 5 Units BOTOX
b Dose distributed bilaterally

Spasticity

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and locati on of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment , or adverse event history with BOTOX.

The recommended dilution is 200 Units/4 mL or 100 Units/2 mL with preservative -free 0.9% Sodium Chloride Injection, USP (see Table 1). The lowest recommended starting dose should be used, and no more than 50 Units p er site should generally be administered. An appropriately sized needle (e.g., 25-30 gauge) may be used for superficial muscles, and a longer 22 gauge needle may be used for deeper musculature. Localization of the involved muscles with techniques such as needle electromyographic guidance or nerve stimulation is recommended.

Repeat BOTOX treatment may be administered when the effect of a previous injection has diminished, but generally no sooner than 12 weeks after the previous injection. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of BOTOX and muscles to be injected.

Upper Limb Spasticity

In clinical trials, doses ranging from 75 Units to 400 Units were divided among selected muscles (see Table 3 and Figure 2) at a given treatment session.

Table 3: BOTOX Dosing by Muscle for Upper Limb Spasticity

Muscle Recommended Dose Total Dosage (Number of Sites)
Biceps Brachii 100 Units-200 Units divided in 4 sites
Flexor Carpi Radialis 12.5 Units-50 Units in 1 site
Flexor Carpi Ulnaris 12.5 Units-50 Units in 1 site
Flexor Digitorum Profundus 30 Units-50 Units in 1 site
Flexor Digitorum Sublimis 30 Units-50 Units in 1 site
Adductor Pollicis 20 Units in 1 site
Flexor Pollicis Longus 20 Units in 1 site

Figure 2: Injection Sites for Upper Limb Spasticity

Injection Sites for Upper Limb Spasticity - Illustration

Lower Limb Spasticity

The recommended dose for treating lower limb spasticity is 300 Units to 400 Units divided among 5 muscles (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus and flexor digitorum longus) (see Table 4 and Figure 3).

Table 4: BOTOX Dosing by Muscle for Lower Limb Spasticity

Muscle Recommended Dose Total Dosage (Number of Sites)
Gastrocnemius medial head 75 Units divided in 3 sites
Gastrocnemius lateral head 75 Units divided in 3 sites
Soleus 75 Units divided in 3 sites
Tibialis Posterior 75 Units divided in 3 sites
Flexor hallucis longus 50 Units divided in 2 sites
Flexor digitorum longus 50 Units divided in 2 sites

Figure 3: Injection Sites for Lower Limb Spasticity

Injection Sites for Lower Limb Spasticity - Illustration

Cervical Dystonia

A double-blind, placebo-controlled study enrolled patients who had extended histories of receiving and tolerating BOTOX injections, with prior individualized adjustment of dose. The mean BOTOX dose administered to patients in this study was 236 Units (25th to 75th percentile range of 198 Units to 300 Units). The BOTOX dose was divided among the affected muscles [see Clinical Studies].

Dosing in initial and sequential treatment sessions should be tailored to the individual patient based on the patient's head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history. The initial dose for a patie nt without prior use of BOTOX should be at a lower dose, with subsequent dosing adjusted based on individual response. Limiting the total dose injected into the sternocleidomastoid muscle to 100 Units or less may decrease the occurrence of dysphagia [see WARNINGS AND PRECAUTIONS].

The recommended dilution is 200 Units/2 mL, 200 Units/4 mL, 100 Units/1 mL, or 100 Units/2 mL with preservative-free 0.9% Sodium Chloride Injection, USP, depending on volume and number of injection sites desired to achieve treatment objectives (see Table 1). In general, no more than 50 Units per site should be administered using a sterile needle (e.g., 25-30 gauge) of an appropriate length. Localization of the involved muscles with electromyographic guidance may be useful.

Clinical improvement generally begins within the first two weeks after injection with maximum clinical benefit at approximately six weeks post-injection. In the double-blind, placebo-controlled study most subjects were observed to have returned to pre-treatment status by 3 months post-treatment.

Primary Axillary Hyperhidrosis

The recommended dose is 50 Units per axilla. The hyperhidrotic area to be injected should be defined using standard staining techniques, e.g., Minor's Iodine-Starch Test. The recommended dilution is 100 Units/4 mL with 0.9% preservative -free sterile saline (see Table 1). Using a sterile 30 gauge needle, 50 Units of BOTOX (2 mL) is injected intradermally in 0.1 to 0.2 mL aliquots to each axilla evenly distributed in multiple sites (10-15) approximately 1-2 cm apart.

Repeat injections for hyperhidrosis should be administered when the clinical effect of a previous injection diminishes.

Instructions For The Minor’s Iodine-Starch Test Procedure:

Patients should shave underarms and abstain from use of over-the-counter deodorants or antiperspirants for 24 hours prior to the test. Patient should be resting comfortably without exercise, hot drinks for approximately 30 minutes prior to the test. Dry the un derarm area and then immediately paint it with iodine solution. Allow the area to dry, then lightly sprinkle the area with starch powder. Gently blow off any excess starch powder. The hyperhidrotic area will develop a deep blue-black color over approximately 10 minutes.

Each injection site has a ring of effect of up to approximately 2 cm in diameter. To minimize th e area of no effect, the injection sites should be evenly spaced as shown in Figure 4.

Figure 4: Injection Pattern for Primary Axillary Hyperhidrosis

Injection Pattern for Primary Axillary Hyperhidrosis - Illustration

Each dose is injected to a depth of approximately 2 mm and at a 45° angle to the skin surface, with the bevel side up to minimize leakage and to ensure the injections remain intradermal. If injection sites are marked in ink, do not inject BOTOX directly t hrough the ink mark to avoid a permanent tattoo effect.

Blepharospasm

For blepharospasm, reconstituted BOTOX is injected using a sterile, 27-30 gauge needle without electromyographic guidance. The initial recommended dose is 1.25 Units-2.5 Units (0.05 mL to 0.1 mL volume at each site) injected into the medial and lateral pre tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid. Avoiding injection near the levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducin g 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 recommended dilution to achieve 1.25 Units is 50 Units/4 mL or 100 Units/8 mL; for 2.5 Units it is 50 Units/2 mL or 100 Units/4 mL (see Table 1).

In general, the initial effect of the injections is seen within three days and reaches a peak at one to t wo weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient, usually defined as an effect that does not last longer than two months. However, there appears to be little benefit obtainable from injecting more than 5 Units per site. Some tolerance may be found when BOTOX is used in treating blepharospasm if treatments are given any more frequently than every three months, and is rare to have the effect be permanent.

The cumulative dose of BOTOX treatment for blepharospasm in a 30-day period should not exceed 200 Units.

Strabismus

BOTOX is intended for injection into extraocular muscles utilizing the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure or electromyographic guidance should no t be attempted. Physicians should be familiar with electromyographic technique.

To prepare the eye for BOTOX injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection.

The volume of BOTOX injected for treatment of strabismus should be between 0.05-0.15 mL per muscle.

The initial listed doses of the reconstituted BOTOX [see Preparation And Dilution Technique] typically create paralysis of the injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2-6 weeks and gradually resolves over a similar time period. Overcorrections lasting over six months have been rare. About one half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose, or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilize the alignment .

Initial Doses In Units

Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.

  • For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1.25 Units-2.5 Units in any one muscle.
  • For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2.5 Units-5 Units in any one muscle.
  • For persistent VI nerve palsy of one month or longer duration: 1.25 Units-2.5 Units in the medial rectus muscle.
Subsequent Doses For Residual Or Recurrent Strabismus
  • It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose.
  • Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
  • Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to two -fold compared to the previously administered dose.
  • Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.
  • The maximum recommended dose as a single injection for any one muscle is 25 Units.

The recommended dilution to achieve 1.25 Units is 50 Units/4 mL or 100 Units/8 mL; for 2.5 Units it is 50 Units/2 mL or 100 Units/4 mL (see Table 1).

HOW SUPPLIED

Dosage Forms And Strengths

Single-use, sterile 50 Units, 100 Units or 200 Units vacuum-dried powder for reconstitution only with sterile, preservative-free 0.9% Sodium Chloride Injection USP prior to injection.

Storage And Handling

BOTOX is supplied in a single-use vial in the following sizes:

50 Units NDC 0023-3920-50
100 Units NDC 0023-1145-01
200 Units NDC 0023-3921-02

Vials of BOTOX have a holographic film on the vial label that contains the name “Allergan” within horizontal lines of rainbow color. In order to see the hologram, rotate the vial back and forth between your fin gers under a desk lamp or fluorescent light source. (Note: the holographic film on the label is absent in the date/lot area.) If you do not see the lines of rainbow color or the name “Allergan”, do not use the product and contact Allergan for additional information at 1-800-890-4345 from 7:00 AM to 3:00 PM Pacific Time.

Storage

Unopened vials of BOTOX should be stored in a refrigerator (2° to 8°C) for up to 36 months. Do not use after the expiration d ate on the vial. Administer BOTOX within 24 hours of reconstitution; during this period reconstituted BOTOX should be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX should be clear, colorless, and free of particulate matter.

Manufactured by:Allergan Pharmaceuticals Ireland a subsidiary of: Allergan, Inc. 2525 Dupont Dr. Irvine, CA 92612. Revised: Apr 2017

Side Effects & Drug Interactions

SIDE EFFECTS

The following adverse reactions to BOTOX Cosmetic (onabotulinumtoxinA) for injection are discussed in greater detail in other sections of the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but have different labeled Indications and Usage. Therefore, adverse events observed with the use of BOTOXalso have the potential to be observed with the use of BOTOX Cosmetic.

In general, adverse reactions occur within the first week following injection of BOTOX Cosmetic and while generally transient, may have a duration of several months or longer. Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Needle-related pain and/or anxiety may result in vasovagal responses (including e.g., syncope, hypotension), which may require appropriate medical therapy.

Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of toxin [see WARNINGS AND PRECAUTIONS].

Glabellar Lines

Table 2 lists selected adverse reactions reported by ≥ 1% of BOTOX Cosmetic treated subjects (N=405) aged 18 to 75 who were evaluated in the randomized, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of glabellar lines.

Table 2: Adverse Reactions Reported by ≥ 1% of the BOTOX Cosmetic treated Patients and More Frequent than in Placebotreated Patients in Double-blind, Placebo-controlled Clinical Studies of Treatment of Glabellar Lines

Adverse Reactions by System Organ Class BOTOX Cosmetic
(N=405)
Placebo
(N=130)
General Disorders and Administration Site Conditions
  Facial pain 6 (1%) 0 (0%)
Nervous System Disorders
  Facial paresis 5 (1%) 0 (0%)
Eye Disorders
  Eyelid ptosis 13 (3%) 0 (0%)
Musculoskeletal and Connective Tissue Disorders
  Muscular Weakness 6 (1%) 0 (0%)

Lateral Canthal Lines

Table 3 lists selected adverse reactions reported within 90 days following injection by ≥ 1% of BOTOX Cosmetic treated subjects (N=526) aged 18 to 75 who were evaluated in two randomized, double-blind, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of lateral canthal lines alone.

Table 3: Adverse Reaction Reported by ≥ 1% of BOTOX Cosmetic treated Patients and More Frequent than in Placebotreated Patients Within 90 Days, in Double-blind, Placebo-controlled Clinical Studies of Treatment of Lateral Canthal Lines

Adverse Reactions by System Organ Class BOTOX Cosmetic 24 Units
(N=526)
Placebo
(N=530)
Eye disorders
  Eyelid edema 5 (1%) 0 (0%)

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Treatment with botulinum toxins may result in the formation of neutralizing antibodies that may reduce the effectiveness of subsequent treatments by inactivating biological activity of the toxin.

In three Lateral Canthal Line trials, 916 subjects (517 subjects at 24 Units and 399 subjects at 44 Units) treated with BOTOX Cosmetic had specimens analyzed for antibody formation. Among the 916 BOTOX Cosmetic treated subjects, 14 subjects (1.5%) developed binding antibodies and no subjects (0%) developed the presence of neutralizing antibodies.

The data reflect the subjects whose test results were considered positive or negative for neutralizing activity to BOTOX Cosmetic in a mouse protection assay. The results of these tests are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to BOTOX Cosmetic with the incidence of antibodies to other products may be misleading.

The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that botulinum toxin injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.

Post-marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin [see WARNINGS AND PRECAUTIONS].

There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease.

New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events.

The following adverse reactions by System Organ Class have been identified during post-approval use of BOTOX/BOTOX Cosmetic:

Ear and labyrinth Disorders

Hypoacusis; tinnitus; vertigo

Eye Disorders

Diplopia; lagophthalmos; strabismus; visual disturbances; vision blurred

Gastrointestinal Disorders

Abdominal pain; diarrhea; dry mouth; nausea; vomiting

General Disorders And Administration Site Conditions

Denervation; malaise; pyrexia

Metabolism And Nutrition Disorders

Anorexia

Musculoskeletal And Connective Tissue Disorders

Muscle atrophy; myalgia

Nervous System Disorders

Brachial plexopathy; dysarthria; facial palsy; hypoaesthesia; localized numbness; myasthenia gravis; paresthesia; peripheral neuropathy; radiculopathy; syncope

Respiratory, Thoracic And Mediastinal Disorders

Aspiration pneumonia; dyspnea; respiratory depression and/or respiratory failure

Skin And Subcutaneous Tissue Disorders

Alopecia, including madarosis; hyperhidrosis; pruritus; skin rash (including erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption)

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with BOTOX Cosmetic (onabotulinumtoxinA) for injection.

Aminoglycosides And Other Agents Interfering With Neuromuscular Transmission

Co-administration of BOTOX Cosmetic and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated.

Anticholinergic Drugs

Use of anticholinergic drugs after administration of BOTOX Cosmetic may potentiate systemic anticholinergic effects.

Other Botulinum Neurotoxin Products

The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

Muscle Relaxants

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX Cosmetic.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lack Of Interchangeability Between Botulinum Toxin Products

The potency Units of BOTOX Cosmetic are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see DESCRIPTION].

Spread Of Toxin Effect

Postmarketing safety data from BOTOX Cosmetic and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, and particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia and upper limb spasticity. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders occur.

No definitive serious adverse event reports of distant spread of toxin effect associated with dermatologic use of BOTOX/BOTOX Cosmetic at the labeled dose of 20 Units (for glabellar lines), 24 Units (for lateral canthal lines), 44 Units (for simultaneous treatment of lateral canthal lines and glabellar lines), or 100 Units (for severe primary axillary hyperhidrosis) have been reported.

No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX for blepharospasm at the recommended dose (30 Units and below), strabismus, or chronic migraine at the labeled doses have been reported.

Serious Adverse Reactions With Unapproved Use

Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant spread of toxin, but may have resulted from the administration of BOTOX to the site of injection and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant disabilities. There is insufficient information to identify factors associated with an increased risk for adverse reactions associated with the unapproved uses of BOTOX. The safety and effectiveness of BOTOX for unapproved uses have not been established.

Hypersensitivity Reactions

Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX Cosmetic should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined.

Cardiovascular System

There have been reports following administration of BOTOXof adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. Use caution when administering to patients with pre-existing cardiovascular disease.

Pre-Existing Neuromuscular Disorders

Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from onabotulinumtoxinA [see Dysphagia And Breathing Difficulties].

Dysphagia And Breathing Difficulties

Treatment with BOTOX and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with preexisting swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing.[see Spread Of Toxin Effect].

Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised.

Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been postmarketing reports of serious breathing difficulties, including respiratory failure.

Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle for the treatment of cervical dystonia have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia.

Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Spread Of Toxin Effect].

Pre-existing Conditions At The Injection Site

Caution should be used when BOTOX Cosmetic treatment is used in the presence of inflammation at the proposed injection site(s), ptosis, or when excessive weakness or atrophy is present in the targeted muscle(s).

Corneal Exposure And Ulceration In Patients Treated With BOTOX For Blepharospasm

Reduced blinking from BOTOX Cosmetic injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.

Spatial Disorientation, Double Vision Or Past-pointing In Patients Treated For Strabismus

Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. Covering the affected eye may alleviate these symptoms.

Human Albumin And Transmission Of Viral Diseases

This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Provide a copy of the Medication Guide and review the contents with the patient.

Swallowing, Speaking Or Breathing Difficulties, Or Other Unusual Symptoms

Patients should be advised to inform their doctor or pharmacist if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing), or if any existing symptom worsens [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Ability To Operate Machinery Or Vehicles

Patients should be counseled that if loss of strength, muscle weakness, blurred vision, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long term studies in animals have not been performed to evaluate carcinogenic potential of BOTOX Cosmetic.

Mutagenesis

BOTOX Cosmetic was negative in a battery of in vitro (microbial reverse mutation assay, mammalian cell mutation assay, and chromosomal aberration assay) and in vivo (micronucleus assay) genetic toxicologic assays.

Impairment Of Fertility

In fertility studies of BOTOX Cosmetic (4, 8, or 16 Units/kg) in which either male or female rats were injected intramuscularly prior to mating and on the day of mating (3 doses, 2 weeks apart for males, 2 doses, 2 weeks apart for females) to untreated animals, reduced fertility was observed in males at the intermediate and high doses and in females at the high dose. The no-effect doses for reproductive toxicity (4 Units/kg in males, 8 Units/kg in females) are approximately 5-10 times the average high human dose for glabellar lines and lateral canthal lines of 44 Units on a body weight basis (Units/kg).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. BOTOX Cosmetic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When BOTOX Cosmetic (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or rats two times during the period of organogenesis (on gestation days 5 and 13), reductions in fetal body weight and decreased fetal skeletal ossification were observed at the two highest doses. The no-effect dose for developmental toxicity in these studies (4 Units/kg) is approximately 5 times the average high human dose for glabellar lines and lateral canthal lines of 44 Units on a body weight basis (Units/kg).

When BOTOX Cosmetic was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and at the highest dose in rabbits.

These doses were also associated with significant maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no-effect doses in these studies of 1 Unit/kg in rats is approximately 1.4 times the average human dose based on Units/kg, and the developmental no-effect dose of 0.25 Units/kg in rabbits is less than the average high human dose based on Units/kg.

When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal development were observed. The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 22 times the average high human dose based on Units/kg.

Nursing Mothers

It is not known whether BOTOX Cosmetic is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BOTOX Cosmetic is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use

Glabellar Lines

In the two initial glabellar lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older [see Clinical Studies].

Lateral Canthal Lines

In the two lateral canthal lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older.

Overdosage & Contraindications

OVERDOSE

Excessive doses of BOTOX Cosmetic (onabotulinumtoxinA) for injection may be expected to produce neuromuscular weakness with a variety of symptoms.

Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur or overdose be suspected, these patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization. The person should be medically supervised for several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from the site of injection [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care.

In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100. More information can be obtained at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm.

CONTRAINDICATIONS

Known Hypersensitivity To Botulinum Toxin

BOTOX Cosmetic is contraindicated in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see WARNINGS AND PRECAUTIONS].

Infection At The Injection Site(s)

BOTOX Cosmetic is contraindicated in the presence of infection at the proposed injection site(s).

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

BOTOX Cosmetic blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a pre-synaptic protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX Cosmetic produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX Cosmetic.

Pharmacodynamics

No formal pharmacodynamic studies have been conducted with BOTOX Cosmetic (onabotulinumtoxinA) for injection.

Pharmacokinetics

Using currently available analytical technology, it is not possible to detect BOTOX Cosmetic in the peripheral blood following intramuscular injection at the recommended doses.

Clinical Studies

Glabellar Lines

Two phase 3 randomized, multi-center, double-blind, placebo-controlled trials of identical design were conducted to evaluate BOTOX Cosmetic for use in the temporary improvement of the appearance of moderate to severe glabellar facial lines. The trials enrolled healthy adults (ages 18 to 75) with glabellar lines of at least moderate severity at maximum frown. Subjects were excluded if they had ptosis, deep dermal scarring, or an inability to substantially lessen glabellar lines even by physically spreading them apart. Subjects received a single treatment with BOTOX Cosmetic (N=405, combined trials) or placebo (N=132, combined trials). Injection volume was 0.1 mL/injection site, for a dose/injection site in the active treatment groups of 4 Units. Subjects were injected intramuscularly in five sites, 1 in the procerus muscle and 2 in each corrugator supercilii muscle, for a total dose in the active treatment groups of 20 Units.

The co-primary efficacy endpoints were the investigator's rating of glabellar line severity at maximum frown and the subject's global assessment of change in appearance of glabellar lines, both at Day 30 post-injection. For the investigator rating, using a 4-point grading scale (0=none, 3=severe) a responder was defined as having a severity grade of 0 or 1. For the subject's global assessment of change, the ratings were from +4 (complete improvement) to -4 (very marked worsening). A responder was defined as having a grade of at least +2 (moderate improvement). After completion of the randomized studies, subjects were offered participation in an open label, repeat treatment study to assess the safety of repeated treatment sessions.

The combined results of these two efficacy trials are presented here. The mean age was 46 years, with 32 subjects (6%) ≥ 65 years of age. Most of the subjects were women (82%), and Caucasian (84%). At baseline, 210 subjects (39%) had glabellar line severity scores at rest of moderate or severe.

In these trials, the severity of glabellar lines was reduced for up to 120 days in the BOTOX Cosmetic group compared to the placebo group as measured both by investigator rating of glabellar line severity at maximum frown (Table 4), and by subject's global assessment of change in appearance of glabellar lines (Table 5).

Table 4: Investigator's Assessment of Glabellar Line Severity at Maximum Frown – Responder Rates (% and Number of Subjects with Severity of None or Mild)

Day BOTOX Cosmetic Placebo Differencea
7 74% 6% 68%
299/405 8/132 (62, 74)
30b 80% 3% 77%
325/405 4/132 (72, 82)
60 70% 2% 69%
283/403 2/130 (64, 74)
90 48% 2% 45%
192/403 3/128 (40, 51)
120 25% 2% 24%
102/403 2/128 (19, 29)
a 95% confidence intervals are shown in parenthesis
b Day 30: Co-Primary Efficacy Time point, p < 0.001

Table 5: Subject's Assessment of Change in Appearance of Glabellar Lines – Responder Rates (% and Number of Subjects with at Least Moderate Improvement)

Day BOTOX Cosmetic Placebo Differencea
7 82% 9% 73%
334/405 12/132 (68, 80)
30b 89% 7% 83%
362/405 9/132 (77, 88)
60 82% 4% 78%
330/403 5/130 (73, 83)
90 63% 3% 60%
254/403 4/128 (54, 66)
120 39% 1% 38%
157/403 1/128 (33, 43)
a 95% confidence intervals are shown in parenthesis
b Day 30: Co-Primary Efficacy Time point, p < 0.001

In the subset of subjects with resting severity scores of moderate or severe, the investigator assessment of a resting severity of mild or none at Day 30 was also achieved by more BOTOX Cosmetic treated subjects (74%, 119/161) than placebo treated subjects (20%, 10/49).

Analysis of the limited number of subjects 65 years or older suggested a lower treatment-associated response compared to subjects less than 65 years of age (Table 6).

Table 6: Investigator's and Subject's Assessment – Responder Rates for Subjects < 65 and ≥ 65 Years of Age at Day 30

Assessment Age Group BOTOX Cosmetic
(N=405)
Placebo
(N=132)
Differencea
Investigators (maximal frown) < 65 83% 2% 81%
316/382 2/123 (77, 86)
Subjects < 65 91% 7% 84%
346/382 8/123 (79, 90)
Investigators (maximal frown) ≥ 65 39% 22% 17%
9/23 2/9 (-17, 51)
Subjects ≥ 65 70% 11% 58%
16/23 1/9 (31, 86)
a 95% confidence intervals are shown in parenthesis

Exploratory analyses by gender suggested that responder rates in the BOTOX Cosmetic treated group were higher for women than for men for both the investigator assessment (Day 30; 85% of 334 women, 59% of 71 men) and the Subject Assessment (Day 30; 93% of women, 72% of men). In the limited number of non-Caucasian subjects (n=64 in the BOTOX Cosmetic treated group) the responder rates were similar to those observed in the Caucasian subjects.

Lateral Canthal Lines

Two multicenter, randomized, double-blind, placebo-controlled trials evaluated BOTOX Cosmetic (N=833, randomized to receive any BOTOX Cosmetic treatment or N=529 randomized to receive placebo) for the temporary improvement in the appearance of moderate to severe lateral canthal lines (LCL). Study 1 assessed BOTOX Cosmetic treatment of LCL alone; Study 2 also assessed simultaneous treatment of LCL and glabellar lines (GL). Both trials enrolled healthy adults with moderate to severe LCL at maximum smile at baseline; Study 2 also required subjects to have moderate to severe GL at maximum frown at baseline.

In the 5-month Study 1, subjects were randomized to receive a single blinded treatment of 24 Units/0.6 mL (12 Units per side) consisting of 4 Units/0.1 mL into 3 sites of each orbicularis oculi muscle with either BOTOX Cosmetic (N=222) or placebo (N=223).

In the 7-month Study 2, subjects were randomized to receive either BOTOX Cosmetic in the LCL region and placebo in the GL region (24 Units; N=306), or BOTOX Cosmetic in the LCL and GL regions (44 Units [24 Units for LCL and 20 Units for GL]; N=305), or placebo in the LCL and GL regions (0 Units; N=306). Subjects received the same 24 Units regimen for LCL as in Study 1, and the labeled 20 Units (5 injections, 4 Units per site) for GL. Subjects received the same treatment at days 1 and 120.

The primary efficacy measure was the assessment of LCL severity at maximum smile using the 4-point Facial Wrinkle Scale with Photonumeric Guide (FWS; 0=none, 1= mild, 2=moderate, 3=severe). The FWS assessment was performed independently by both investigators and subjects. The primary timepoint was day 30 following the first treatment, as compared to baseline.

The primary efficacy response definition used for the pivotal trials was a composite ≥ 2-grade improvement from baseline in LCL severity at maximum smile, assessed by both investigator and subject on a per-subject basis. For Studies 1 and 2, the proportion of responders was statistically significant favoring BOTOX Cosmetic (24 Units [LCL alone] and 44 Units [LCL and GL]) compared to placebo at day 30 (Table 7).

Table 7: Studies 1 and 2: Composite Investigator and Subject Assessment of LCL at Maximum Smile at Day 30 – Responder Rates (% and Number of Subjects Achieving ≥ 2-Grade Improvement from Baseline)

Study BOTOX Cosmetic 24 Units BOTOX Cosmetic 24 Units LCL and 20 Units GL Placebo
Study 1 26.1% - 1.3%
58/222 3/223
Study 2 20.3% 21.3% 0.0%
62/306 65/305 0/306

The secondary endpoint of a responder defined as achieving a grade of none or mild for Study 1 as measured by the investigator is presented in Figure 4 below.

Figure 4: Percentage of Subjects with Treatment Success (% of Subjects achieving None or Mild from Baseline) by Visit (Study 1)

Percentage of Subjects with Treatment Success - Illustration

Medication Guide

PATIENT INFORMATION

BOTOX®
BOTOX®Cosmetic
(Boe-tox)
(onabotulinumtoxinA) for Injection

What is the most important information I should know about BOTOX and BOTOX Cosmetic?

BOTOX and BOTOX Cosmetic may cause serious side effects that can be life threatening, including:

  • Problems breathing or swallowing
  • Spread of toxin effects

These problems can happen hours, days, to weeks after an injection of BOTOX or BOTOX Cosmetic. Call your doctor or get medical help right away if you have any of these problems after treatment with BOTOX or BOTOX Cosmetic:

1. Problems swallowing, speaking, or breathing. These problems can happen hours, days, to weeks after an injection of BOTOX or BOTOX Cosmetic usually because the muscles that you use to breathe and swallow can become weak after the injection. Death can happen as a complication if you have severe problems with swallowing or breathing after treatment with BOTOX or BOTOX Cosmetic.

  • People with certain breathing problems may need to use muscles in their neck to help them breathe. These people may be at greater risk for serious breathing problems with BOTOX or BOTOX Cosmetic.
  • Swallowing problems may last for several months. People who cannot swallow well may need a feeding tube to receive food and water. If swallowing problems are severe, food or liquids may go into your lungs. People who already have swallowing or breathing problems before receiving BOTOX or BOTOX Cosmetic have the highest risk of getting these problems.

2. Spread of toxin effects. In some cases, the effect of botulinum toxin may affect areas of the body away from the injection site and cause symptoms of a serious condition called botulism. The symptoms of botulism include:

  • loss of strength and muscle weakness all over the body
  • double vision
  • blurred vision and drooping eyelids
  • hoarseness or change or loss of voice (dysphonia)
  • trouble saying words clearly (dysarthria)
  • loss of bladder control
  • trouble breathing
  • trouble swallowing

These symptoms can happen hours, days, to weeks after you receive an injection of BOTOX or BOTOX Cosmetic.

These problems could make it unsafe for you to drive a car or do other dangerous activities. See “What should I avoid while receiving BOTOX or BOTOX Cosmetic?”

There has not been a confirmed serious case of spread of toxin effect away from the injection site when BOTOX has been used at the recommended dose to treat chronic migraine, severe underarm sweating, blepharospasm, or strabismus, or when BOTOX Cosmetic has been used at the recommended dose to treat frown lines and/or crow's feet lines.

What are BOTOX and BOTOX Cosmetic?

BOTOX is a prescription medicine that is injected into muscles and used:

  • to treat overactive bladder symptoms such as a strong need to urinate with leaking or wetting accidents (urge urinary incontinence), a strong need to urinate right away (urgency), and urinating often (frequency) in adults when another type of medicine (anticholinergic) does not work well enough or cannot be taken.
  • to treat leakage of urine (incontinence) in adults with overactive bladder due to neurologic disease when another type of medicine (anticholinergic) does not work well enough or cannot be taken.
  • to prevent headaches in adults with chronic migraine who have 15 or more days each month with headache lasting 4 or more hours each day.
  • to treat increased muscle stiffness in elbow, wrist, and finger muscles in adults with upper limb spasticity.
  • to treat increased muscle stiffness in ankle and toe muscles in adults with lower limb spasticity.
  • to treat the abnormal head position and neck pain that happens with cervical dystonia (CD) in adults.
  • to treat certain types of eye muscle problems (strabismus) or abnormal spasm of the eyelids (blepharospasm) in people 12 years and older.

BOTOX is also injected into the skin to treat the symptoms of severe underarm sweating (severe primary axillary hyperhidrosis) when medicines used on the skin (topical) do not work well enough.

BOTOX Cosmetic is a prescription medicine that is injected into muscles and used to improve the look of moderate to severe frown lines between the eyebrows (glabellar lines) in adults for a short period of time (temporary).

BOTOX Cosmetic is a prescription medicine that is injected into the area around the side of the eyes to improve the look of crow's feet lines in adults for a short period of time (temporary).

You may receive treatment for frown lines and crow's feet lines at the same time.

It is not known whether BOTOX is safe or effective in people younger than:

  • 18 years of age for treatment of urinary incontinence
  • 18 years of age for treatment of chronic migraine
  • 18 years of age for treatment of spasticity
  • 16 years of age for treatment of cervical dystonia
  • 18 years of age for treatment of hyperhidrosis
  • 12 years of age for treatment of strabismus or blepharospasm

BOTOX Cosmetic is not recommended for use in children younger than 18 years of age.

It is not known whether BOTOX and BOTOX Cosmetic are safe or effective to prevent headaches in people with migraine who have 14 or fewer headache days each month (episodic migraine).

It is not known whether BOTOX and BOTOX Cosmetic are safe or effective for other types of muscle spasms or for severe sweating anywhere other than your armpits.

Who should not take BOTOX or BOTOX Cosmetic?

Do not take BOTOX or BOTOX Cosmetic if you:

  • are allergic to any of the ingredients in BOTOX or BOTOX Cosmetic. See the end of this Medication Guide for a list of ingredients in BOTOX and BOTOX Cosmetic.
  • had an allergic reaction to any other botulinum toxin product such as Myobloc®, Dysport®, or Xeomin®
  • have a skin infection at the planned injection site
  • are being treated for urinary incontinence and have a urinary tract infection (UTI)
  • are being treated for urinary incontinence and find that you cannot empty your bladder on your own (only applies to people who are not routinely catheterizing)

What should I tell my doctor before taking BOTOX or BOTOX Cosmetic?

Tell your doctor about all your medical conditions, including if you:

  • have a disease that affects your muscles and nerves (such as amyotrophic lateral sclerosis [ALS or Lou Gehrig's disease], myasthenia gravis or Lambert-Eaton syndrome). See “What is the most important information I should know about BOTOX and BOTOX Cosmetic?”
  • have allergies to any botulinum toxin product
  • had any side effect from any botulinum toxin product in the past
  • have or have had a breathing problem, such as asthma or emphysema
  • have or have had swallowing problems
  • have or have had bleeding problems
  • have plans to have surgery
  • had surgery on your face
  • have weakness of your forehead muscles, such as trouble raising your eyebrows
  • have drooping eyelids
  • have any other change in the way your face normally looks
  • have symptoms of a urinary tract infection (UTI) and are being treated for urinary incontinence. Symptoms of a urinary tract infection may include pain or burning with urination, frequent urination, or fever.
  • have problems emptying your bladder on your own and are being treated for urinary incontinence
  • are pregnant or plan to become pregnant. It is not known if BOTOX or BOTOX Cosmetic can harm your unborn baby.
  • are breast-feeding or plan to breastfeed. It is not known if BOTOX or BOTOX Cosmetic passes into breast milk.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal products. Using BOTOX or BOTOX Cosmetic with certain other medicines may cause serious side effects. Do not start any new medicines until you have told your doctor that you have received BOTOX or BOTOX Cosmetic in the past.

Especially tell your doctor if you:

  • have received any other botulinum toxin product in the last four months
  • have received injections of botulinum toxin, such as Myobloc® (rimabotulinumtoxinB), Dysport® (abobotulinumtoxinA), or Xeomin® (incobotulinumtoxinA) in the past. Be sure your doctor knows exactly which product you received.
  • have recently received an antibiotic by injection
  • take muscle relaxants
  • take an allergy or cold medicine
  • take a sleep medicine
  • take anti-platelets (aspirin-like products) and/or anti-coagulants (blood thinners)

Ask your doctor if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take BOTOX or BOTOX Cosmetic?

  • BOTOX or BOTOX Cosmetic is an injection that your doctor will give you.
  • BOTOX is injected into your affected muscles, skin, or bladder.
  • BOTOX Cosmetic is injected into your affected muscles.
  • Your doctor may change your dose of BOTOX or BOTOX Cosmetic, until you and your doctor find the best dose for you.
  • Your doctor will tell you how often you will receive your dose of BOTOX or BOTOX Cosmetic injections.

What should I avoid while taking BOTOX or BOTOX Cosmetic?

BOTOX and BOTOX Cosmetic may cause loss of strength or general muscle weakness, vision problems, or dizziness within hours to weeks of taking BOTOX or BOTOX Cosmetic. If this happens, do not drive a car, operate machinery, or do other dangerous activities. See “What is the most important information I should know about BOTOX and BOTOX Cosmetic?”

What are the possible side effects of BOTOX and BOTOX Cosmetic?

BOTOX and BOTOX Cosmetic can cause serious side effects. See “What is the most important information I should know about BOTOX and BOTOX Cosmetic?”

Other side effects of BOTOX and BOTOX Cosmetic include:

  • dry mouth
  • discomfort or pain at the injection site
  • tiredness
  • headache
  • neck pain
  • eye problems: double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of your eyelids, and dry eyes.
  • urinary tract infection in people being treated for urinary incontinence
  • painful urination in people being treated for urinary incontinence
  • inability to empty your bladder on your own and are being treated for urinary incontinence. If you have difficulty fully emptying your bladder after getting BOTOX, you may need to use disposable selfcatheters to empty your bladder up to a few times each day until your bladder is able to start emptying again.
  • allergic reactions. Symptoms of an allergic reaction to BOTOX or BOTOX Cosmetic may include: itching, rash, red itchy welts, wheezing, asthma symptoms, or dizziness or feeling faint. Tell your doctor or get medical help right away if you are wheezing or have asthma symptoms, or if you become dizzy or faint.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of BOTOX and BOTOX Cosmetic. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.

General information about BOTOX and BOTOX Cosmetic:

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about BOTOX and BOTOX Cosmetic. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about BOTOX and BOTOX Cosmetic that is written for healthcare professionals.

What are the ingredients in BOTOX and BOTOX Cosmetic?

Active ingredient: botulinum toxin type A

Inactive ingredients: human albumin and sodium chloride

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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