1.1 Detrusor Overactivity associated with a Neurologic Condition
Botox (onabotulinumtoxinA) for injection 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 month) in seven placebo-controlled studies.
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) and finger flexors (flexor digitorum profundus and flexor digitorum sublimis).
Important limitations
Safety and effectiveness of Botox have not been established for the treatment of other upper limb muscle groups, or for the treatment of lower limb spasticity. 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 neck 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.
Botox 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 (5.1) and Description (11)].
Indication specific dosage and administration recommendations should be followed. In treating adult patients for one or more indications, the maximum cumulative dose should generally not exceed 360 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. Physicians administering Botox must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. An understanding of standard electromyographic techniques is also required for treatment of strabismus and of upper limb spasticity, and may be useful for the treatment of cervical dystonia.
Use caution when Botox treatment is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle(s).
Preparation and Dilution Technique
Botox is supplied in single-use 100 Units and 200 Units per vial. Prior to injection, reconstitute each vacuum-dried vial of Botox with sterile, non-preserved 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 detrusor 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 (100 Units and 200 Units)
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 |
|---|
*Preservative-free 0.9% Sodium Chloride Injection, USP Only
|
1 mL
2 mL
4 mL
8 mL |
10 Units
5 Units
2.5 Units
1.25 Units |
1 mL
2 mL
4 mL
8 mL
10 mL |
20 Units
10 Units
5 Units
2.5 Units
2 Units |
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 products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit.
2.3 Detrusor Overactivity associated with a Neurologic Condition
Patients should not have an acute urinary tract infection prior to treatment. Prophylactic antibiotics (except aminoglycosides, see Drug Interactions (7)) should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment.
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.
An intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is 200 Units of Botox per treatment, and should not be exceeded.
Reconstitute a 200 Unit vial of Botox with 6 mL of 0.9% non-preserved saline solution 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 0.9% non-preserved saline solution into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of reconstituted Botox. Use immediately after reconstitution in the syringe. Dispose of any unused saline.
Alternatively, reconstitute two 100 Unit vials of Botox, each with 6 mL of 0.9% non-preserved saline solution and mix the vials gently. Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe. Complete the reconstitution by adding 6 mL of 0.9% non-preserved saline solution into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 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 trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL of reconstituted Botox prior to the start of injections (depending on the needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor, and 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 saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post-injection.
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.
Figure 1: Injection Pattern for Detrusor Overactivity associated with a Neurologic Condition
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 administered intramuscularly (IM) 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 thru G) for Chronic Migraine
Table 2: Botox Dosing by Muscle for Chronic Migraine
| Head/Neck Area |
Recommended Dose (Number of Sitesa) |
|---|
a Each IM injection site = 0.1 mL = 5 Units Botox
|
b Dose distributed bilaterally
|
| 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 |
Upper Limb Spasticity
Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location 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. In clinical trials, doses ranging from 75 Units to 360 Units were divided among selected muscles 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 |
The recommended dilution is 200 Units/4 mL or 100 Units/2 mL with 0.9% non-preserved sterile saline (see Table 1). The lowest recommended starting dose should be used, and no more than 50 Units per 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 electromyographic guidance or nerve stimulation techniques 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.
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 (14.4)].
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 patient 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 (5.2, 5.5, 5.6)].
The recommended dilution is 200 Units/2 mL, 200 Units/4 mL, 100 Units/1 mL, or 100 Units/2 mL with 0.9% non-preserved sterile saline, 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. 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 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 Dilution Table). Using a 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 underarm 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 the area of no effect, the injection sites should be evenly spaced as shown in Figure 2.
Figure 2: Injection Pattern for Primary Axillary Hyperhidrosis
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 through 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 reducing diffusion into the inferior oblique, may reduce the complication of diplopia. Ecchymosis occurs easily in the soft eyelid tissues. This can be prevented by applying pressure at the injection site immediately after the injection.
The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is 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 two 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 not 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 Dosage and Administration (2.2)] 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 100 Units/8 mL; for 2.5 Units it is 100 Units/4 mL (see Table 1).
Dosage Forms and Strengths
Single-use, sterile 100 Units or 200 Units vacuum-dried powder for reconstitution only with sterile, non-preserved 0.9% Sodium Chloride Injection USP prior to injection.
Contraindications
Known Hypersensitivity to Botulinum Toxin
Botox is contraindicated in patients who are hypersensitive to any botulinum toxin preparation or to any of the components in the formulation [see Warnings and Precautions (5.4)].
Infection at the Injection Site(s)
Botox is contraindicated in the presence of infection at the proposed injection site(s).
4.3 Acute Urinary Tract Infection and/or Acute Urinary Retention
Intradetrusor injection of Botox is contraindicated in patients with detrusor overactivity associated with a neurologic condition who have acute urinary tract infection, and in patients with acute urinary retention who are not routinely performing clean intermittent self-catheterization (CIC).
Warnings and Precautions
Lack of Interchangeability between Botulinum Toxin Products
The potency Units of Botox 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 Dosage and Administration (2.1), Description (11)].
Spread of Toxin Effect
Postmarketing safety data from Botox 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. 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) 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 for chronic migraine at the labeled doses have been reported.
5.3 Injections In or Near Vulnerable Anatomic Structures
Care should be taken when injecting in or near vulnerable anatomic structures. Serious adverse events including fatal outcomes have been reported in patients who had received Botox injected directly into salivary glands, the oro-lingual-pharyngeal region, esophagus and stomach. Some patients had pre-existing dysphagia or significant debility. (Safety and effectiveness have not been established for indications pertaining to these injection sites.) Pneumothorax associated with injection procedure has been reported following the administration of Botox near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices.
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 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.
Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia
Treatment with Botox and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing 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 swallowing. When distant effects occur, additional respiratory muscles may be involved [see Warnings and Precautions (5.2)].
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 of cervical dystonia 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, in cervical dystonia patients.
Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle 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 Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
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 particularly closely when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including severe dysphagia and respiratory compromise from therapeutic doses of Botox [see Adverse Reactions (6.1)].
Pulmonary Effects of Botox in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity associated with a Neurologic Condition
Patients with compromised respiratory status treated with Botox for upper limb spasticity should be monitored closely. In a double-blind, placebo-controlled, parallel group study in patients with stable reduced pulmonary function (defined as FEV1 40-80% of predicted value and FEV1/FVC ≤ 0.75), the event rate in change of Forced Vital Capacity ≥15% or ≥20% was generally greater in patients treated with Botox than in patients treated with placebo (see Table 4).
Table 4: Event rate per patient treatment cycle among patients with reduced lung function who experienced at least a 15% or 20% decrease in forced vital capacity from baseline at Week 1, 6, 12 post-injection with up to two treatment cycles with Botox or placebo
Differences from placebo were not statistically significant
|
|
Botox
360 Units |
Botox
240 Units |
Placebo |
| ≥15% |
≥20% |
≥15% |
≥20% |
≥15% |
≥20% |
|
| Week 1 |
4% |
0% |
3% |
0% |
7% |
3% |
| Week 6 |
7% |
4% |
4% |
2% |
2% |
2% |
| Week 12 |
10% |
5% |
2% |
1% |
4% |
1% |
In patients with reduced lung function, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with Botox than in patients treated with placebo [see Warnings and Precautions (5.10)].
In an ongoing double-blind, placebo-controlled, parallel group study in adult patients with detrusor overactivity associated with a neurologic condition and restrictive lung disease of neuromuscular etiology [defined as FVC 50-80% of predicted value in patients with spinal cord injury between C5 and C8, or MS] the event rate in change of Forced Vital Capacity ≥15% or ≥20% was generally greater in patients treated with Botox than in patients treated with placebo (see Table 5).
Table 5: Number and percent of patients experiencing at least a 15% or 20% decrease in FVC from baseline at Week 2, 6, 12 post-injection with Botox or placebo
|
Botox
200 Units |
Placebo |
| ≥15% |
≥20% |
≥15% |
≥20% |
|
| Week 2 |
0/12 (0%) |
0/12 (0%) |
1/11 (9%) |
0/11 (0%) |
| Week 6 |
2/11 (18%) |
1/11 (9%) |
0/11 (0%) |
0/11 (0%) |
| Week 12 |
0/11 (0%) |
0/11 (0%) |
0/6 (0%) |
0/6 (0%) |
Corneal Exposure and Ulceration in Patients Treated with Botox for Blepharospasm
Reduced blinking from Botox injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with 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.
Retrobulbar Hemorrhages in Patients Treated with Botox for Strabismus
During the administration of Botox for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred. It is recommended that appropriate instruments to decompress the orbit be accessible.
Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity
Bronchitis was reported more frequently as an adverse reaction in patients treated for upper limb spasticity with Botox (3% at 251 Units-360 Units total dose), compared to placebo (1%). In patients with reduced lung function treated for upper limb spasticity, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with Botox (11% at 360 Units total dose; 8% at 240 Units total dose) compared to placebo (6%).
5.11 Autonomic Dysreflexia and Urinary Retention in Patients Treated for Detrusor Overactivity associated with a Neurologic Condition
Autonomic dysreflexia associated with intradetrusor injections of Botox could occur in patients treated for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy. In clinical trials, the incidence of autonomic dysreflexia was greater in patients treated with Botox 200 Units compared with placebo (1.5% versus 0.4%, respectively).
In double-blind, placebo-controlled trials, the proportion of subjects who were not using clean intermittent catheterization (CIC) prior to injection and who subsequently required catheterization for urinary retention following treatment with Botox or placebo is shown in Table 6. The duration of post-injection catheterization is also shown.
Table 6: Proportion of Patients not using CIC at baseline and then Catheterizing for Urinary Retention and Duration of Catheterization following injection in double-blind, placebo-controlled clinical trials
Timepoint |
Botox 200 Unit
(N=108) |
Placebo
(N=104) |
|---|
| Proportion of Patients Catheterizing for Urinary Retention |
| At any time during complete treatment cycle |
33 (30.6%) |
7 (6.7%) |
| Duration of Catheterization for Urinary Retention (Days) |
| Median |
289 |
358 |
| Min, Max |
1, 530 |
2, 379 |
Among patients not using CIC at baseline, those with MS were more likely to require CIC post-injection than those with SCI (see Table 7).
Table 7: Proportion of Patients by Etiology (MS and SCI) not using CIC at baseline and then Catheterizing for Urinary Retention following injection in double-blind, placebo-controlled clinical trials
| Timepoint |
MS |
SCI |
|---|
Botox 200 Unit
(N=86) |
Placebo
(N=88) |
Botox
200 Unit
(N=22) |
Placebo
(N=16) |
|---|
| At any time during complete treatment cycle |
27 (31%) |
4 (5%) |
6 (27%) |
3 (19%) |
Due to the risk of urinary retention, only patients who are willing and/or able to initiate catheterization post-treatment, if required, should be considered for treatment.
In patients who are not catheterizing, post-void residual (PVR) urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Catheterization should be instituted if PVR urine volume exceeds 200 mL and continued until PVR falls below 200 mL. Patients should be instructed to contact their physician if they experience difficulty in voiding as catheterization may be required.
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.
Adverse Reactions
The following adverse reactions to Botox (onabotulinumtoxi
