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Botox

WARNINGS

Included as part of the PRECAUTIONS section.

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, DESCRIPTION].

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.

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.

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].

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 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 swallowing. When distant effects occur, additional respiratory muscles may be involved.

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 ADVERSE REACTIONS].

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

  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%

Differences from placebo were not statistically significant

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.

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%).

Autonomic Dysreflexia 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).

Urinary Tract Infections in Patients with Overactive Bladder

BOTOX increases the incidence of urinary tract infection [see ADVERSE REACTIONS]. Clinical trials for overactive bladder excluded patients with more than 2 UTIs in the past 6 months and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX for the treatment of overactive bladder in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk.

Urinary Retention in Patients Treated for Bladder Dysfunction

Due to the risk of urinary retention, treat only patients who are willing and able to initiate catheterization post-treatment, if required, for urinary retention.

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, particularly in patients with multiple sclerosis or diabetes mellitus. Depending on patient symptoms, institute catheterization if PVR urine volume exceeds 200 mL and continue until PVR falls below 200 mL. Instruct patients to contact their physician if they experience difficulty in voiding as catheterization may be required.

The incidence and duration of urinary retention is described below for patients with overactive bladder and detrusor overactivity associated with a neurologic condition who received BOTOX or placebo injections.

Overactive Bladder

In double-blind, placebo-controlled trials in patients with OAB, the proportion of subjects who initiated clean intermittent catheterization (CIC) for urinary retention following treatment with BOTOX or placebo is shown in Table 6. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table 6: Proportion of Patients Catheterizing for Urinary Retention and Duration of Catheterization following an injection in double-blind, placebo-controlled clinical trials in OAB

Timepoint BOTOX 100 Units
(N=552)
Placebo
(N=542)
Proportion of Patients Catheterizing for Urinary Retention
At any time during complete treatment cycle 6.5% (n=36) 0.4% (n=2)
Duration of Catheterization for Urinary Retention (Days)
Median 63 11
Min, Max 1, 214 3, 18

Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary retention than those without diabetes, as shown in Table 7.

Table 7: Proportion of Patients Experiencing Urinary Retention following an injection in double-blind, placebo-controlled clinical trials in OAB according to history of Diabetes Mellitus

  Patients with Diabetes Patients without Diabetes
BOTOX 100 Units
(N=81)
Placebo
(N=69)
BOTOX 100 Units
(N=526)
Placebo
(N=516)
Urinary retention 12.3% (n=10) 0 6.3% (n=33) 0.6% (n=3)

Detrusor Overactivity associated with a Neurologic Condition

In double-blind, placebo-controlled trials in patients with detrusor overactivity associated with a neurologic condition, 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 8. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table 8: Proportion of Patients not using CIC at baseline and then Catheterizing for Urinary Retention and Duration of Catheterization following an injection in double-blind, placebo-controlled clinical trials

Timepoint BOTOX 200 Units
(N=108)
Placebo
(N=104)
Proportion of Patients Catheterizing for Urinary Retention
At any time during complete treatment cycle 30.6% (n=33) 6.7% (n=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 9).

Table 9: Proportion of Patients by Etiology (MS and SCI) not using CIC at baseline and then Catheterizing for Urinary Retention following an injection in double-blind, placebo-controlled clinical trials

Timepoint MS SCI
BOTOX 200 Units
(N=86)
Placebo
(N=88)
BOTOX 200 Units
(N=22)
Placebo
(N=16)
At any time during complete treatment cycle 31% (n=27) 5% (n=4) 27% (n=6) 19% (n=3)

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

Advise patients 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

Advise patients 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.

Voiding Symptoms after Bladder Injections

After bladder injections for urinary incontinence, advise patients to contact their physician if they experience difficulties in voiding or burning sensation upon voiding.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

BOTOX 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 (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 equal to the average high human dose for upper limb spasticity of 360 Units on a body weight basis (Units/kg).

Use In Specific Populations

Pregnancy

Pregnancy Category C

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

When BOTOX (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 0.7 times the average high human dose for upper limb spasticity of 360 Units on a body weight basis (Units/kg).

When BOTOX 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 and 0.25 Units/kg in rabbits are 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 3 times the average high human dose based on Units/kg.

Nursing Mothers

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

Pediatric Use

Bladder Dysfunction

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

Prophylaxis of Headaches in Chronic Migraine

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

Spasticity

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

Axillary Hyperhidrosis

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

Cervical Dystonia

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

Blepharospasm and Strabismus

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use

Overall, with the exception of Overactive Bladder (see below), clinical studies of BOTOX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. There were too few patients over the age of 75 to enable any comparisons. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overactive Bladder

Of 1242 overactive bladder patients in placebo-controlled clinical studies of BOTOX, 41.4% (n=514) were 65 years of age or older, and 14.7% (n=182) were 75 years of age or older. Adverse reactions of UTI and urinary retention were more common in patients 65 years of age or older in both placebo and BOTOX groups compared to younger patients (see Table 15). Otherwise, there were no overall differences in the safety profile following BOTOX treatment between patients aged 65 years and older compared to younger patients in these studies.

Table 15: Incidence of Urinary Tract Infection and Urinary Retention according to Age Group during First Placebo-controlled Treatment, Placebo-controlled Clinical Trials in Patients with OAB

Adverse Reactions < 65 Years 65 to 74 Years ≥ 75 Years
BOTOX 100 Units
N=344
Placebo
N=348
BOTOX 100 Units
N=169
Placebo
N=151
BOTOX 100 Units
N=94
Placebo
N=86
Urinary tract infection 73 (21%) 23 (7%) 51 (30%) 20 (13%) 36 (38%) 16 (19%)
Urinary retention 21 (6%) 2 (0.6%) 14 (8%) 0 (0%) 8 (9%) 1 (1%)

Observed effectiveness was comparable between these age groups in placebo-controlled clinical studies.

Last reviewed on RxList: 2/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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