BOTULINUM TOXIN TYPE A Drug Interactions: What You Need to Know

INTERACTIONS Concomitant use of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission or muscle relaxants, should be observed closely because effect of DYSPORT may be potentiated ( 7.1 , 7.4 ) Anticholinergic drugs may potentiate systemic anticholinergic effects ( 7.2 ) The effect of administering different botulinum neurotoxins during the course of treatment with DYSPORT is unknown ( 7.3 )

7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents) should only be performed with caution because the effect of the botulinum toxin may be potentiated. If co-administered, observe the patient closely.

7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of DYSPORT may potentiate systemic anticholinergic effects such as blurred vision.

7.3 Other Botulinum Neurotoxin Products The effect of administering botulinum neurotoxin products including DYSPORT, at the same time or within several months of each other is unknown. Excessive weakness may be exacerbated by another administration of botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

7.4 Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of DYSPORT.

BOTOX is contraindicated: In patients who are hypersensitive to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions ( 5.4 )] . In the presence of infection at the proposed injection site(s). For intradetrusor injection in patients with a urinary tract infection; or in patients with urinary retention or post-void residual (PVR) urine volume >200 mL who are not routinely performing clean intermittent self-catheterization (CIC) [see Warnings and Precautions ( 5.12 , 5.13 )] . Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation ( 4 , 5.4 , 6 ) Infection at the proposed injection site ( 4 )

Intradetrusor

Injections: Urinary tract infection or urinary retention ( 4 )

AND PRECAUTIONS Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur ( 5.1 , 5.6 )

Potency

Units of BOTOX are not interchangeable with other preparations of botulinum toxin products ( 5.2 , 11 ) Potential serious adverse reactions after BOTOX injections for unapproved uses ( 5.3 ) Concomitant neuromuscular disorder may exacerbate clinical effects of treatment ( 5.5 ) Use with caution in patients with compromised respiratory function ( 5.6 , 5.7 , 5.10 ) Corneal exposure and ulceration due to reduced blinking may occur with BOTOX treatment of blepharospasm ( 5.8 ) Retrobulbar hemorrhages and compromised retinal circulation may occur with BOTOX treatment of strabismus ( 5.9 ) Bronchitis and upper respiratory tract infections in patients treated for spasticity ( 5.10 ) Urinary tract infections in patients treated for OAB ( 5.12 ) Urinary retention: Post-void residual urine volume should be monitored in patients treated for OAB or adult detrusor overactivity associated with a neurologic condition who do not catheterize routinely, particularly patients with multiple sclerosis or diabetes mellitus. ( 5.13 ) 5. 1 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 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 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 BOTOX for blepharospasm at the recommended dose (30 Units and below), severe primary axillary hyperhidrosis at the recommended dose (100 Units), strabismus, or for chronic migraine at the labeled doses have been reported.

5.2 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 <span class="opacity-50 text-xs">[see Description ( 11 )]</span> .

5.3 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.

5.4 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.

5.5 Increased Risk of Clinically Significant Effects with 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 known or unrecognized neuromuscular disorders or neuromuscular junction disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from therapeutic doses of BOTOX <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.6 ) ]</span> .

5.6 Dysphagia and Breathing Difficulties 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 oropharyngeal muscles that control swallowing or breathing <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

5.7 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 spasticity should be monitored closely. In a double-blind, placebo-controlled, parallel group study in adult patients treated for upper limb spasticity with stable reduced pulmonary function (defined as FEV 1 40-80% of predicted value and FEV 1 /FVC ≤ 0.75), the event rate in change of Forced Vital Capacity (FVC) ≥15% or ≥20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 8 ).

Table

8: Event Rate Per Patient Treatment Cycle Among Adult Upper Limb Spasticity Patients with Reduced Lung Function Who Experienced at Least a 15% or 20% Decrease in FVC 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 adult spasticity 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 [se e Warnings and Precautions ( 5.10 )] . In a 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 9 ).

Table

9: 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 0/15 (0%) 0/15 (0%) 1/11 (9%) 0/11 (0%)

Week

6 2/13 (15%) 1/13 (8%) 0/12 (0%) 0/12 (0%)

Week

12 0/12(0%) 0/12 (0%) 0/7 (0%) 0/7 (0%)

5.8 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.

5.9 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.

5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity Bronchitis was reported more frequently as an adverse reaction in adult patients treated for upper limb spasticity with BOTOX (3% at 251 Units-360 Units total dose), compared to placebo (1%). In adult 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%). In adult patients treated for lower limb spasticity, upper respiratory tract infections were reported more frequently as an adverse reaction in patients treated with BOTOX (2% at 300 Units to 400 Units total dose) compared to placebo (1%). In pediatric patients treated for upper limb spasticity, upper respiratory tract infections were reported more frequently as an adverse reaction in patients treated with BOTOX (17% at 6 Units/kg and 10% at 3 Units/kg) compared to placebo (9%). In pediatric patients treated for lower limb spasticity, upper respiratory tract infection was not reported with an incidence greater than placebo.

5.11 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 adult patients treated with BOTOX 200 Units compared with placebo (1.5% versus 0.4%, respectively).

5.12 Urinary Tract Infections in Patients with Overactive Bladder BOTOX increases the incidence of urinary tract infection <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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.

5.13 Urinary Retention in Adults 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 adult 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 10. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table

10: 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 11.

Table

11: 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 Diabet e s Patients without D iabet e s 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)

Adult Detrusor

Overactivity associated with a Neurologic Condition In two double-blind, placebo-controlled trials in adult patients with detrusor overactivity associated with a neurologic condition (NDO-1 and NDO-2), 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 200 Units or placebo is shown in Table 12. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table

12: Proportion of Adult 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 adult patients not using CIC at baseline, those with Multiple Sclerosis (MS) were more likely to require CIC post-injection than those with Spinal Cord Injury (SCI) (see Table 13 ).

Table

13: Proportion of Adult 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) A placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) was conducted in non-catheterizing adult MS patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition. Catheterization for urinary retention was initiated in 15.2% (10/66) of patients following treatment with BOTOX 100 Units versus 2.6% (2/78) on placebo at any time during the complete treatment cycle. The median duration of post-injection catheterization for those who developed urinary retention was 64 days for BOTOX 100 Units and 2 days for placebo.

5.14 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 and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.