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Indications
DYSPORT is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for: The treatment of cervical dystonia in adults ( 1.1 ) The temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adults < 65 years of age ( 1.2 ) The treatment of spasticity in patients 2 years of age and older ( 1.3 )
1.1Cervical Dystonia
DYSPORT is indicated for the treatment of cervical dystonia in adults.
1.2Glabellar Lines
DYSPORT is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adults less than 65 years of age.
1.3Spasticity
DYSPORT is indicated for the treatment of spasticity in patients 2 years of age and older.
Contraindications
DYSPORT is contraindicated in patients with: Known hypersensitivity to any botulinum toxin products, cow's milk protein, or to any of the components in the formulation [see Warnings and Precautions (5.3) ]. This product may contain trace amounts of cow's milk protein [see Description (11) ] . Infection at the proposed injection site(s). Hypersensitivity to: any botulinum toxin product or excipients ( 4 , 5.3 ) cow's milk protein ( 4 , 5.3 ) Infection at the proposed injection site(s) ( 4 )
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The potency units of DYSPORT are not interchangeable with other preparations of botulinum toxin products ( 5.2 ) Immediate medical attention may be required in cases of respiratory, speech or swallowing difficulties ( 5.4 ) Recommended dose and frequency of administration should not be exceeded ( 5.5 ) Dry eye may occur with glabellar line treatment; if symptoms persist, consider referring patient to an ophthalmologist ( 5.6 ) Concomitant neuromuscular disorder may exacerbate clinical effects of treatment ( 5.7 )
5.1Spread of Toxin Effect
Postmarketing safety data from DYSPORT 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, blurred vision, 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, particularly in those patients who have underlying conditions that would predispose them to these symptoms.
In unapproved uses and approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than the maximum recommended total dose .
5.2 Lack of Interchangeability between Botulinum Toxin Products The potency Units of DYSPORT 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 DYSPORT cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method [see Description (11) ] .
5.3Hypersensitivity Reactions
Serious hypersensitivity reactions have been reported with DYSPORT. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a serious hypersensitivity reaction occurs, discontinue further injection of DYSPORT and institute appropriate medical therapy immediately.
5.4Dysphagia and Breathing Difficulties Treatment with
DYSPORT 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 Boxed Warning and 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 weeks 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 post-marketing reports of serious breathing difficulties, including respiratory failure. 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 Boxed Warning , Warnings and Precautions (5.2) , Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ] .
5.5Facial Anatomy in the Treatment of Glabellar Lines
Caution should be exercised when administering DYSPORT to patients with surgical alterations to the facial anatomy, marked facial asymmetry, inflammation at the injection site(s), ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin [see Dosage and Administration (2.4) ] or the inability to substantially lessen glabellar lines by physically spreading them apart [see Clinical Studies (14.2) ] .
Do not exceed the recommended dosage and frequency of administration of DYSPORT. In clinical trials, subjects who received a higher dose of DYSPORT had an increased incidence of eyelid ptosis.
5.6Dry Eye with the Treatment of Glabellar Lines
Dry eye has been reported with the use of DYSPORT in the treatment of glabellar lines [see Adverse Reactions (6.3) ] . Reduced tear production, reduced blinking, and corneal disorders, may occur with use of botulinum toxins, including DYSPORT. If symptoms of dry eye (e.g., eye irritation, photophobia, or visual changes) persist, consider referring patient to an ophthalmologist [see Boxed Warning and Warnings and Precautions 5.2 ].
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 typical doses of DYSPORT [see Adverse Reactions (6.1) ] .
5.8Human 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.
5.9Intradermal Immune Reaction
The possibility of an immune reaction when injected intradermally is unknown. The safety of DYSPORT for the treatment of hyperhidrosis has not been established. DYSPORT is approved only for intramuscular injection.
5.10Pre-existing Conditions at the Injection Site
Caution should be exercised when DYSPORT is used where the targeted muscle shows excessive weakness or atrophy.
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 )
7.1Aminoglycosides 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.
7.2Anticholinergic Drugs Use
of anticholinergic drugs after administration of DYSPORT may potentiate systemic anticholinergic effects such as blurred vision.
7.3Other 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.
7.4Muscle Relaxants
Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of DYSPORT.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There are no adequate and well-controlled clinical studies with DYSPORT in pregnant women. DYSPORT should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. DYSPORT produced embryo-fetal toxicity in relation to maternal toxicity when given to pregnant rats and rabbits at doses lower than or similar to the maximum recommended human dose (MRHD) of 1000 Units on a body weight (Units/kg) basis (see Data ).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Data Animal Data In a study in which pregnant rats received daily intramuscular injections of DYSPORT (2.2, 6.6, or 22 Units/kg on gestation days 6 through 17 or intermittently 44 Units/kg on gestation days 6 and 12 only) during organogenesis, increased early embryonic death was observed with both schedules at the highest tested doses (22 and 44 Units/kg), which were associated with maternal toxicity.
The no-effect dose for embryo-fetal developmental toxicity was
2.2 Units/kg (less than the maximum recommended human dose [MRHD] on a body weight basis). In a study in which pregnant rabbits received daily intramuscular injections of DYSPORT (0.3, 3.3, or
6.7Units/kg)
on gestation days 6 through 19 or intermittently (13.3 Units/kg on gestation days 6 and 13 only) during organogenesis, no embryofetal data were available at the highest dose administered daily (6.7 Units/kg) because of premature death in all doses at that dose. At the lower daily doses or with intermittent dosing, no adverse developmental effects were observed. All doses for which data were available are less than the MRHD on a body weight basis.
In a study in which pregnant rats received 6 weekly intramuscular injections of DYSPORT (4.4, 11.1, 22.2, or 44 Units/kg) beginning on day 6 of gestation and continuing through parturition to weaning, an increase in stillbirths was observed at the highest dose tested, which was maternally toxic. The no-effect dose for pre- and post-natal developmental toxicity was
22.2 Units/kg (similar to the MRHD).
Adverse reactions
The following serious adverse reactions are discussed below and elsewhere in labeling: Spread of Toxin Effect [see Warnings and Precautions (5.1) ] Lack of Interchangeability between Botulinum Toxin Products [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.4) ] Facial Anatomy in the Treatment of Glabellar Lines [see Warnings and Precautions (5.5) ] Dry Eye with the Treatment of Glabellar Lines [see Warnings and Precautions (5.6) ] Pre-existing Neuromuscular Disorders [see Warnings and Precautions (5.7) ] Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.8) ] Intradermal Immune Reaction [see Warnings and Precautions (5.9) ] Pre-existing Conditions at the Injection Site [see Warnings and Precautions (5.10) ] Most commonly observed adverse reactions are ( 6.1 ): Cervical Dystonia (≥5%): muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, musculoskeletal pain, dysphonia, injection site pain and eye disorders Glabellar Lines (≥2%): nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine Spasticity in Adults Upper limb spasticity (≥4%): muscular weakness Lower limb spasticity (≥5%): falls, muscular weakness, and pain in extremity Spasticity in Pediatric Patients Upper limb spasticity (≥10%): upper respiratory tract infection and pharyngitis Lower limb spasticity (≥10%): nasopharyngitis, cough, and pyrexia To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, 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 practice. Cervical Dystonia The data described below reflect exposure to DYSPORT in 446 cervical dystonia patients in 7 studies. Of these, two studies were randomized, double-blind, single treatment, placebo-controlled studies with subsequent optional open-label treatment in which dose optimization (250 to 1000 Units per treatment) over the course of 5 treatment cycles was allowed [see Clinical Studies (14.1) ].
The population was almost entirely Caucasian (99%) with a median age of 51 years (range 18–82 years). Most patients (87%) were less than 65 years of age; 58.4% were women. Common Adverse Reactions The most commonly reported adverse reactions (occurring in 5% or more of patients who received 500 Units of DYSPORT in the placebo-controlled clinical trials) in cervical dystonia patients were: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, musculoskeletal pain, dysphonia, injection site pain and eye disorders (consisting of blurred vision, diplopia, and reduced visual acuity and accommodation).
Other than injection site reactions, most adverse reactions became noticeable about one week after treatment and lasted several weeks. The rates of adverse reactions were higher in the combined controlled and open-label experience than in the placebo-controlled trials. During the clinical studies, two patients (<1%) experienced adverse reactions leading to withdrawal. One patient experienced disturbance in attention, eyelid disorder, feeling abnormal and headache, and one patient experienced dysphagia.
Table 7 compares the incidence of the most frequent adverse reactions from a single treatment cycle of 500 Units of DYSPORT compared to placebo [see Clinical Studies (14.1) ] . Table 7: Most Common Adverse Reactions (≥5%) and Greater than Placebo in the Pooled, Double-Blind, Placebo-Controlled Phase of Clinical Trials in Patients with Cervical Dystonia Adverse Reactions DYSPORT 500 Units (N=173) % Placebo (N=182) % Any Adverse Reaction 61 51 General disorders and administration site conditions Injection site discomfort 13 8 Fatigue 12 10 Injection site pain 5 4 Musculoskeletal and connective tissue disorders Muscular weakness 16 4 Musculoskeletal pain 7 3 Gastrointestinal disorders Dysphagia 15 4 Dry mouth 13 7 Nervous system disorders Headache 11 9 Respiratory, thoracic and mediastinal disorders Dysphonia 6 2 Eye Disorders The following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus. 7 2 Dose-response relationships for common adverse reactions in a randomized multiple fixed-dose study in which the total dose was divided between two muscles (the sternocleidomastoid and splenius capitis) are shown in Table 8.
Table 8: Common Adverse Reactions by Dose in Fixed-Dose Study in Patients with Cervical Dystonia Adverse Reactions DYSPORT Dose 250 Units % 500 Units % 1000 Units % Placebo % Any Adverse Reaction 37 65 83 30 Dysphagia 21 29 39 5 Dry Mouth 21 18 39 10 Muscular Weakness 11 12 56 0 Injection Site Discomfort 5 18 22 10 Dysphonia 0 18 28 0 Facial Paresis 5 0 11 0 Eye Disorders The following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus. 0 6 17 0 Injection Site Reactions Injection site discomfort and injection site pain were common adverse reactions following DYSPORT administration.
Less Common Adverse Reactions The following adverse reactions were reported less frequently (<5%). Breathing Difficulty Breathing difficulties were reported by approximately 3% of patients following DYSPORT administration and in 1% of placebo patients in clinical trials during the double-blind phase. These consisted mainly of dyspnea. The median time to onset from last dose of DYSPORT was approximately one week, and the median duration was approximately three weeks.
Other adverse reactions with incidences of less than 5% in the DYSPORT 500 Units group in the double-blind phase of clinical trials included dizziness in 3.5% of DYSPORT-treated patients and 1% of placebo-treated patients, and muscle atrophy in 1% of DYSPORT-treated patients and in none of the placebo-treated patients. Laboratory Findings Patients treated with DYSPORT exhibited a small increase from baseline (0.23 mol/L) in mean blood glucose relative to placebo-treated patients.
This was not clinically significant among patients in the development program but could be a factor in patients whose diabetes is difficult to control. Electrocardiographic Findings ECG measurements were only recorded in a limited number of patients in an open-label study without a placebo or active control. This study showed a statistically significant reduction in heart rate compared to baseline, averaging about three beats per minute, observed thirty minutes after injection.
Glabellar Lines In placebo-controlled clinical trials of DYSPORT, the most common adverse reactions (≥2%) following injection of DYSPORT were nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine. Table 9 reflects exposure to DYSPORT in 398 patients 19 to 75 years of age who were evaluated in the randomized, placebo-controlled clinical studies that assessed the use of DYSPORT for the temporary improvement in the appearance of glabellar lines [see Clinical Studies (14.2) ] .
Adverse reactions of any cause occurred in 48% of the DYSPORT-treated patients and 33% of the placebo-treated patients. Table 9: Most Common Adverse Reactions with > 1% Incidence in Pooled, Placebo-Controlled Trials for Glabellar Lines Adverse Reactions by Body System DYSPORT (N=398) % Patients who received treatment with placebo and DYSPORT are counted in both treatment columns.
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Composition
Active ingredients
abobotulinumtoxinA 300 UNITS/VIAL
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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