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These highlights do not include all the information needed to use DYSPORT™ for Injection safely and effectively. See full prescribing information for DYSPORT™ for Injection. DYSPORT™ for Injection(abobotulinumtoxinA)Initial U.S. Approval: April 200 | Dysport

13:52 EDT 24th July 2014 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Distant Spread of Toxin Effect

Postmarketing reports indicate that the effects of DYSPORT™ and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, 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. 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, including spasticity in children and adults, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses.

DYSPORT™ (abobotulinumtoxinA) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients.

DYSPORT™ (abobotulinumtoxinA) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients <65 years of age.

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) ].

Reconstitution instructions are specific for each of the 300 Unit vial and the 500 Unit vial. These volumes yield concentrations specific for the use for each indication.

The recommended initial dose of DYSPORT™ for the treatment of cervical dystonia is 500 Units given intramuscularly as a divided dose among affected muscles in patients with or without a history of prior treatment with botulinum toxin. (A description of the average DYSPORT™ dose and percentage of total dose injected into specific muscles in the pivotal clinical trials can be found in Table 5 of Section 14.1, Clinical Studies—Cervical Dystonia.) Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Clinical studies with DYSPORT™ in cervical dystonia suggest that the peak effect occurs between two and four weeks after injection. Simultaneous EMG-guided application of DYSPORT™ may be helpful in locating active muscles not identified by physical examination alone.

Dose Modification

Where dose modification is necessary for the treatment of cervical dystonia, uncontrolled open-label studies suggest that dose adjustment can be made in 250 Unit steps according to the individual patient's response, with re-treatment every 12 weeks or longer, as necessary, based on return of clinical symptoms. Uncontrolled open-label studies also suggest that the total dose administered in a single treatment should be between 250 Units and 1000 Units. Re-treatment, if needed, should not occur in intervals of less than 12 weeks. Doses above 1000 Units have not been systematically evaluated.

2.1.1 Special Populations

Adults and elderly

The starting dose of 500 Units recommended for cervical dystonia is applicable to adults of all ages [see Use in Specific Populations (8.5) ].

Children

The safety and effectiveness of DYSPORT™ in the treatment of cervical dystonia in pediatric patients less than 18 years of age has not been assessed [see Warnings and Precautions (5.2) ].

2.1.2 Instructions for Preparation and Administration

DYSPORT™ is supplied as a single-use vial. Each 500 Unit vial of DYSPORT™ is to be reconstituted with 1 mL of 0.9% Sodium Chloride Injection USP (without preservative) to yield a solution of 500 Units per mL. Each 300 Unit vial of DYSPORT™ is to be reconstituted with 0.6 mL of 0.9% Sodium Chloride Injection USP (without preservative) to yield a solution equivalent to 250 Units per 0.5 mL.

Using an appropriately sized sterile syringe, needle and aseptic technique, draw up 1.0 mL or 0.6 mL of sterile, 0.9% Sodium Chloride Injection USP (without preservative) for 500 and 300 Unit vials, respectively. Insert the needle into the DYSPORT™ vial. The partial vacuum will begin to pull the saline into the vial. Any remaining required saline should be expressed into the vial manually. Do not use the vial if no vacuum is observed. Swirl gently to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT™ should be a clear, colorless solution, free of particulate matter, otherwise it should not be injected.

Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach an appropriately sized new sterile needle.

Once reconstituted, DYSPORT™ should be stored in a refrigerator at 2–8°C (36–46°F) protected from light and used within four hours. Do not freeze reconstituted DYSPORT™. Discard the vial and needle in accordance with local regulations.

The dose of DYSPORT™ for the treatment of glabellar lines is a total of 50 Units given intramuscularly in five equal aliquots of 10 Units each to achieve clinical effect (see Figure 1).

2.2.1 Special Populations

Adults

A total dose of 50 Units of DYSPORT™, in five equal aliquots, should be administered to achieve clinical effect.

The clinical effect of DYSPORT™ may last up to four months. Repeat dose clinical studies demonstrated continued efficacy with up to four repeated administrations. It should be administered no more frequently than every three months. When used for re-treatment, DYSPORT™ should be reconstituted and injected using the same techniques as the initial treatment.

Children

DYSPORT™ for glabellar lines is not recommended for use in pediatric patients less than 18 years of age [see Warnings and Precautions (5.2) ].

2.2.2 Instructions for Preparation and Administration

DYSPORT™ is supplied as a single-use vial. Each 300 Unit vial of DYSPORT™ is to be reconstituted with 2.5 mL of 0.9% Sodium Chloride Injection USP (without preservative) prior to injection. The concentration of the resulting solution will be 10 Units per 0.08 mL to be delivered in five equally divided aliquots of 0.08 mL each. DYSPORT™ may also be reconstituted with 1.5 mL of 0.9% Sodium Chloride Injection USP (without preservative) for a solution of 10 Units per 0.05 mL to be delivered in five equally divided aliquots of 0.05 mL each.

Using an appropriately sized sterile syringe, needle and aseptic technique, draw up 2.5 mL or 1.5 mL of 0.9% Sodium Chloride Injection USP (without preservative). Insert the needle into the DYSPORT™ vial. The partial vacuum will begin to pull the saline into the vial. Any remaining required saline should be expressed into the vial manually. Do not use the vial if no vacuum is observed. Swirl gently to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT™ should be a clear, colorless solution, free of particulate matter otherwise it should not be injected.

Draw a single patient dose of DYSPORT™ into a sterile syringe. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach a 30 gauge needle.

Once reconstituted, DYSPORT™ should be stored in a refrigerator at 2–8°C (36–46°F) protected from light and used within four hours. Do not freeze reconstituted DYSPORT™. Discard the vial and needle in accordance with local regulations.

2.2.3 Injection Technique

Glabellar facial lines arise from the activity of the lateral corrugator and vertical procerus muscles. These can be readily identified by palpating the tensed muscle mass while having the patient frown. The corrugator depresses the skin creating a "furrowed" vertical line surrounded by tensed muscle (i.e., frown lines). The location, size, and use of the muscles vary markedly among individuals. Physicians administering DYSPORT™ must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures.

Risk of ptosis can be mitigated by careful examination of the upper lid for separation or weakness of the levator palpebrae muscle (true ptosis), identification of lash ptosis, and evaluation of the range of lid excursion while manually depressing the frontalis to assess compensation.

In order to reduce the complication of ptosis, the following steps should be taken:

To inject DYSPORT™, advance the needle through the skin into the underlying muscle while applying finger pressure on the superior medial orbital rim. Inject patients with a total of 50 Units in five equally divided aliquots. Using a 30 gauge needle, inject 10 Units of DYSPORT™ into each of five sites, two in each corrugator muscle, and one in the procerus muscle (see Figure 1).

Figure 1

IMAGE dysport-01.jpg

DYSPORT™ is supplied as:

DYSPORT™ is supplied as:

DYSPORT™ is contraindicated in patients with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Adverse Reactions (6.1), Description (11) ].

This product may contain trace amounts of cow's milk protein. Patients known to be allergic to cow's milk protein should not be treated with DYSPORT™.

DYSPORT™ is contraindicated for use in patients with infection at the proposed injection site(s).

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) ].

Post-marketing 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 the 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 underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, 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.

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 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, in cervical dystonia patients.

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), Adverse Reactions (6.1), Clinical Pharmacology (12.2) ].

Caution should be exercised when administering DYSPORT™ to patients with surgical alterations to the facial anatomy, excessive weakness or atrophy in the target muscle(s), marked facial asymmetry, inflammation at the injection site(s), ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin [see Dosage and Administration (2.2.3) ] 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.

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 typical doses of DYSPORT™ [see Adverse Reactions (6.1) ].

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.

The possibility of an immune reaction when injected intradermally is unknown. The safety of DYSPORT™ for the treatment of hyperhidrosis has not been established.

The following adverse reactions to DYSPORT™ are discussed in greater detail in other sections of the labeling.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating incidence rates.

Cervical Dystonia

The data described below reflect exposure to DYSPORT™ in 357 cervical dystonia patients in 6 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.

The population was almost entirely Caucasian (99.2%) with a median age of 51 years (range 18–82 years). Most patients (86.6%) were less than 65 years of age; 58.4% were women.

Common Adverse Events

The most commonly reported adverse events (occurring in more than 5% 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, neck pain, musculoskeletal pain, dysphonia, injection site pain, and eye disorders (consisting of blurred vision, diplopia, and reduced visual acuity and accommodation). Most adverse events were reported as mild or moderate in severity. Other than injection site reactions, most adverse events became noticeable about one week after treatment and lasted several weeks.

The rates of adverse events 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 events leading to withdrawal. One patient experienced disturbance in attention, eyelid disorder, feeling abnormal and headache, and one patient experienced dysphagia.

Table 1 compares the incidence of the most frequent treatment-emergent adverse events (TEAEs) from a single treatment cycle of 500 Units of DYSPORT™ compared to placebo [see Clinical Studies (14.1) ].

Dose-response relationships for common adverse events 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 2.

Table 1: Most Common TEAEs (>5%) and Greater than Placebo: Double-blind Phase of Clinical Trials
Double-blind Phase
System Organ Class
  Preferred Term
DYSPORT™ 500 Units
(N=173)
Placebo
(N=182)
% %
Any TEAE 61 51
General disorders and administration site conditions 30 23
  Injection site discomfort 13 8
  Fatigue 12 10
  Injection site pain 5 4
Musculoskeletal and connective tissue disorders 30 18
  Muscular weakness 16 4
  Musculoskeletal pain 7 3
Gastrointestinal disorders 28 15
  Dysphagia 15 4
  Dry mouth 13 7
Nervous system disorders 16 13
  Headache 11 9
Infections and infestations 13 9
Respiratory, thoracic and mediastinal disorders 12 8
  Dysphonia 6 2
Eye DisordersThe following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus. 7 2
Table 2: Common TEAEs by Dose in Fixed-dose Study
System Organ Class
  Preferred Term
DYSPORT™ Dose
Placebo 250 Units 500 Units 1000 Units
Any Adverse Event 30% 37% 65% 83%
  Dysphagia 5% 21% 29% 39%
  Dry Mouth 10% 21% 18% 39%
  Muscular Weakness 0% 11% 12% 56%
  Injection Site Discomfort 10% 5% 18% 22%
  Dysphonia 0% 0% 18% 28%
  Facial Paresis 0% 5% 0% 11%
  Eye Disorders 0% 0% 6% 17%

Injection Site Reactions

Injection site discomfort and injection site pain were common adverse events following DYSPORT™ administration. These events were mainly of mild or moderate intensity.

Less Common Adverse Events

The following selected adverse events were reported less frequently (<5%).

Breathing Difficulties

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 and were generally mild in intensity. The median time to onset from last dose of DYSPORT™ was approximately one week, and the median duration was approximately three weeks.

Other selected adverse events 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 subjects and 1% of placebo-treated subjects, and muscle atrophy in 1% of DYSPORT™-treated subjects and in none of the placebo-treated subjects.

Laboratory Findings

Subjects treated with DYSPORT™ exhibited a small increase from baseline (0.23 mol/L) in mean blood glucose relative to placebo-treated subjects. This was not clinically significant among subjects 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 subjects 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

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 be predictive of rates observed in practice.

In placebo-controlled clinical trials of DYSPORT™, the most frequently reported adverse events (≥2%) following injection of DYSPORT™ were nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis and nausea.

Table 3 reflects exposure to DYSPORT™ in 398 subjects aged 19 to 75 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) ]. Adverse events of any cause were reported for 48% of the DYSPORT™-treated subjects and 33% of the placebo-treated subjects. Treatment-emergent adverse events were generally mild to moderate in severity.

In the overall safety database, where some subjects received up to twelve treatments with DYSPORT™, adverse events were reported for 57% (1425/2491) of subjects. The most frequently reported of these adverse events were headache, nasopharyngitis, injection site pain, sinusitis, URI, injection site bruising, and injection site reaction (numbness, discomfort, erythema, tenderness, tingling, itching, stinging, warmth, irritation, tightness, swelling).

Adverse events that emerged after repeated injections in 2–3% of the population included bronchitis, influenza, pharyngolaryngeal pain, cough, contact dermatitis, injection site swelling, and injection site discomfort.

The incidence of eyelid ptosis did not increase in the long-term safety studies with multiple re-treatments at intervals ≥ three months. The majority of eyelid ptosis events were mild to moderate in severity and resolved over several weeks. [see Injection Technique (2.2.3) ].

Table 3: Treatment-emergent Adverse Events with >1% incidence
Adverse Events by Body System DYSPORT™
n=398 (%)Subjects who received treatment with placebo and DYSPORT™ are counted in both treatment columns.
Placebo
n=496 (%)
Any Treatment-emergent Adverse Event 191 (48) 163 (33)
Eye Disorders
  Eyelid Edema 8 (2) 0
  Eyelid Ptosis 6 (2) 1 (<1)
Gastrointestinal Disorders
  Nausea 6 (2) 5 (1)
General Disorders and Administration Site Conditions
  Injection Site Pain 11 (3) 8 (2)
  Injection Site Reaction 12 (3) 2 (<1)
Infections and Infestations
  Nasopharyngitis 38 (10) 21 (4)
  Upper Respiratory Tract Infection 12 (3) 9 (2)
  Sinusitis 8 (2) 6 (1)
Investigations
  Blood Urine Present 6 (2) 1 (<1)
Nervous System Disorders
  Headache 37 (9) 23 (5)

There is extensive post-marketing experience outside the U.S. for the treatment of glabellar lines. Adverse reactions are reported voluntarily from a population of uncertain size; thus, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-marketing use: vertigo, eyelid ptosis, diplopia, vision blurred, photophobia, dysphagia, nausea, injection site reaction, malaise, influenza-like illness, hypersensitivity, sinusitis, amyotrophy, burning sensation, facial paresis, dizziness, headache, hypoesthesia, erythema, and excessive granulation tissue.

As with all therapeutic proteins, there is a potential for immunogenicity.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products in this class may be misleading.

Cervical Dystonia

About 3% of subjects developed antibodies (binding or neutralizing) over time with DYSPORT™ treatment. The significance of these antibodies is unknown since in the presence of binding and neutralizing antibodies some patients may continue to experience clinical benefit.

Glabellar Lines

Testing for antibodies to DYSPORT™ was performed for 1554 subjects who had up to nine cycles of treatment. Two subjects (0.13%) tested positive for binding antibodies at baseline. Three additional subjects tested positive for binding antibodies after receiving DYSPORT™ treatment. None of the subjects tested positive for neutralizing antibodies.

No formal drug interaction studies have been conducted with DYSPORT™.

Patients treated concomitantly with botulinum toxins and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents) should be observed closely because the effect of the botulinum toxin may be potentiated. Use of anticholinergic drugs after administration of DYSPORT™ may potentiate systemic anticholinergic effects such as blurred vision.

The effect of administering different botulinum neurotoxin products 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.

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

Pregnancy Category C

DYSPORT™ produced embryo-fetal toxicity when given to pregnant rats at doses similar to or greater than the maximum recommended human dose (MRHD) of 1000 Units on a body weight (Units/kg) basis.

In an embryo-fetal development study in which pregnant rats received intramuscular injections daily (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 dosing schedules. The no-effect dose for embryo-fetal developmental toxicity was 2.2 Units/kg (one-tenth the MRHD on a body weight basis). Maternal toxicity was seen at 22 and 44 Units/kg. In a pre-and post-natal development study in which female rats received 6 weekly intramuscular injections (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, which was maternally toxic. The no-effect dose for pre- and post-natal developmental toxicity was 22.2 Units/kg (approximately equal to the MRHD on a body weight basis).

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

It is not known whether DYSPORT™ is excreted in human milk.

Cervical Dystonia

Safety and effectiveness in pediatric patients have not been established [see Warnings and Precautions (5.2) ].

Glabellar Lines

DYSPORT™ is not recommended for use in pediatric patients less than 18 years of age.

Cervical Dystonia

There were insufficient numbers of patients aged 65 and over in the clinical studies to determine whether they respond differently than younger patients. In general, elderly patients should be observed to evaluate their tolerability of DYSPORT™, due to the greater frequency of concomitant disease and other drug therapy [see Dosage and Administration (2.1.1) ].

Glabellar Lines

Of the total number of subjects in the placebo-controlled clinical studies of DYSPORT™, 8 (1%) were 65 and over. Efficacy was not observed in subjects 65 years and over [see Clinical Studies (14.2) ]. For the entire safety database of geriatric subjects, although there was no increase in the incidence of eyelid ptosis, geriatric subjects did have an increase in the number of ocular adverse events compared to younger subjects (11% vs. 5%) [see Dosage and Administration (2.2) ].

Exploratory analyses in trials for glabellar lines in African-American subjects with Fitzpatrick skin types IV, V, or VI and in Hispanic subjects suggested that response rates at Day 30 were comparable to and no worse than the overall population.

Excessive doses of DYSPORT™ may be expected to produce neuromuscular weakness with a variety of symptoms. Respiratory support may be required where excessive doses cause paralysis of respiratory muscles. In the event of overdose, the patient should be medically monitored for symptoms of excessive muscle weakness or muscle paralysis [see Warnings and Precautions (5.2) ]. Symptomatic treatment may be necessary.

Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur, the person should be medically supervised for several weeks for signs and symptoms of excessive muscle weakness or paralysis.

There is no significant information regarding overdose from clinical studies in cervical dystonia. Doses exceeding 1000 Units of DYSPORT™ were rarely studied in clinical settings for any indication.

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

Botulinum toxin type A, the active ingredient in DYSPORT™ (abobotulinumtoxinA), is a purified neurotoxin type A complex produced by fermentation of the bacterium Clostridium botulinum type A, Hall Strain. It is purified from the culture supernatant by a series of precipitation, dialysis, and chromatography steps. The neurotoxin complex is composed of the neurotoxin, hemagglutinin proteins and non-toxin non-hemagglutinin protein.

DYSPORT™ is supplied in a single-use, sterile vial for reconstitution intended for intramuscular injection. Each vial contains 500 or 300 Units of lyophilized abobotulinumtoxinA, 125 micrograms human serum albumin and 2.5 mg lactose. DYSPORT™ may contain trace amounts of cow's milk proteins [see Contraindications (4) ].

One unit of DYSPORT™ corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. The method for performing the assay is specific to Ipsen's product DYSPORT™. Due to differences in specific details such as vehicle, dilution scheme and laboratory protocols for various mouse LD50 assays, Units of biological activity of DYSPORT™ are not interchangeable with Units of any other botulinum toxin or any toxin assessed with any other specific assay method [see Dosage Forms and Strengths (3) ].

DYSPORT™ inhibits release of the neurotransmitter, acetylcholine, from peripheral cholinergic nerve endings. Toxin activity occurs in the following sequence: Toxin heavy chain mediated binding to specific surface receptors on nerve endings, internalization of the toxin by receptor mediated endocytosis, pH-induced translocation of the toxin light chain to the cell cytosol and cleavage of SNAP25 leading to intracellular blockage of neurotransmitter exocytosis into the neuromuscular junction. This accounts for the therapeutic utility of the toxin in diseases characterized by excessive efferent activity in motor nerves.

Recovery of transmission occurs gradually as the neuromuscular junction recovers from SNAP25 cleavage and as new nerve endings are formed.

The primary pharmacodynamic effect of DYSPORT™ is due to chemical denervation of the treated muscle resulting in a measurable decrease of the compound muscle action potential, causing a localized reduction of muscle activity.

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

Carcinogenicity

Studies to evaluate the carcinogenic potential of DYSPORT™ have not been conducted.

Mutagenicity

Genotoxicity studies have not been conducted for DYSPORT™.

Impairment of Fertility

In a fertility and early embryonic development study in rats in which either males (2.9, 7.2, 14.5 or 29 Units/kg) or females (7.4, 19.7, 39.4 or 78.8 Units/kg) received weekly intramuscular injections prior to and after mating, dose-related increases in pre-implantation loss and reduced numbers of corpora lutea were noted in treated females. Failure to mate was observed in males that received the high dose. The no-effect dose for effects on fertility was 7.4 Units/kg in females and 14.5 Units/kg in males (approximately one-half and equal to, respectively, the maximum recommended human dose of 1000 Units on a body weight basis).

The efficacy of DYSPORT™ was evaluated in two well-controlled, randomized, double-blind, placebo controlled, single dose, parallel group studies in treatment-naïve cervical dystonia patients. The principal analyses from these trials provide the primary demonstration of efficacy involving 252 patients (121 on DYSPORT™, 131 on placebo) with 36% male and 64% female. Ninety-nine percent of the patients were Caucasian.

In both placebo controlled studies (Study 1 and Study 2), a dose of 500 Units DYSPORT™ was given by intramuscular injection divided among two to four affected muscles. These studies were followed by long-term open label extensions that allowed titration in 250 Unit steps to doses in a range of 250 to 1000 Units, after the initial dose of 500 Units. In the extension studies, re-treatment was determined by clinical need after a minimum of 12 weeks. The median time to re-treatment was 14 weeks and 18 weeks for the 75 percentile.

The primary assessment of effi cacy was based on the total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) change from baseline at Week 4 for both studies. The scale evaluates the severity of dystonia, patient perceived disability from dystonia, and pain. The adjusted mean change from baseline in the TWSTRS total score was statistically significantly greater for the DYSPORT™ group than the placebo group at Weeks 4 in both studies (see Table 4).

Analyses by gender, weight, geographic region, underlying pain, cervical dystonia severity at baseline and history of treatment with botulinum toxin did not show any meaningful differences between groups.

Table 5 indicates the average DYSPORT™ dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trials.

Table 4: TWSTRS Total Score Efficacy Outcome from the Phase 3 Cervical Dystonia Studies Intent to Treat Population
Study 1 Study 2
DYSPORT™
500 Units
N=55
Placebo

N=61
DYSPORT™
500 Units
N=37
Placebo

N=43
Baseline (week 0)
Mean (SD) 43.8 (8.0) 45.8 (8.9) 45.1 (8.7) 46.2 (9.4)
Week 4
Mean (SD) 30.0 (12.7) 40.2 (11.8) 35.2 (13.8) 42.4 (12.2)
Change from BaselineChange from baseline is expressed as adjusted least squares mean (SE) -15.6 (2.0) -6.7 (2.0) -9.6 (2.0) -3.7 (1.8)
Treatment difference -8.9Significant at p-value<0.05 -5.9
95% confiden

Manufacturer

Tercica, Inc.

Active Ingredients

Source

Drugs and Medications [1 Associated Drugs and Medications listed on BioPortfolio]

Dysport [Medicis Pharmaceutical Corp]

These highlights do not include all the information needed to use Dysport for Injection safely and effectively. See full prescribing information for Dysport for Injection. Dysport for Injection(abobo...

Clinical Trials [42 Associated Clinical Trials listed on BioPortfolio]

Dysport in Post-Surgical Neuralgia (RESPITE)

The study is designed to determine whether a currently licensed version of botulinum toxin (Dysport®) is effective for the treatment of pain that has developed and/or persisted for months...

Dysport in Hallux Abducto Valgus (HAV) Phase IIa

The purpose of this study is to investigate the efficacy and safety of treatment with multiple doses of Dysport in adults suffering from clinically significant pain associated with HAV who...

Dysport in Vulvodynia Phase II Study

This study is designed to define optimal doses of Dysport and evaluate its efficacy and safety compared with placebo for the treatment of vulvodynia. The study will consist of a dose esca...

Study of a Single Administration of 3 Doses of Dysport® for the Treatment of Benign Essential Blepharospasm

The purpose of this study is to compare the effectiveness of 3 doses of Dysport® with placebo by assessing functional disability in blepharospasm.

Open-label Extension Study of AbobotulinumtoxinA (Dysport®) for the Treatment of Cervical Dystonia

The aim of this study is to assess longer term safety and effectiveness of Dysport®.

PubMed Articles [3 Associated PubMed Articles listed on BioPortfolio]

Assessment of Subject and Physician Satisfaction after Long-Term Treatment of Glabellar Lines with AbobotulinumtoxinA (Dysport/Azzalure): Primary Results of the APPEAL Noninterventional Study.

Although the short- and long-term effectiveness of abobotulinumtoxinA (Dysport/Azzalure) for glabellar line (GL) treatment is well established, reporting of subject satisfaction over repeat treatment ...

Split face comparison between common concentration vs double dilution of intradermal abobotulinum toxin type A (Dysport) injection for facial lifting in Asians.

The most efficacious concentration of botulinum toxin for facial lifting is not well established.

Development of a Pediatric Goal-Centered Upper Limb Spasticity Home Exercise Therapy Program for Use in a Phase-III Trial of Abobotulinumtoxina (Dysport).

To create a standardized home exercise therapy program that could be implemented by international sites to provide a consistent level of therapeutic intervention for pediatric patients participating i...

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