1.1 Cervical Dystonia

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.

1.2 Glabellar Lines

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.

2.1 Cervical Dystonia

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.

2.2 Glabellar Lines

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).

2.2.3 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 eva luation 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:

• Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes.
• Medial corrugator injections should be placed at least 1 centimeter above the bony supraorbital ridge.
• Ensure the injected volume/dose is accurate and where feasible kept to a minimum.
• Do not inject toxin closer than 1 centimeter above the central eyebrow.

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

3.1 Cervical Dystonia

Dysport is supplied as:

• a single-use, sterile 500 Unit vial for reconstitution with 1 mL of 0.9% Sodium Chloride Injection USP (without preservative) to yield a solution of 500 Units per mL.
• a single-use, sterile 300 Unit vial for reconstitution 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.

3.2 Glabellar Lines

Dysport is supplied as:

• a single-use, sterile 300 Unit vial for reconstitution with 0.9% Sodium Chloride Injection USP (without preservative). Dysport may be reconstituted with either 2.5 mL to yield a solution of 10 Units per 0.08 mL or with 1.5 mL to yield a solution of 10 Units per 0.05 mL.

5.1 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)].

5.2 Spread of Toxin Effect

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.

5.3 Dysphagia and Breathing Difficulties in Treatment of 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)].

5.4 Facial Anatomy in the Treatment of Glabellar Lines

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.

5.5 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 typical doses of Dysport [see Adverse Reactions (6.1)].

5.6 Human Albumin

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.

5.7 Intradermal 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.

6.1 Clinical Studies Experience

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.

6.2 Post-marketing Spontaneous Reports

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.

6.3 Immunogenicity

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.