Dysport Drug Information

Cervical Dystonia DYSPORT is indicated for the treatment of cervical dystonia in adults.

Glabellar 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.

Spasticity DYSPORT is indicated for the treatment of spasticity in patients 2 years of age and older.

Instructions for Safe Use

The potency units of Dysport 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. Reconstituted Dysport is intended for intramuscular injection only.

Preparation of Dysport Solution for Administration Dysport is supplied as a dry powder, in single-dose 300 Unit and 500 Unit vials, which must be reconstituted with preservative-free 0.9% Sodium Chloride Injection, USP using aseptic technique prior to intramuscular injection. Table 1 provides dilution instructions for the 300 Unit and 500 Unit vials, depending on the desired final concentration. The desired final concentration after dilution varies depending on the indication (see Table 2 for the recommended solution concentration after dilution).

Complete the following steps: Reconstitute a 500 Unit vial of Dysport with 2.5 mL of Preservative-free 0.9% Sodium Chloride Injection, USP, gently mix, and set the vital aside. Withdraw 2.5 mL of Preservative-free 0.9 Sodium Chloride Infection, USP into a 5 mL syringe Take the 5 mL syringe with 2.5 ml Preservative-free Sodium Chloride Injection, USP and draw up the Dysport solution from the reconstituted vial without inverting and mix gently. The resulting concentration will be 10 units/0.1 mL Use immediately after reconstitution in the syringe.

Dispose of any unused 0.9% Sodium Chloride Injection, USP. Using an appropriately sized sterile syringe, needle and aseptic technique, draw up the required amount of sterile, preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1 ). 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 partial 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 for injection. After reconstitution, Dysport should be used for only one injection session and for only one patient.

Discard any unused portion. Once reconstituted, unused Dysport may be stored in the original container, in a refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 24 hours until time of use. It must be discarded if not used within 24 hours.

Do not freeze reconstituted Dysport. Discard the vial and needle in accordance with local regulations. Table 2: Recommended Solution Concentration and Dosing Range of Dysport by should generally be administered at any single injections site No more than 0.5 mL of Dysport should be administered in any single injection site Further dilution with preservative-free 0.9% Sodium Chloride Injection, USP, may be required to achieve the final volume for injection.

Dosing in Cervical Dystonia

The recommended initial dose of Dysport for the treatment of cervical dystonia in adults 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 15 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 guided injection of Dysport with EMG and/or ultrasound may be helpful in locating active muscles.

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.

Dosing in Glabellar Lines

The dose of Dysport for the treatment of glabellar lines in adults is a total of 50 Units given intramuscularly in five equal aliquots of 10 Units each to achieve clinical effect (see Figure 1 ). The clinical effect of Dysport may last up to four months. Repeat dosing in 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. 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: 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 an appropriately sized 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 Figure 1

Dosing in Spasticity in Adults Dosing in initial and subsequent treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse reaction history with botulinum toxins. The maximum recommended total dose (upper and lower limb combined) of Dysport for the treatment of spasticity in adults is 1500 Units. Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique (e.g., electromyography, electrical stimulation, or ultrasound) is recommended to target the injection sites.

Upper Limb Spasticity In the clinical trial that assessed the efficacy and safety of Dysport for treatment of upper limb spasticity in adults, doses of 500 Units and 1000 Units were divided among selected muscles at a given treatment session (see Table 3 and Figure 2 ). Table 3: Dysport Dosing by s for Injection for Upper Limb Spasticity in Adults Repeat Dysport treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were retreated between 12-16 weeks; however some patients had a longer duration of response (i.e. 20 weeks).

The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected. Clinical improvement may be expected one week after administration of Dysport.

Dosing in Spasticity in Pediatric Patients

Dysport dosing for spasticity in pediatric patients is based on Units per kilogram of body weight. To calculate the total units of Dysport required for treatment of one limb, select the dose of Dysport in Units/kg and the body weight (kg) of the patient (see Tables 5 and 6). The maximum recommended total dose of Dysport in a single treatment session for spasticity in pediatric patients 2 years or older is 30 Units/kg or 1000 Units in a 3-month interval.

Upper Limb Spasticity in Pediatric Patients 2 Years of Age and Older In the clinical trial that assessed the efficacy and safety of Dysport for treatment of upper limb spasticity in pediatric patients 2 years of age or older with a weight of at least 10 kg, doses of 8 Units/kg or 16 Units/kg were divided among selected muscles of the target upper limb at a given treatment session (see Table 5 and Figure 4). Table 5 describes the recommended Units/kg dose of Dysport per muscle. The maximum recommended total dose of Dysport administered for treatment of upper limb spasticity must not exceed 16 Units/kg or 640 Units, whichever is lower.

A majority of patients in the clinical study were retreated between 16-28 weeks; however, some patients had a longer duration of response (i.e., 34 weeks or more). However, the total dose of Dysport administered in a 3-month interval must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral lower limb injections, or 1000 units, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s).

When possible, the dose should be distributed across more than 1 injection site in any single muscle (see Table 6). Table 6. The safety and effectiveness of Dysport injected into proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established. figure4_upper_limb_pediatric figure4-2_pediatric_spasticity Figure_4_Muscles_Lower_Limb_Spasticity_Pediatric

Clinical 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.

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. 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 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 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.

Adverse reactions of any cause occurred in 48% of the Dysport-treated patients and 33% of the placebo-treated patients. The most frequently reported of these adverse reactions 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 reactions that occurred 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 the reports of eyelid ptosis were mild to moderate in severity and resolved over several weeks. ]. Spasticity in Adults Injection Site Reactions Injection site reactions (e.g. pain, bruising, hemorrhage, erythema/hematoma etc.) have occurred following administration of Dysport in adults treated for spasticity.

Upper Limb Spasticity in Adults Table 10 lists the adverse reactions that occurred in ≥ 2% of patients in any Dysport dose group and more frequent than placebo in double-blind studies evaluating the treatment of upper limb spasticity in adults. The most common adverse reactions (≥ 4%) in any Dysport dose group was muscular weakness. Table 10: Most Common Adverse Reactions Observed in at Least 2% of Patients Treated in Pooled, Double-Blind Trials of Adult Patients with Upper Limb Spasticity Reported More Frequently than with In a pooled analysis of clinical studies, adverse reactions with an incidence of less than 2% reported in Dysport treatment groups included dysphagia 0.5%, gait disturbance 0.5%, hypertonia 0.5%, and sensation of heaviness 0.3%.

Lower Limb Spasticity in Adults The data described below reflect exposure to Dysport in 255 adults with lower limb spasticity. The most common of these adverse reactions (≥ 5%) in any Dysport dose group were falls, muscular weakness, and pain in extremity. Table 11: Adverse Reactions Observed in at Least 2% of Patients Treated in the Double-Blind Trial of Adults with Lower Limb Spasticity and Reported More Frequently than with for the treatment of lower limb spasticity in adults, muscular weakness was reported more frequently in women (10%) treated with 1500 units of Dysport compared to men (5%).

Falls were reported more frequently in patients 65 years of age and over. Upper Limb Spasticity in Pediatric Patients Table 12 reflects exposure to Dysport in 210 patients, 2 to 17 years of age, who were evaluated in a double blind, active-controlled, multicenter study in patients treated for upper limb spasticity. The most commonly observed adverse reactions (≥10% of patients) were: upper respiratory tract infection and pharyngitis.

Table 12: Adverse Reactions Observed in ≥ 3% of Patients Treated in the Double-Blind Study of Pediatric Patients with Upper Limb Spasticity and Reported More Frequently than Control Group 1 Low dose active comparator arm 2 Includes pharyngitis, pharyngitis streptococcal, pharyngotosilitis Additional adverse reactions occurring below 3% and considered to be drug related include: myalgia, pain in extremity, fatigue, influenza-like illness, injection site eczema, injection site bruising, injection site rash, injection site pain, and injection site swelling. Lower Limb Spasticity in Pediatric Patients Table 13 reflects exposure to Dysport in 160 patients, 2 to 17 years of age, who were evaluated in the randomized, placebo-controlled clinical study that assessed the use of Dysport for the treatment of unilateral or bilateral lower limb spasticity in pediatric cerebral palsy patients. Table 13: Adverse Reactions Observed in ≥ 4% of Patients Treated in the Double-Blind Trial of Pediatric Patients with Lower Limb Spasticity and Reported More Frequently than with 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.

Cervical Dystonia About 3% of subjects developed antibodies (binding or neutralizing) over time with Dysport treatment. 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. Spasticity in Adults Upper Limb Spasticity From 230 subjects treated with Dysport and tested for the presence of binding antibodies, 5 subjects were positive at baseline and 17 developed antibodies after treatment.

Among those 17 subjects, 10 subjects developed neutralizing antibodies. An additional 51 subjects from a separate repeat-dose study were tested for the presence of neutralizing antibodies only. None of the subjects tested positive.

In total, from the 281 subjects treated in the long-term studies and tested for the presence of neutralizing antibodies, 3.6% developed neutralizing antibodies after treatment. In the presence of binding and neutralizing antibodies to Dysport some patients continue to experience clinical benefit. Lower Limb Spasticity From 367 subjects treated with Dysport and tested for the presence of binding antibodies, 4 subjects were positive at baseline and 2 developed binding antibodies after treatment.

No subjects developed neutralizing antibodies. An additional 85 subjects from two separate studies were tested for the presence of neutralizing antibodies only. One subject tested positive for the presence of neutralizing antibodies.

In total, from the 452 subjects treated in with DYSORT and tested for the presence of neutralizing antibodies, 0.2% developed neutralizing antibodies after treatment. Spasticity in Pediatric Patients 2 Years of Age or Older Upper Limb Spasticity From 178 subjects treated with Dysport for up to 4 treatment cycles and tested for the presence of binding antibodies at baseline and end of study, 7 subjects previously receiving botulinum toxin injections had binding antibodies after treatment. Among those 7 subjects, 4 subjects (2.3%) developed neutralizing antibodies when tested in the mice bioassay.

Lower Limb Spasticity From 226 subjects treated with Dysport and tested for the presence of binding antibodies, 5 subjects previously receiving botulinum toxins were positive at baseline and 9 patients developed binding antibodies after injections. Among those 9 subjects, 3 subjects developed neutralizing antibodies, while one subject developed neutralizing antibodies from the 5 subjects testing positive for binding antibodies at baseline who previously received botulinum toxin injections. Two subjects were positive for neutralizing antibodies at baseline and 5 subjects developed neutralizing antibodies after treatments.

In total, from the 429 patients tested for the presence of neutralizing antibodies, 2.1% developed neutralizing antibodies after treatment.

Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Dysport: vertigo, photophobia, influenza-like illness, amyotrophy, muscle atrophy, burning sensation, facial paresis, hypoesthesia, erythema, dry eye, and excessive granulation tissue. Hypersensitivity reactions including anaphylaxis have been reported.

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.

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

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.

Muscle Relaxants

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

Pregnancy 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 population is unknown. The no-effect dose for embryo-fetal developmental toxicity was 2.2 Units/kg (less than maximum recommended human on a body weight basis).

At the lower daily doses or with intermittent dosing, no adverse developmental effects were observed. All dosed 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 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 development toxicity was 22.2 Units/kg (similar to the MRHD).

Females and Males of Reproductive Potential Infertility In rats, DYSPORT produced adverse effects on mating behavior and fertility.

• 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. This product may contain trace amounts of cow's milk protein. Infection at the proposed injection site(s).
• Hypersensitivity to:
• Any botulinum toxin product or excipients
• Cow's milk protein
• Infection at the proposed injection site(s)

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.

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 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 https://www.cdc.gov/laboratory/drugservice/index.html.