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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions to DYSPORT ® are discussed in greater detail in other sections of the labeling. • Hypersensitivity [ see Contraindications (4) ] • Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia [ see Warnings and Precautions (5.3) ] • Spread of Effects from Toxin [ see Warnings and Precautions (5.2) ] Cervical Dystonia Most commonly observed adverse reactions (> 5% of patients) are: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, neck pain, musculoskeletal pain, dysphonia, injection site pain, and eye disorders. ( 6 ) Glabellar Lines The most frequently reported adverse events (≥2%) are nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact 877-397-7671 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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. Cervical Dystonia The data described below reflect exposure to DYSPORT ® in 357 cervical dystonia patients in 6 studies. Of these, two studies were randomized, doubleblind, 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) ]. 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 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 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 2: Common TEAEs by Dose in Fixed-dose Study System Organ Class DYSPORT ® Dose Preferred Term 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. 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) 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) ]. 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. 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.