Myobloc

1 INDICATIONS AND USAGE MYOBLOC is an acetylcholine release inhibitor indicated for: Treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia in adults ( 1.1 ) Treatment of chronic sialorrhea in adults ( 1.2 ) 1.1 Cervical Dystonia MYOBLOC is indicated for the treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia in adults. 1.2 Chronic Sialorrhea MYOBLOC is indicated for the treatment of chronic sialorrhea in adults.

2 DOSAGE AND ADMINISTRATION Cervical Dystonia: for patients with demonstrated tolerance of botulinum toxin injection, recommended total dosage is 2,500 Units to 5,000 Units divided among effected muscles ( 2.2 ) Chronic Sialorrhea: recommended dosage is 1,500 Units to 3,500 Units; 500 Units to 1,500 Units per parotid gland and 250 Units per submandibular gland; no more frequent than every 12 weeks ( 2.3 ) 2.1 Instructions for Safe Use The potency units of MYOBLOC are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and cannot be compared to or converted into units of any other botulinum toxin products [see Warnings and Precautions (5.2) , Description (11) ] . Each single-dose vial should only be used during one session and only for one patient. Discard any remaining solution in the vial. MYOBLOC is ready to use; no reconstitution required. MYOBLOC may be diluted with 0.9% Sodium Chloride Injection. Once diluted, the product must be used within 4 hours as the formulation does not contain a preservative. 2.2 Dosing for Cervical Dystonia The recommended initial dosage of MYOBLOC for cervical dystonia patients with a prior history of tolerating botulinum toxin injections is 2,500 Units to 5,000 Units divided among affected muscles [see Clinical Studies (14.1) ] . Patients without a prior history of tolerating botulinum toxin injections should receive a lower initial dosage [see Adverse Reactions (6.1) ] . Subsequent dosing should be determined by the patient's individual response. MYOBLOC should be administered by physicians familiar with and experienced in the assessment and management of patients with cervical dystonia. The duration of effect in patients responding to MYOBLOC treatment for cervical dystonia has been observed in studies to be between 12 and 16 weeks at doses of 5,000 Units or 10,000 Units [see Clinical Studies (14.1) ] . 2.3 Dosing for Chronic Sialorrhea Dosing Information The recommended dosage of MYOBLOC for chronic sialorrhea is 1,500 Units to 3,500 Units, divided among the parotid and submandibular glands (Table 1). Patient response to treatment should be considered when determining subsequent MYOBLOC dosage [see Clinical Studies (14.2) ] . The typical duration of effect of each treatment is up to 3 months; however, the effect may vary in individual patients. The frequency of MYOBLOC repeat treatments should be determined by clinical response but should generally be no more frequent than every 12 weeks. Table 1: Dosing by Gland for Chronic Sialorrhea in Adults Gland Recommended Dosage Parotid 500 Units to 1,500 Units per gland Submandibular 250 Units per gland Administration Information A suitable sterile needle (e.g., 30-gauge, 0.5 inch) should be used for intra-salivary gland administration. Figure 1: Glands for Injection in Chronic Sialorrhea Guidelines for locating salivary glands using anatomical landmarks (Figure 1): 1. To inject the parotid gland, bisect the distance between the tip of the tragus (Site A) and the angle of the mandible (Site B). Inject one finger breadth anterior to this site (Injection Site 1). 2. To inject the submandibular gland, bisect the distance between the angle of the mandible (Site B) and the tip of the chin (Site C). Inject one finger breadth medial to the inferior surface of the point of bisection (Injection Site 2). In clinical studies, MYOBLOC was injected using anatomical landmarks to localize the salivary glands, or using ultrasound guidance for gland location. Both methods produced similar reduction in the unstimulated salivary flow rate. Figure 1

4 CONTRAINDICATIONS MYOBLOC is contraindicated in patients with: A known hypersensitivity to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions (5.3) , Description (11) ] Infection at the proposed injection site(s) MYOBLOC is contraindicated in patients with: Known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation ( 4 , 5.3 ) Infection at the proposed injection site(s) ( 4 )

5 WARNINGS AND PRECAUTIONS Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur ( 5.1 , 5.4 ) MYOBLOC potency units cannot be compared to or converted into units of other botulinum toxins ( 5.2 ) Patients with neuromuscular disorders should be monitored closely for swallowing/breathing difficulty ( 5.4 ) 5.1 Spread of Toxin Effect Postmarketing safety data from MYOBLOC 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, 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. 5.2 Lack of Interchangeability between Botulinum Toxin Products The potency units of MYOBLOC are specific to the preparation and biological activity assay method utilized. Due to differences in the aspects of this assay such as the vehicle, dilution scheme, and laboratory protocols for various potency assays, potency units are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of MYOBLOC cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method [see Description (11) ] . 5.3 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported with botulinum toxin products. Angioedema, urticaria, and rash have occurred with MYOBLOC treatment [see Adverse Reactions (6.3) ]. Hypersensitivity reactions can also include anaphylaxis, serum sickness, soft tissue edema, and dyspnea. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of MYOBLOC and institute appropriate medical therapy immediately. The use of MYOBLOC in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction [see Contraindications (4) , Adverse Reactions (6.3) ]. 5.4 Dysphagia and Breathing Difficulties Treatment with MYOBLOC 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. Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months 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 postmarketing 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 Adverse Reactions (6.1) ] . Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional 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 MYOBLOC [see Adverse Reactions (6.1) ] . 5.5 Human 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 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.

7 DRUG INTERACTIONS Co-administration with aminoglycosides or other agents interfering with neuromuscular transmission may potentiate effects of MYOBLOC ( 7.1 ) Co-administration or overlapping of botulinum toxin serotypes (within 4 months) may potentiate neuromuscular paralysis ( 7.3 ) 7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of MYOBLOC and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated. 7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of MYOBLOC may potentiate systemic anticholinergic effects. 7.3 Other Botulinum Neurotoxin Products The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. 7.4 Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of MYOBLOC.

6 ADVERSE REACTIONS The following clinically significant adverse reactions to MYOBLOC are discussed in greater detail in other sections of the 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) ] Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.5) ] The most common adverse reactions (>5% of MYOBLOC-treated patients at any dose and >5% more common than placebo) include: Cervical Dystonia: dry mouth, dysphagia, injection site pain, and headache ( 6.1 ) Chronic Sialorrhea: dry mouth and dysphagia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Solstice Neurosciences at 1-888-461-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 clinical trials of another drug and may not reflect the rates observed in practice. Cervical Dystonia In the treatment of cervical dystonia, MYOBLOC was studied in both placebo-controlled single treatment studies and open-label repeated treatment studies; most treatment sessions and patients were in the uncontrolled studies. The data described below reflect exposure to MYOBLOC at varying dosages in 570 subjects, including more than 300 patients with 4 or more treatment sessions. Most treatment sessions were at dosages of 12,500 Units or less. Adverse reactions occurring in at least 5% of patients exposed to MYOBLOC treatment in pooled placebo-controlled clinical trials are shown in Table 2. The mean age of the population in these studies was 55 years, and approximately 66% were female. Most of the patients studied were Caucasian, and all had moderate to severe symptoms of cervical dystonia. The most common adverse reactions (greater than 5% of MYOBLOC-treated patients at any dosage and at least 5% more common than placebo) in studies of cervical dystonia (Studies 1, 2, and 4) were dry mouth, dysphagia, injection site pain, and headache. Dry mouth and dysphagia were the adverse reactions most frequently resulting in discontinuation of treatment. There was an increased incidence of dysphagia with increased dose in the sternocleidomastoid muscle. The incidence of dry mouth showed some dose-related increase with doses injected into the splenius capitis, trapezius, and sternocleidomastoid muscles. In the cervical dystonia program, only nine patients without a prior history of tolerating injections of type A botulinum toxin have been studied. Adverse reaction rates have not been adequately evaluated in these patients and may be higher than those described in Table 2. Table 2: Adverse Reactions in at Least 5% of MYOBLOC-Treated Patients and Greater than Placebo, Following Single Treatment Session in Controlled Cervical Dystonia Studies (Studies 1, 2, and 4) Adverse Reaction MYOBLOC 2,500 Units (N=31) % MYOBLOC 5,000 Units (N=67) % MYOBLOC 10,000 Units (N=106) % Placebo (N=104) % Dry Mouth 3 12 34 3 Dysphagia 16 10 25 3 Injection Site Pain 16 12 15 9 Pain 6 6 13 10 Headache 10 16 11 8 Dyspepsia 3 0 10 5 Flu Syndrome 6 9 8 4 Arthralgia 0 1 7 5 Back Pain 3 4 7 3 Cough Increased 3 6 7 3 Asthenia 3 0 6 4 Dizziness 3 3 6 2 In the overall clinical trial experience with MYOBLOC in cervical dystonia (570 patients, including the uncontrolled studies), most cases of dry mouth or dysphagia were reported as mild or moderate in severity. Severe dysphagia was reported by 3% of patients [see Warnings and Precautions (5.4) ]. Severe dry mouth was reported by 6% of patients. Dysphagia and dry mouth were the most frequent adverse reactions reported as a reason for discontinuation from repeated treatment studies. These adverse reactions led to discontinuation from further treatments with MYOBLOC in some patients even when not reported as severe. The following additional adverse events were reported in 2% or greater of patients participating in any of the clinical studies in cervical dystonia (by body system): Body as a Whole : chest pain, chills, hernia, malaise, abscess, cyst, viral infection; Respiratory : dyspnea, pneumonia; Nervous System : migraine; anxiety, hyperesthesia, vertigo, vasodilation; Digestive System : gastrointestinal disorder; Skin and Appendages : pruritis; Urogenital System : urinary tract infection, cystitis; Special Senses : amblyopia, abnormal vision; Metabolic and Nutritional Disorders : edema; Hemic and Lymphatic System : ecchymosis. Chronic Sialorrhea In the double-blind placebo-controlled studies (Study 1 and Study 2), 166 patients were treated with a single treatment of MYOBLOC (1,500 Units; 2,500 Units; or 3,500 Units) and 75 patients received placebo. The mean age of patients treated with MYOBLOC in these studies was 65 years; 83% of the patients were male; and 95% were White. Four MYOBLOC-treated patients and three patients on placebo discontinued because of an adverse event. One patient discontinued because of dry mouth (3,500 Unit dose). The adverse reactions that occurred in at least 5% of MYOBLOC-treated patients and were more frequent than placebo are shown in Table 3. Table 3: Adverse Reactions in At Least 5% of MYOBLOC-Treated Patients and Greater than Placebo in Pooled Chronic Sialorrhea Studies (Studies 1 and 2) Adverse Reaction MYOBLOC 1,500 Units (N=14) Adverse reactions for 1,500 Unit dose were only evaluated in Study 2 % MYOBLOC 2,500 Units (N=75) Adverse reactions for 2,500 Unit and 3,500 Unit doses were evaluated in Studies 1 and 2 % MYOBLOC 3,500 Units (N=77) % Placebo (N=75) % Dry mouth 14 36 39 7 Dental caries 0 7 5 3 Dysphagia 0 9 4 3 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing 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 in the studies described below with the incidence of antibodies in other studies or to other rimabotulinumtoxinB products may be misleading. Cervical Dystonia A two-stage assay was used to test for immunogenicity and neutralizing activity induced by treatment with MYOBLOC. In order to account for varying lengths of follow-up, life-table analysis methods were used to estimate the rates of development of immune responses and neutralizing activity. During the repeated treatment studies, 446 subjects were followed with periodic ELISA based evaluations for development of antibody responses against MYOBLOC. Only patients who showed a positive ELISA assay were subsequently tested for the presence of neutralizing activity against MYOBLOC in the mouse neutralization assay (MNA). 12% of patients had positive ELISA assays at baseline. Patients began to develop new ELISA responses after a single treatment session with MYOBLOC. By six months after initiating treatment, estimates for ELISA positive rate were 20%, which continued to rise to 36% at one year and 50% positive ELISA status at 18 months. Serum neutralizing activity was primarily not seen in patients until after 6 months. Estimated rates of development were 10% at one year and 18% at 18 months in the overall group of patients, based on analysis of samples from ELISA positive individuals. The effect of conversion to ELISA or MNA positive status on efficacy was not evaluated in these studies, and the clinical significance of development of antibodies has not been determined. The data reflect the percentage of patients whose test results were considered positive for antibodies to MYOBLOC in both an in vitro and in vivo assay. The results of these antibody tests are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to MYOBLOC with the incidence of antibodies to other products may be misleading. Chronic Sialorrhea Immunogenicity potential was not further evaluated for MYOBLOC in the treatment of chronic sialorrhea. 6.3 Postmarketing Experience The following adverse reactions have been reported during postmarketing use of MYOBLOC: angioedema, urticaria, rash, constipation, dry eye, and accommodation disorder. Because these 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.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of MYOBLOC in pregnant women. No developmental toxicity was observed in pregnant rats administered MYOBLOC by intramuscular injection during gestation and lactation, at doses producing maternal toxicity. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When MYOBLOC was administered by intramuscular injection to pregnant rats (0, 300, 1000, or 3000 Units/kg/day) or rabbits (0, 0.03, 0.1, 0.3, or 1.0 Units/kg/day) throughout gestation, no adverse effects on embryofetal development were observed. The highest dose tested in rat, which was associated with maternal toxicity, was 36 times the maximum recommended human dose (MRHD) for cervical dystonia (5000 Units) on a body weight (Units/kg) basis. The highest dose tested in rabbit was substantially less than the MRHD for cervical dystonia on a Units/kg basis; maternal toxicity was observed at all but the lowest dose tested.