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.

2.1 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

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.

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.

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.

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.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

12.1 Mechanism of Action

MYOBLOC blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerved terminals. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of synaptic Vesicle Associated Membrane Protein (VAMP, also known as synaptobrevin), a presynaptic target protein essential for the release of acetylcholine. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.

12.2 Pharmacodynamics

In responders, the return of increased muscle tone or saliva production typically starts within 3 to 4 months after injection.

12.3 Pharmacokinetics

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Cervical Dystonia

Two Phase 3, randomized, multi-center, double-blind, placebo-controlled studies of the treatment of cervical dystonia were conducted (Study 1 and Study 2). Both studies enrolled only adult patients who had a history of receiving botulinum toxin type A in an open-label manner, with a perceived good response and tolerable adverse effects. Study 1 enrolled patients who were perceived as having an acceptable response to type A toxin, while Study 2 enrolled only patients who had secondarily lost responsiveness to type A toxin. Other eligibility criteria common to both studies were that all patients had moderate or greater severity of cervical dystonia with at least 2 muscles involved, no neck contractures or other causes of decreased neck range of motion, and no history of any other neuromuscular disorder. Patients in Study 1 were randomized to receive placebo, MYOBLOC 5,000 Units or MYOBLOC 10,000 Units. Patients in Study 2 were randomized to receive placebo or 10,000 Units of MYOBLOC. The study agent was administered to subjects in a single treatment session by investigators who selected 2 to 4 muscles per subject from the following: splenius capitis, sternocleidomastoid, levator scapulae, trapezius, semispinalis capitis, and scalene muscles. The total dose was divided between the selected muscles, and from 1 to 5 injections were made per muscle. There were 109 patients enrolled into Study 1, and 77 into Study 2. Patient evaluations continued for 16 weeks post injection.

The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total Score (scale range of possible scores is 0–87) at Week 4. TWSTRS is comprised of three sub-scales which examine 1) Severity—the severity of the patient's abnormal head position; 2) Pain—the severity and duration of pain due to the dystonia; and 3) Disability— the effects of the abnormal head position and pain on a patient's activities. The secondary endpoints were the Patient Global and Physician Global Assessments of change at Week 4. Both Global Assessments used a 100-point visual-analog scale (VAS). The Patient Global Assessment allows patients to indicate how they feel at the time of their evaluation compared to the pre-injection baseline. Likewise, the Physician Global Assessment indicates the physician's assessment of a patient's change from baseline to Week 4. Scores of 50 indicate no change, 0 much worse, and 100 much better. Results of comparisons of the primary and secondary efficacy variables are summarized in Table 4.

There were no statistically significant differences in results between the 5,000 Unit and 10,000 Unit doses in Study 1. Exploratory analyses of these two studies suggested that the majority of patients who showed a beneficial response by Week 4 had returned to their baseline status between Weeks 12 to 16 post injection. Although there was a MYOBLOC-associated decrease in pain, there remained many patients who experienced an increase in dystonia-related neck pain irrespective of treatment group [ See Adverse Reactions, (6.1)] . TWSTRS Total Score at Week 4 and Patient Global Assessment among subgroups by gender or age showed consistent treatment-associated effects across these subgroups [see Use in Specific Populations (8.5)]. There were too few non-Caucasian patients enrolled to draw any conclusions regarding relative efficacy in racial subsets.

MYOBLOC was studied in two Phase 2 dose-ranging studies, Studies 3 and 4, which preceded the Phase 3 studies. Studies 3 and 4 had a study design similar to the Phase 3 studies, including eligibility criteria. Study 3 enrolled 85 patients randomized to placebo, MYOBLOC 400 Units, MYOBLOC 1,200 Units, or MYOBLOC 2,400 Units (21 or 22 patients per group). Study 4 enrolled 122 patients randomized to placebo, MYOBLOC 2,500 Units, MYOBLOC 5,000 Units, or MYOBLOC 10,000 Units (30 or 31 patients per group). These studies demonstrated efficacy on the TWSTRS-Total, baseline to Week 4, at doses of 2,400 Units; 2,500 Units; 5,000 Units; and 10,000 Units. Study 3 showed mean improvement from baseline on the Week 4 TWSTRS for placebo and 2,400 Units of 2.0 and 8.5 points respectively (from baselines of 42.0 and 42.4 points). Study 4 showed mean improvement from baseline to Week 4 for placebo, MYOBLOC 2,500 Units, MYOBLOC 5,000 Units, and MYOBLOC 10,000 Units of 3.3, 11.6, 12.5, and 16.4 points, respectively (from baseline of 45.5, 45.6, 45.2, and 47.5 points). Study 3 also showed less response for doses below 2,400 Units.

Study 5 was an open-label, intrapatient dose-escalation study of 3 treatment sessions where each patient with cervical dystonia sequentially received 10,000 Units; 12,500 Units; and 15,000 Units of MYOBLOC, at periods of 12 to 16 weeks between treatment sessions irrespective of their response to their previous dose. This study enrolled 145 patients, of whom 125 received all three treatments. Although this was an open-label design where investigators and patients knew the dose at each treatment session, there were similar mean improvements on the TWSTRS-Total, from baseline to Week 4, for all three doses.

In the MYOBLOC-treated patients (n=112) of the Phase 3 studies, 19% had 2 muscles injected, 48% had 3 muscles injected, and 33% had 4 muscles injected. Table 5 indicates the frequency of use for each of the permitted muscles, and the fraction of the total dose of the treatment injected into each muscle, for those patients in whom the muscle was injected.

14.2 Chronic Sialorrhea

16.1 How Supplied

MYOBLOC (rimabotulinumtoxinB) injection is supplied as a clear and colorless to light-yellow solution in single-dose glass vials.

MYOBLOC is available in three presentations (Table 10).

No U.S. Standard of Potency

16.2 Storage and Handling

Store under refrigeration at 2°C to 8°C (36°F- 46°F) in the original carton to protect from light.

DO NOT FREEZE. DO NOT SHAKE.

All vials of expired MYOBLOC and equipment used in the administration of MYOBLOC should be carefully discarded according to standard medical waste practices.

Do not use after the expiration date stamped on the vial.

Swallowing, Speaking, or Breathing Difficulties or Other Unusual Symptoms

Advise patients to inform their healthcare provider if they develop any unusual symptoms, including difficulty with swallowing, speaking or breathing, or if any existing symptom worsens [see Box Warning and Warnings and Precautions (5.1, 5.4)]. Inform patients of the risk of aspiration.

Ability to Operate Machinery or Vehicles

Counsel patients that if loss of strength, muscle weakness, or impaired vision occur, they should avoid driving a car or engaging in other potentially hazardous activities.