HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use
MYOBLOC® safely and effectively. See full prescribing information for
MYOBLOC®.
MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or
intraglandular use
Initial U.S. Approval: 2000
WARNING: DISTANT SPREAD OF TOXIN EFFECT
See full prescribing information for complete boxed warning.
The effects of MYOBLOC and all botulinum toxin products may spreadfrom the area of injection to produce symptoms consistent withbotulinum toxin effects. These symptoms have been reported hours
to weeks after injection. Swallowing and breathing difficulties can belife threatening and there have been reports of death. The risk ofsymptoms is probably greatest in children treated for spasticity but
symptoms can also occur in adults, particularly in those patients who
have an underlying condition that would predispose them to these
symptoms (5.1).

----------------------------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)----------------------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)---------------------DOSAGE FORMS AND STRENGTHS---------------------Injection: 2,500 Units/0.5 mL; 5,000 Units/mL; or 10,000 Units/2 mL (5,000
Units/mL) in a single-dose vial (3)-------------------------------CONTRAINDICATIONS-----------------------------MYOBLOC is contraindicated in patients with:• Known hypersensitivity to any botulinum toxin preparation or to any of thecomponents in the formulation (4, 5.3)
• Infection at the proposed injection site(s) (4)------------------------WARNINGS AND PRECAUTIONS----------------------• Spread of toxin effects; swallowing and breathing difficulties can lead todeath. 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 ofother botulinum toxins (5.2)• Patients with neuromuscular disorders should be monitored closely for
swallowing/breathing difficulty (5.4)------------------------------ADVERSE REACTIONS------------------------------The most common adverse reactions (>5% of MYOBLOC-treated patients atany 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.
------------------------------DRUG INTERACTIONS------------------------------• Co-administration with aminoglycosides or other agents interfering withneuromuscular transmission may potentiate effects of MYOBLOC (7.1)• Co-administration or overlapping of botulinum toxin serotypes (within 4months) may potentiate neuromuscular paralysis (7.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 03/2021

FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: DISTANT SPREAD OF TOXIN EFFECT
1
INDICATIONS AND USAGE
1.1 Cervical Dystonia
1.2 Chronic Sialorrhea
2
DOSAGE AND ADMINISTRATION
2.1 Instructions for Safe Use
2.2 Dosing for Cervical Dystonia
2.3 Dosing for Chronic Sialorrhea
3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS5WARNINGS AND PRECAUTIONS
5.1 Spread of Toxin Effect
5.2 Lack of Interchangeability between Botulinum Toxin Products
5.3 Hypersensitivty Reactions
5.4 Dysphagia and Breathing Difficulties
5.5 Human Albumin and Transmission of Viral Diseases
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Aminoglycosides and Other Agents Interfering with
Neuromuscular Transmission
7.2 Anticholinergic Drugs

8

10
11
12

13
14
16
17

7.3 Other Botulinum Neurotoxin Products
7.4 Muscle Relaxants
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
OVERDOSAGEDESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
14.1 Cervical Dystonia
14.2 Chronic Sialorrhea
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are notlistedMYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
FULL PRESCRIBING INFORMATIONWARNING: DISTANT SPREAD OF TOXIN EFFECT
Postmarketing reports indicate that the effects of MYOBLOC and all botulinum toxin products may
spread from the area of injection to produce symptoms consistent with botulinum toxin effects. Thesemay include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia,
dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have beenreported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening
and there have been reports of death. The risk of symptoms is probably greatest in children treatedfor spasticity but symptoms can also occur in adults treated for spasticity and other conditions,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, cases of spread of effect have occurred at doses comparable to those used to treat cervicaldystonia and at lower doses [see Warnings and Precautions (5.1)].
1

INDICATIONS AND USAGE

1.1

Cervical Dystonia
MYOBLOC is indicated for the treatment of cervical dystonia to reduce the severity of abnormal head position andneck 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

2.1

Instructions for Safe Use
The potency units of MYOBLOC are specific to the preparation and assay method utilized. They are notinterchangeable 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 4hours 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 [seeAdverse 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 patientswith cervical dystonia.
The duration of effect in patients responding to MYOBLOC treatment for cervical dystonia has been observed instudies to be between 12 and 16 weeks at doses of 5,000 Units or 10,000 Units [see Clinical Studies (14.1)].

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
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 theparotid 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 themandible (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 ofthe 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.

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
3

DOSAGE FORMS AND STRENGTHSMYOBLOC is a clear and colorless to light-yellow solution available as:•

Injection: 2,500 Units/0.5 mL in a single-dose vial•

Injection: 5,000 Units/mL in a single-dose vial•

Injection: 10,000 Units/2 mL (5,000 Units/mL) in a single-dose vial

4

CONTRAINDICATIONSMYOBLOC is contraindicated in patients with:•

A known hypersensitivity to any botulinum toxin product or to any of the components in the formulation [seeWarnings and Precautions (5.3), Description (11)]•Infection at the proposed injection site(s)5

WARNINGS AND PRECAUTIONS

5.1

Spread of Toxin EffectPostmarketing 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 mechanismof 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 beenreported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there havebeen reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treatedfor spasticity, but symptoms can also occur in adults treated for spasticity and other conditions, and particularly inthose 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 todifferences 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 otherbotulinum 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 rashhave 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 (humanalbumin, 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

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
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 ofventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may havebecome dependent upon these accessory muscles. There have been postmarketing reports of serious breathingdifficulties, 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 productmanufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant CreutzfeldtJakob 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 viraldiseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed
products.

6

ADVERSE REACTIONS
The following clinically significant adverse reactions to MYOBLOC are discussed in greater detail in other sectionsof the labeling:

6.1•

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)]
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 andopen-label repeated treatment studies; most treatment sessions and patients were in the uncontrolled studies. The data

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
described below reflect exposure to MYOBLOC at varying dosages in 570 subjects, including more than 300 patientswith 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 cervicaldystonia.
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 thesternocleidomastoid 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 andmay 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
Dry Mouth
Dysphagia
Injection Site Pain
Pain
HeadacheDyspepsia
Flu Syndrome
Arthralgia
Back Pain
Cough Increased
Asthenia
Dizziness

MYOBLOC 2,500 Units MYOBLOC 5,000 Units MYOBLOC 10,000 Units(N=31)(N=67)(N=106)
%
%
%
3
12
34
16
10
25
16
12
15
6
6
13
10
16
11
3
0
10
6
9
8
0
1
7
3
4
7
3
6
7
3
0
6
3
3
6

Placebo(N=104)
%
3
3
9
10
8
5
4
5
3
3
4
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 wasreported 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 fromrepeated treatment studies. These adverse reactions led to discontinuation from further treatments with MYOBLOC insome 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 clinicalstudies 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

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
In the double-blind placebo-controlled studies (Study 1 and Study 2), 166 patients were treated with a single treatmentof MYOBLOC (1,500 Units; 2,500 Units; or 3,500 Units) and 75 patients received placebo. The mean age of patientstreated 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
Dry mouth
Dental caries
Dysphagia
a

b

6.2

MYOBLOC 1,500 Units MYOBLOC 2,500 Units MYOBLOC 3,500 Units(N=14)a(N=75)b(N=77)b
%
%
%
14
36
39
0
7
5
0
9
4

Adverse reactions for 1,500 Unit dose were only evaluated in Study 2
Adverse reactions for 2,500 Unit and 3,500 Unit doses were evaluated in Studies 1 and 2

Placebo(N=75)%
7
3
3

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 otherstudies 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 ofneutralizing 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 notseen 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 ofdevelopment 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 andspecificity of the assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced byseveral 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.

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
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

DRUG INTERACTIONS

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 otheris unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxinprior 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

USE IN SPECIFIC POPULATIONS

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 recognizedpregnancies 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.

8.2

Lactation
Risk Summary

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
There are no data on the presence of MYOBLOC in human milk, the effects on the breastfed infant, or the effects on
milk production. The developmental and health benefits of breastfeeding should be considered along with themother’s clinical need for MYOBLOC and any potential adverse effects on the breastfed infant from MYOBLOC orfrom the underlying maternal condition.
8.4

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

8.5

Geriatric Use
Cervical Dystonia
In the controlled studies for MYOBLOC in patients with cervical dystonia, 152 (75%) were under the age of 65, and
52 (26%) were 65 years of age or older [see Clinical Studies (14.1)]. For these age groups, the most frequently
reported adverse reactions occurred at similar rates in both age groups. Efficacy results did not suggest any large
differences between these age groups.
Very few patients age 75 or older were enrolled; therefore, no conclusions regarding the safety and efficacy of
MYOBLOC within this age group can be determined.
Chronic Sialorrhea
Of the 166 MYOBLOC-treated patients in the placebo-controlled studies for treatment of chronic sialorrhea [seeClinical Studies (14.2)], 105 (63%) were 65 years of age or older, and 43 (26%) were 75 years of age or older. No
overall differences in safety or effectiveness were observed between patients over 65 years of age and younger
patients, but greater sensitivity of some older patients cannot be ruled out.

10

OVERDOSAGE
Excessive doses of MYOBLOC 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[see Warnings and Precautions (5.1, 5.4)]. Symptomatic treatment may be necessary.
Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection ororal ingestion occur, the person should be medically supervised for several weeks for signs and symptoms ofexcessive muscle weakness or muscle paralysis.
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 http://cdc.gov/ncidod/srp/drugs/drug-service.html.

11

DESCRIPTION
RimabotulinumtoxinB is an acetylcholine release inhibitor. RimabotulinumtoxinB is a 700 kDA botulinum toxin type
B complex produced from fermentation of the bacterium Clostridium botulinum type B (Bean strain) and exists innoncovalent association with hemagglutinin and nonhemagglutinin proteins as a neurotoxin complex. The neurotoxin
complex is recovered from the fermentation process and purified through a series of precipitation and chromatography
steps.
MYOBLOC (rimabotulinumtoxinB) injection is a sterile, preservative-free, clear and colorless to light-yellow
solution in a single-dose vial for intramuscular or intraglandular use. Each vial contains 2,500 Units/0.5 mL; 5,000

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
units/mL; or 10,000 Units/2 mL of rimabotulinumtoxinB at a concentration of 5,000 Units/mL at approximately pH
5.6.
Each 2,500 Units/0.5 mL vial of MYOBLOC contains 2,500 Units rimabotulinumtoxinB, 0.235 mg albumin human,
2.9 mg sodium chloride and 1.35 mg sodium succinate.
Each 5,000 Units/mL vial of MYOBLOC contains 5,000 Units rimabotulinumtoxinB, 0.47 mg albumin human, 5.8
mg sodium chloride and 2.7 mg sodium succinate.
Each 10,000 Units/2 mL vial of MYOBLOC contains 10,000 Units rimabotulinumtoxinB, 0.94 mg albumin human,
11.6 mg sodium chloride and 5.4 mg sodium succinate.
One unit of MYOBLOC corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. The method
for performing the assay is specific to Solstice Neurosciences’ manufacture of MYOBLOC. Due to differences in
specific details such as the vehicle, dilution scheme and laboratory protocols for various mouse LD50 assays, Units ofbiological activity of MYOBLOC cannot be compared to or converted into Units of any other botulinum toxin or any
toxin assessed with any other specific assay method. Therefore, differences in species sensitivities to different
botulinum neurotoxin serotypes preclude extrapolation of animal dose-activity relationships to human dose estimates.
The specific activity of MYOBLOC ranges between 70 to 130 Units/ng.
12

CLINICAL PHARMACOLOGY

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 thefollowing 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 enzymaticcleavage 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 reestablished 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

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
No long-term carcinogenicity studies in animals have been conducted.
Mutagenesis
No genetic toxicology studies have been conducted.
Impairment of Fertility
Intramuscular administration of MYOBLOC (0, 300, 1000, or 3000 Units/kg/day) to male and female rats prior to andthroughout the mating period and continuing in females to gestation day 6 resulted in decreases in implantation sites

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
and viable fetuses at the high dose of 3000 Units/kg/day, which was associated with maternal toxicity. The no-effectdose for reproductive toxicity (1000 Units/kg/day) is 12 times the maximum recommended human dose for cervicaldystonia (5000 Units) on a body weight (Units/kg) basis.
14

CLINICAL STUDIES

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 neckcontractures 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 wasadministered to subjects in a single treatment session by investigators who selected 2 to 4 muscles per subject fromthe 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 durationof 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 patientsto indicate how they feel at the time of their evaluation compared to the pre-injection baseline. Likewise, thePhysician 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 andsecondary efficacy variables are summarized in Table 4.
Table 4:

Efficacy Results From Two Phase 3 MYOBLOC Studies in Cervical Dystonia
STUDY 1

Assessments*

STUDY 2

Placebo(N=36)

MYOBLOC 5,000 Units(N=36)

MYOBLOC 10,000 Units(N=37)

Placebo(N=38)

MYOBLOC 10,000 Units(N=39)

Mean at Baseline

43.6

46.4

46.9

51.2

52.8

Change fromBaseline

-4.3

-9.3

-11.7

-2.0

-11.1

(-8.9, -1.2)(-11.1, -3.3)(-12.2, -5.2)

0.012

0.00040.0001

60.6

64.6

TWSTRS Total

95% ConfidenceInterval
P value
Patient Global
Mean at Week Four

43.6

39.5

60.2

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
STUDY 1
Assessments*

Placebo(N=36)

95% ConfidenceInterval
P value

STUDY 2

MYOBLOC 5,000 Units(N=36)

MYOBLOC 10,000 Units(N=37)

Placebo(N=38)

MYOBLOC 10,000 Units(N=39)(7.0, 26.9)(11.3, 31.1)(11.2, 29.1)

0.001

0.00010.0001

65.3

64.2(5.5, 21.3)(3.9, 19.7)(7.4, 18.1)

0.001

0.004

0.0001

Physician Global
Mean at Week Four

52.0

95% ConfidenceInterval
P value

47.9

60.6

TWSTRSSubscales– Severity
Mean at Baseline

18.4

20.2

20.2

22.1

22.6

Change fromBaseline

-2.3

-3.2

-4.8

-1.2

-3.7

(-2.5, 0.6)(-4.0, -1.0)(-3.9, -1.0)

0.22

0.002

0.001

95% ConfidenceInterval
P value– PainMean at Baseline

10.9

11.8

12.4

12.2

11.9

Change fromBaseline

-0.5

-3.6

-4.2

-0.2

-3.6

(-4.7, -1.1)(-5.1, -1.4)(-5.0, -2.1)

0.002

0.00080.0001

95% ConfidenceInterval
P value– Disability
Mean at Baseline

14.3

14.4

14.4

16.9

18.3

Change fromBaseline

-1.6

-2.5

-2.7

0.8

-3.8

(-2.7, 0.7)(-2.8, 0.6)(-4.1, -1.0)

0.26

0.19

0.002

95% ConfidenceInterval
P value* 95% Cl are for the differences between the active and placebo groups. The P values are for the comparison of active dose andplacebo. For TWSTRS-Total and TWSTRS-subscale scores, P values are from ANCOVA for each variable with center and treatmentin the model and the baseline value of the variable included as a covariate. For the Patient Global and Physician Global Assessments,
P values are from ANOVA for each variable with center and treatment in the model.
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® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
MYOBLOC-associated decrease in pain, there remained many patients who experienced an increase in dystoniarelated neck pain irrespective of treatment group [See Adverse Reactions, (6.1)]. TWSTRS Total Score at Week 4 andPatient Global Assessment among subgroups by gender or age showed consistent treatment-associated effects acrossthese 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, and16.4 points, respectively (from baseline of 45.5, 45.6, 45.2, and 47.5 points). Study 3 also showed less response fordoses below 2,400 Units.
Study 5 was an open-label, intrapatient dose-escalation study of 3 treatment sessions where each patient with cervicaldystonia 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 andpatients knew the dose at each treatment session, there were similar mean improvements on the TWSTRS-Total, frombaseline 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 wasinjected.
Table 5:

Study 1 and Study 2 Combined Data Fraction of Total Dose Injected into Involved Muscles inPatients with Cervical Dystonia

Muscle Injected

Percent Frequency
Injected*

Fraction of Total Dose Injected by Percentiles
25th

50th

75th

Splenius Capitis

88

0.30

0.40

0.50

Sternocleidomastoid

80

0.20

0.25

0.30

Semispinalis Capitis

52

0.30

0.36

0.50

Levator Scapulae

46

0.13

0.20

0.20

Trapezius

38

0.20

0.25

0.35

Scalene Complex

13

0.20

0.25

0.30

* Percent frequency of patients in whom each muscle was injected
14.2

Chronic Sialorrhea

Study 1
Study 1 (NCT01994109) was a multicenter, randomized, double-blind, placebo-controlled study of a single treatmentof chronic sialorrhea (with 13-week follow-up), followed by an open-label treatment period. 187 adult patients with

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
chronic, troublesome sialorrhea for at least 3 months were randomized to receive treatment with MYOBLOC 2,500
Units, MYOBLOC 3,500 Units, or placebo. Patients had chronic sialorrhea associated with Parkinson’s disease(n=122), amyotrophic lateral sclerosis(ALS) (n=12), stroke (n=13), and other causes (n=40). Patients with a historyof aspiration or severe dysphagia in the last 6 months and ALS patients with a forced vital capacity of less than 20%
of predicted were excluded from the study. A single treatment was administered, consisting of bilateral injections of
MYOBLOC into the parotid (1,000 Units or 1,500 Units per gland) and submandibular (250 Units per gland) salivary
glands or volume matched placebo. A total of 114 patients received 4 consecutive treatments with 3,500 Units of
MYOBLOC every 11 to 15 weeks.
The co-primary efficacy endpoints for Study 1 were the change from baseline in Unstimulated Salivary Flow Rate
(USFR) and the Clinical Global Impression of Change (CGI-C) assessed 4 weeks after treatment in the double-blindpart of the study. The CGI-C is a seven-point Likert scale with scores ranging from “1=very much improved” to“7=very much worse”. The change from baseline (i.e., decrease) in USFR at Week 4 was significantly greater forpatients treated with MYOBLOC than in patients on placebo (Table 6). Similarly, CGI-C scores at Week 4 weresignificantly lower (i.e., better) in patients treated with MYOBLOC than in patients on placebo (Table 7). Chronic
sialorrhea was ‘much improved’ or ‘very much improved’, according to CGI-C scores at Week 4 post injection, inpatients treated with MYOBLOC 2,500 Units (60%) and MYOBLOC 3,500 Units (53%) than in patients on placebo(12%).
Figure 2 and Figure 3 show change in the USFR and CGI-C, respectively over the 13-week double-blind part of Study
1. The change from baseline to Week 4 on the USFR and the CGI-C was similar for MYOBLOC 2,500 Units and3,500 Units, but there was a trend for more prolonged effect in patients treated with MYOBLOC 3,500 Units (Figure2). CGI-C scores over the double-blind period were similar for both dose groups (Figure 3).
Table 6:Visit

Mean USFR Change from Baseline (g/min) at Week 4 in Study 1
MYOBLOC 2,500 Units MYOBLOC 3,500 Units Placebo(N=63)(N=64)(N=57)

Week 4-0.37**Primary endpoint, p< 0.0001-0.36*

Table 7:CGI-C Score at Week 4 in Study 1

Visit

MYOBLOC 2,500 Units(N=63)

Week 42.38**Co-primary endpoint, p< 0.0001-0.07

MYOBLOC 3,500 Units(N=64)

Placebo(N=57)

2.45*

3.59

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
Figure 2: Mean Unstimulated Salivary Flow Rate over Time in Study 1

Figure 3: Mean Clinical Global Impression of Change Score over Time in Study 1

Study 2
Study 2 (NCT00515437) was a multicenter, double-blind, placebo-controlled, sequential dose-escalation study of
MYOBLOC 1,500 Units; 2,500 units; or 3,500 Units versus matching placebo for the treatment of troublesome
chronic sialorrhea in patients with Parkinson’s disease. Patients were randomized to receive a single treatment with
MYOBLOC 1,500 Units (n=14); MYOBLOC 2,500 Units (n=12); or MYOBLOC 3,500 Units (n=13). Each groupalso included 5 patients who received placebo (n=15). Patients were followed for up to 20 weeks after injection. The
mean age of patients in the study was 71 years. In the study, 89% of patients were male, and 96% White.
The change from baseline in the unstimulated salivary flow rate (USFR) and the Clinical Global Impression of
Change (CGI-C) was assessed 4 weeks after treatment. There was a significant reduction in the USFR for all threedosage groups of MYOBLOC, compared with patients on placebo (Table 8). Similarly, the CGI-C scores weresignificantly lower in all three MYOBLOC dosage groups than in patients on placebo (Table 9). The mean change
from baseline to Week 4 on the USFR was similar in all three MYOBLOC dosage groups.
Table 8:Visit
Week 4

Mean USFR Change from Baseline (g/min) at Week 4 in Study 2
MYOBLOC 1,500 Units(N=14)-0.44*

MYOBLOC 2,500 Units(N=12)-0.38*

MYOBLOC 3,500 Units(N=13)-0.30**

Placebo(N=14)
0.01

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
Nominal p-value <0.0001; **Nominal p-value < 0.001*

Table 9:CGI-C Score at Week 4 in Study 2

MYOBLOC 1,500 Units(N=14)
Week 4
2.14**
Nominal p-value < 0.0001
Visit

MYOBLOC 2,500 Units(N=12)
2.00*

16

HOW SUPPLIED/STORAGE AND HANDLING

16.1

How Supplied

MYOBLOC 3,500 Units(N=13)
1.62*

Placebo(N= 14)
3.93

MYOBLOC (rimabotulinumtoxinB) injection is supplied as a clear and colorless to light-yellow solution in singledose glass vials.
MYOBLOC is available in three presentations (Table 10).
Table 10:

MYOBLOC Presentations

Strength per Vial

Single-Vial Carton

2,500 Units/0.5 mL NDC 10454-710-10
5,000 Units/mL

NDC 10454-711-10

10,000 Units/2 mL

NDC 10454-712-10

No U.S. Standard of Potency
16.2

Storage and HandlingStore 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.
17

PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Swallowing, Speaking, or Breathing Difficulties or Other Unusual Symptoms
Advise patients to inform their healthcare provider if they develop any unusual symptoms, including difficulty withswallowing, speaking or breathing, or if any existing symptom worsens [see Box Warning and Warnings andPrecautions (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.
Manufactured By:
Solstice Neurosciences, LLC, Rockville, MD 20852

MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use
U.S. License No. 1718
“MYOBLOC” and the “MYOBLOC Logo” are registered trademarks of Solstice Neurosciences, Inc.
Protected by U.S. Patent No.

6,290,961; 6,632,433; 6,872,397; 6,887,476© 2019 Solstice Neurosciences, LLC
64183
RA-MYO-V5