Botulinum Toxin Type B
Class: Other Miscellaneous Therapeutic Agents
VA Class: MS900
[UPDATED 08/03/2009] FDA notified healthcare professionals of changes to the established drug names for botulinum toxin Type A (Botox/Botox Cosmetic, Dysport) and botulinum toxin Type B (Myobloc) to reinforce individual potencies and prevent medication errors, and provided recommendations for healthcare professionals to consider, plus information for patients, family members, and caregivers. For more information visit the FDA website at: and .
[Posted 04/30/2009] FDA notified healthcare professionals that after an ongoing safety review initiated in February 2008, the manufacturers of licensed botulinum toxin products [botulinum toxin Type A (Botox and Botox Cosmetic) and botulinum toxin Type B (Myobloc)] will be required by FDA to strengthen warnings in product labeling and add a boxed warning regarding the risk of adverse events when the effects of the toxin spread beyond the site where it was injected.
FDA will also require that manufacturers develop and implement a Risk Evaluation and Mitigation Strategy [REMS], including a communication plan to provide more information regarding the risk for distant spread of botulinum toxin effects after local injection, as well as information to explain that botulinum toxin products cannot be interchanged. The REMS would also include a Medication Guide that explains the risks to patients, their families, and caregivers. FDA is requiring the manufacturers to submit safety data after multiple administrations of the product in a specified number of children and adults with spasticity to assess the signal of serious risk regarding distant spread of toxin effects.
FDA’s evaluation of the data continues to support the recommendations made in the 2008 Early Communication. For more information visit the FDA website at: , and .
FDA approved a REMS for rimabotulinumtoxinb (formerly botulinum toxin b) to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of rimabotulinumtoxinb (formerly botulinum toxin b) and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().
Neurotoxin produced by Clostridium botulinum;1 2 3 5 31 37 70 73 79 7 structurally similar but antigenically and serologically distinct botulinum toxin serotypes (A, B, C, D, E, F, and G) exist.2 3 31 32 37 70 73 75 79
Botulinum toxin disrupts neurotransmission by inhibiting release of acetylcholine at cholinergic nerve terminals of the peripheral nervous system and at ganglionic nerve terminals of the autonomic nervous system, inducing a chemical denervation and flaccid paralysis and inhibiting glandular secretion.2 3 31 32 37 43 72 73 75 194
Uses for Botulinum Toxin Type B
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Botulinum toxin type B (Myobloc) and type A (Botox, Botox Cosmetic) currently are the only botulinum toxin serotypes commercially available in the US;1 2 5 types C and F reportedly under clinical investigation in other countries.4
Management of cervical dystonia (also referred to as spasmodic torticollis) to decrease severity of associated abnormal head position and neck pain;2 3 4 9 14 16 29 30 32 35 37 40 54 65 69 81 85 95 96 122 123 designated an orphan drug by US FDA for this use.81
Considered first-line therapy for cervical dystonia because of efficacy, relatively low incidence of adverse effects, and temporary dose-related therapeutic effects (compared with surgery).3 15 30 33 34 35 54 83 86 90 296 297
Also considered an effective and safe treatment for cervical dystonia in patients who are not responsive to therapy with botulinum toxin type A.3 14 15 16 17 32 35 41 42 60 64 65 79 137 348 350 354 355
Comparative safety and efficacy of botulinum toxin types A and B in cervical dystonia have not been established;14 69 botulinum toxin type B appears to be effective in patients who develop tolerance to type A as well as in those who are responsive to botulinum toxin type A.2 14 17 42 69 123 297 345
Has been used for temporary improvement in the appearance of facial wrinkles associated with hyperactivity of the orbiculus oculi muscle† (lateral canthal wrinkles†, also known as “crow’s feet”†) in a limited number of individuals.152 156 310 337 338
Botulinum Toxin Type B Dosage and Administration
Lower doses may be required in patients with preexisting weakness or when there is concern about weakness, in those with milder disease severity, and in women and patients with lower body weights.4
Patients with cervical dystonia who have not previously received botulinum toxin should receive a lower initial dose; very limited experience in patients who have not received prior therapy with botulinum toxin type A.2 296 297
Carefully dispose of all used vials, including expired vials and/or equipment used in preparation and administration, as medical waste.2
Commercially available vials of botulinum toxin type B (Myobloc) are overfilled to ensure delivery of the labeled volume of drug: the vial labeled as containing 2500 units in 0.5 mL actually contains approximately 4100 units in 0.82 mL, the vial labeled as containing 5000 units in 1 mL actually contains approximately 6800 units in 1.36 mL, and the vial labeled as containing 10,000 units in 2 mL actually contains approximately 12,650 units in 2.53 mL.2 156 297 338 Drug solutions should not be diluted in the vial since this may result in a solution with a higher concentration than expected due to overfill.297 338
May be diluted with 0.9% sodium chloride injection to obtain desired concentration; however, since the drug solution does not contain a preservative, use diluted solutions within 4 hours of preparation.2 296 297 Diluted solutions reportedly stable for at least 24 hours at 25°C.157 172
Some clinicians suggest that injection pain (possibly due to acidity of the solution)152 157 286 may be decreased by adding a small amount of sodium bicarbonate to the injection solution†.152 157 However, the compatibility and stability of such solutions remain to be fully elucidated.157 296 297
IM Injection Techniques
Targeting the injection to the appropriate muscle(s) may be facilitated by active electromyography (EMG), ultrasonography, palpation of muscle belly, and/or use of anatomic landmarks (e.g., evidence of muscular hypertrophy, stiffness, tenderness, visible abnormal muscular activity).4 120 147 229
EMG-guided injections often are recommended to ensure optimal placement of toxin for efficacy, particularly in patients who have not responded adequately to previous injections, and to minimize adverse effects on nonaffected tissue.120 140 143 147 296 297
Identify affected muscles by careful clinical evaluation, including physical examination (e.g., for areas of hypertrophy, pain) and palpation.9 33 65 Palpation of contracting muscles while patient’s head is placed in position most favored by dystonic pulling of neck muscles is reportedly helpful.9 65
Cosmesis of Lateral Canthal Wrinkles (“Crow’s Feet”)†
If concurrent cosmetic alteration of the eyebrow† is planned,157 296 297 defer treatment of the lateral eyebrow until after treatment of lateral canthal wrinkles (“crow’s feet”); increased diffusion may accomplish sufficient cosmetic alteration of the eyebrow to eliminate the need for further treatment.157 296 297
Administration Precautions for Facial Cosmesis
Appears to have increased diffusion within the muscle (potentially reducing the number of injections and complications)142 157 301 302 353 354 and a somewhat faster onset of action (e.g., within 24–48 hours) than botulinum toxin type A;142 152 157 160 297 353 however, additional experience needed to establish the optimal dose, number of injection sites, and frequency of treatment for facial cosmesis.142 156 301 310 337
In older individuals, do not inject lower portion of brow (this muscle is used to raise eyebrows in order to see).143
Avoid eyelid ptosis by asking individual to remain upright (e.g., avoid naps in reclining position) for 4 hours following treatment, avoid rubbing or massaging treated area for 4 hours (to prevent excess diffusion and possible weakness of adjacent muscles), and frown and smile repeatedly for at least 1–4 hours143 296 297 following treatment.140 141 143 296 297
Apply digital pressure at border of supraorbital ridge while injecting corrugator muscle to minimize potential for diffusion into levator muscle and resultant weakening.143
Before injection, instruct the individual to accentuate specific facial lines to be treated by squinting (for lateral canthal wrinkles).140
Controlling Injection Pain
Pretreatment with ice packs or topical or local anesthetics (e.g., lidocaine/prilocaine cream [EMLA] and an occlusive dressing, proparacaine hydrochloride ophthalmic drops) has been recommended prior to injection.120 140 275 296
Dilution with 0.9% sodium chloride injection containing a preservative (benzyl alcohol)† has been reported to reduce pain on injection;62 64 138 157 297 344 however, the manufacturer recommends use of 0.9% sodium chloride injection without preservative for reconstitution and/or dilution.1 2 5 298
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Data on several different serotypes (e.g., botulinum toxin types A, B, C, F) and/or formulations of botulinum toxin have been reported;1 2 4 5 255 257 assay methods used to determine potency of these various toxins are specific to each individual manufacturer and/or formulation.1 2 4 5
Unless otherwise noted, all botulinum toxin doses in this monograph refer to units of Myobloc.
Patients With a History of Tolerating Botulinum Toxin TreatmentIM
Titrate initial and subsequent dosage considering previous response, adverse reactions, and severity of dystonia based on head and neck position, localization of pain, mass of target muscles and their proximity to critical toxin-sensitive anatomic structures (e.g., larynx, pharynx), and muscular hypertrophy.56 296 297
Initially, total recommended dose per treatment session is 2500–5000 units divided among affected muscles.2
Cosmesis of Lateral Canthal Wrinkles (“Crow’s Feet”)†
750 units divided among 3 injection sites per side also has been used (total dosage 1500 units if both sides treated); resolution of wrinkles occurred at 7 days.152
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.296
Cautions for Botulinum Toxin Type B
Hypersensitivity to botulinum toxin type B or any ingredient in the formulation.2
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Adherence to Recommended Dosage
Do not exceed recommended dosage or frequency of administration; safety and efficacy of higher dosages have not been evaluated.2 296 Severe adverse effects, including a botulism-like syndrome, have been reported with use of higher than recommended dosages of botulinum toxins and/or unlicensed preparations of botulinum toxins.371 374 376 377 378 379
Increased risk of serious adverse systemic effects, including severe dysphagia, muscle weakness, and/or respiratory compromise, with recommended doses in patients with underlying conditions such as peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junction disorders (e.g., myasthenia gravis, Lambert-Eaton syndrome); exercise caution when used in such patients.2 4 18 27 29 37 57 58 140 141 219 259 371 375 376 May be related to use of higher dosages in such patients.374 376
Rarely, extreme sensitivity to systemic effects of usual clinical doses reported in patients with known or unrecognized neuromuscular disorders; some patients experienced several months of severe dysphagia and required a gastrostomy or nasogastric tube.2 9 57 69
Some clinicians state that use for cosmetic treatment of neck wrinkles is contraindicated in patients with amyotrophic lateral sclerosis.141
Serious systemic effects related to distant spread of botulinum toxin reported, more often and with greater severity in children with cerebral palsy receiving such therapy; hospitalizations and deaths have occurred.371 372 373 374
Dysphagia is the most common serious adverse effect reported in patients with cervical dystonia;2 11 14 15 16 17 35 53 57 65 69 95 96 122 261 also can occur in patients receiving botulinum toxin type B for other indications (e.g., torticollis, muscle spasticity associated with cerebral palsy).371 375 376 Results from the diffusion of the toxin to tissues (e.g., posterior pharyngeal muscles) outside the injected muscles.29 30 33 57 58 60 65 83 371 Rarely, dysphagia may require placement of gastric feeding tube.2
Risk increased in patients with cervical dystonia and smaller neck muscle mass (e.g., female) receiving bilateral injections and/or relatively high doses into the sternocleidomastoid muscle.2 9 35 57 86
Risk of Creutzfeldt-Jakob Disease
Formulation contains human albumin derived from blood.2 Theoretical but remote risk of transmission of Creutzfeldt-Jakob disease (CJD) via albumin component; however, no cases of CJD identified to date.2
Systemic Toxicity (Botulism)
Serious systemic toxicity, including respiratory compromise and death, reported during an ongoing FDA safety review of botulinum toxins type A and type B.371 372 373 374 More frequent and severe in children with limb spasticity associated with cerebral palsy.371 372 373 374 Causal relationship not established to date; FDA will review additional safety data from clinical studies, medical literature, and postmarketing adverse event reports to further evaluate risk of systemic toxicity.371 372 374
Botulism also possible after iatrogenic overdose or misinjection of botulinum toxin.1 2 5 51 58 59 60 65 70 87 377 378 Following IM injection of usual therapeutic doses, botulinum toxin type B generally not present in the peripheral blood and generally does not induce systemic effects (e.g., generalized or distant muscle weakness) in patients without predisposing neuromuscular dysfunction.2 14 However, systemic autonomic or anticholinergic effects (e.g., dry mouth, dyspepsia,296 swallowing difficulties, accommodation difficulty, corneal and conjunctival irritation, dryness of nasal mucosa, reduced sweating, and urinary voiding difficulties) reported.160 261 296 340 352
To date, botulism not reported after IM injections of botulinum toxin type B;2 however, generalized muscle weakness and a generalized botulism-like syndrome, including respiratory arrest, reported rarely after IM injections of therapeutic doses of another botulinum toxin serotype (type A).14 26 32 33 38 52 58 142 293
Maximum safe dose that does not produce toxicity is not known.37 Serious systemic toxicity has been reported during postmarketing experience with doses of 388–625 units/kg in children and doses of 10,000–20,000 units in adults.371
Manifestations of overdose (botulism) include diplopia, ptosis, blurred vision, photophobia, dry mouth, difficulty speaking and swallowing, autonomic dysfunction such as bowel stasis, and generalized muscle weakness that can progress to a symmetric, descending flaccid paralysis;70 87 89 250 manifestations not apparent immediately after the drug is injected.2
If accidental injection or ingestion occurs, closely monitor patient for up to several weeks for manifestations of systemic weakness or muscle paralysis.2 If botulism suspected, hospitalization may be required to monitor closely for systemic weakness, paralysis, and incipient respiratory failure.2 Recovery occurs through neurogenesis of axonal sprouts and motor end plates; can require weeks or months.32 37 79 70
In event of an overdose or misinjection (i.e., wrong muscle), contact manufacturer immediately for additional information and state health department to obtain botulinum antitoxin through CDC;2 if state health department is not available, contact CDC by telephone at 404-639-2206 or 404-639-2888 (after hours).70 Antitoxin will not reverse botulinum toxin-induced muscle weakness already evident at the time of antitoxin administration but may stabilize the deficits.2 265
Botulinum Toxin-naive Patients
Initiate treatment of botulinum toxin-naive patients with lower doses from the recommended dosage range.2
Experience of Clinician
The manufacturer states that the drug should be administered to patients with cervical dystonia only by clinicians familiar with and experienced in the assessment and management of this condition.2
Thorough knowledge of diagnosis, management, and regional anatomy of the treated disorder, careful dose selection, and accomplished injection techniques are critical to obtaining therapeutic benefit and minimizing adverse effects.2 54 56 Some experts recommend limiting use to clinicians with specialized training.37 65 66 296 297
Working knowledge of EMG techniques useful for accurate injection of target muscles in patients with cervical dystonia,35 particularly when palpation is inadequate or adequate relief not obtained with conventional administration.9 35 83
Local spread of toxin may result in weakness to adjacent muscles.9 10 11 12 13 18 30 31 32 33 34 35 37 65 142 371 Systemic spread of botulinum toxin also is possible and can cause a botulism-like syndrome (e.g., dysphagia, muscle weakness, ptosis, respiratory failure).371 372 373 374 Condition treated determines muscles injected and therefore proximate muscles possibly affected by infiltration and resultant undesired weakness.29 37
Systemic autonomic or anticholinergic effects (e.g., dry mouth, dyspepsia,296 swallowing difficulties, accommodation difficulty, corneal and conjunctival irritation, dryness of nasal mucosa, reduced sweating, and urinary voiding difficulties) reported; incidence not fully elucidated.160 261 296 340 352 369
Incidence of autonomic effects (e.g., anticholinergic effects such as dry mouth, ptosis, accommodation difficulty) may be higher with botulinum toxin type B than with type A, possibly because of diffusion characteristics and systemic distribution of type B and/or different relative affinities of toxin serotypes for neuromuscular and autonomic nerve endings.142 160 261 296 320 340 345 352
Incidence of dry mouth appears dose-related in cervical dystonia after injections in the splenius capitis, trapezius, and sternocleidomastoid muscles.2
Monitor patients for possible systemic effects including dysphagia, dysphonia, respiratory compromise, and generalized weakness following administration of botulinum toxin type B.371
Antibody Formation and Tolerance
Clinical importance has not been determined.2 It is not known if patients with neutralizing antibodies to botulinum toxin type A are at increased risk of developing tolerance to the type B toxin.345 351
Neutralizing antibodies generally not detected until after 6 months of treatment.2
Patients who develop tolerance to botulinum toxin type A may respond to botulinum toxin type B or other botulinum toxin serotypes (e.g., botulinum toxin type F);3 32 35 41 42 60 64 65 79 137 348 350 however, long-term response to other serotypes in such patients has not been fully elucidated.14 32 33 41 359
Ensure accuracy of dosing information; units of biologic activity for different serotypes or formulations of botulinum toxin cannot be compared with or converted to units of other botulinum toxins.2 4
Dosing errors reported;32 76 77 157 173 296 297 use care in evaluating medical literature on different toxin serotypes (e.g., botulinum toxin types A, B, C, F) since assay methods used to determine potency of different serotypes are specific to each individual manufacturer and/or formulation.1 2 4 5 255 257
Serious systemic toxicity resembling botulism (e.g., dysphagia, respiratory failure) reported during postmarketing experience in children <16 years of age.371 Such effects were observed with botulinum toxin type B doses of 388–625 units/kg.371 Severe cases involving death or hospitalization or requiring use of gastric feeding tubes and/or mechanical ventilation have occurred, principally in children with cerebral palsy-associated limb spasticity.371 372 373 374 No deaths or serious complications requiring intubation or ventilatory support reported among such cases of botulism in adults.371 374
Safety and/or efficacy in those ≥65 years of age similar to that in younger adults.2
Safety and efficacy data in patients ≥75 years of age insufficient for any comparison to that in younger adults.2
Common Adverse Effects
Interactions for Botulinum Toxin Type B
Potential for prolonged paralytic effect of toxin297
Other botulinum toxin serotypes
Possible increased paralytic effect with concurrent or sequential use within several months of administration of type B2
Concurrent or sequential use has not been evaluated2
Anti-infective agents interfering with neuromuscular transmission (aminoglycosides, lincosamides, polymyxins)
Magnesium salts (magnesium sulfate)
Potential for prolonged paralytic effect of toxin297
Neuromuscular blocking agents (e.g., atracurium, succinylcholine)
Potential for prolonged paralytic effect of toxin297
Botulinum Toxin Type B Pharmacokinetics
Formal pharmacokinetic studies with botulinum toxin type B have not been performed; the manufacturer states that the drug is not expected to be present in peripheral circulation in measurable concentrations following IM or intradermal injection of recommended doses.2
For information on systemic interactions resulting from concomitant use, see Interactions.
Some clinicians suggest that the addition of a small amount of sodium bicarbonate to the botulinum toxin type B solution may decrease pain on injection;152 157 however, use of such buffering agents reportedly may destabilize the toxin and/or alter its diffusion characteristics.157 296 297
Induces chemical denervation and flaccid paralysis by disruption of neurotransmission; inhibits release of acetylcholine at presynaptic cholinergic nerve terminals of the peripheral nervous system and at ganglionic nerve terminals of the autonomic nervous system.2 3 16 31 32 37 72 73 75 194
At therapeutic doses, muscular paralysis limited to injected muscle; however, weakness or paralysis of adjacent muscles may occur as a result of local diffusion.31
Response in autonomic disorders involving excessive glandular secretion (e.g., hyperHIDrosis) may be longer than in conditions involving overactivity of striated or smooth muscle;4 296 297 additional study needed to elucidate mechanism in glandular and non-muscle tissue.4
Advice to Patients
Inform patients with cervical dystonia of possibility of dysphagia (typically mild to moderate);9 14 57 69 rarely, severe dysphagia occurs, sometimes associated with aspiration, dyspnea, pneumonia, and need to reestablish an airway.2
Importance of informing patients of possible systemic effects (e.g., weakness, shortness of breath, respiratory complications, swallowing difficulties) following local injection.371
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., neuromuscular disorders).
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.2
Importance of informing patients of other important precautionary information.2 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
5000 units/mL (of Clostridium botulinum Toxin Type B)
AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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