RimabotulinumtoxinB

Mechanism of Action

Neurotoxin from Clostridium botulinum; blocks cholinergic transmission at the neuromuscular junction by inhibiting acetylcholine release from the peripheral cholinergic nerve endings

Pharmacokinetics

Duration: 12-16 weeks

Absorption: Minimal levels in circulation after IM injection

Since botulinum toxin has a temporary effect and is given at widely spaced intervals, missing a dose is not likely to be harmful.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may not appear right away, but can include muscle weakness, trouble swallowing, and weak or shallow breathing.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

The botulinum toxin contained in this medicine can spread to other body areas beyond where it was injected. This has caused serious life-threatening side effects in some people receiving botulinum toxin injections, even for cosmetic purposes.

Call your doctor at once if you have any of these side effects, some of which can occur up to several weeks after an injection:

• trouble breathing, talking, or swallowing;

• hoarse voice, drooping eyelids;

• unusual or severe muscle weakness (especially in a body area that was not injected with the medication);

• loss of bladder control;

• problems with vision; or

• chest pain.

Common side effects may include:

• pain or muscle weakness near where the medicine was injected;

• headache, joint or back pain;

• dry mouth, nausea, upset stomach;

• fever, cough, sore throat, flu symptoms;

• pain or stiffness in your neck; or

• dizziness, drowsiness, anxiety.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs such as cold or allergy medicines, muscle relaxers, sleeping pills, bronchodilators, bladder or urinary medications, and irritable bowel medications can increase some of the side effects of Myobloc. Tell your doctor if you regularly use any of these medicines.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• an antibiotic such as amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Mycifradin, Neo-Fradin, Neo-Tab), paromomycin (Humatin, Paromycin), streptomycin, tobramycin (Nebcin, Tobi).

This list is not complete. Other drugs may interact with Myobloc, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Neurotoxin produced by Clostridium botulinum;1 2 3 5 31 37 70 79 disrupts neurotransmission by inhibiting release of acetylcholine from peripheral and ganglionic autonomic cholinergic nerve terminals.2 3 16 31 32 37 70 250 399

General

• Adjust dosage carefully according to response and particular condition treated.2 120

• Generally, the effective IM dose depends on muscle mass; the larger the muscle, the higher the required dose.120

• Optimal dosages for a number of conditions have not been fully elucidated.37 142 156 219 301 302 337 338

• If a patient fails to respond, consider possibility of an inadequate drug dose, improperly stored drug solution, and/or misinjection.65 296

Controlling Injection Pain

• Pretreatment with ice packs or topical or local anesthetics (e.g., lidocaine/prilocaine cream and an occlusive dressing, proparacaine ophthalmic solution) has been recommended.120 296

• Some clinicians report that topical or local anesthetics are not useful to prevent injection pain since they do not penetrate underlying muscles and/or require additional injections.296 297

• Dilution with 0.9% sodium chloride injection containing a preservative (benzyl alcohol)† has been reported to reduce pain on injection;157 297 344 however, the manufacturer recommends use of 0.9% sodium chloride injection without preservative for dilution.1 2 5 298

• 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

• IV sedation or general anesthesia may be needed prior to injection in some patients (e.g., those in considerable pain).120 296 297

Administration

Administer by IM injection into affected muscles.2 3 120

Has been administered intradermally†,60 79 157 160 intracutaneously†,60 157 296 297 sub-Q†,60 157 296 297 or directly into affected glands†.320

IM Administration

Administer by IM injection into affected muscles.2 3 120

Commercially available as a sterile solution containing 5000 units of rimabotulinumtoxinB per mL.2 Do not shake vial.2

Myobloc vials 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 Do not dilute drug solutions in the vial since this may result in a solution with a higher concentration than expected due to overfill.297 338

Allow stopper of the vial to dry thoroughly after cleansing with alcohol before entering vial with a needle to prevent toxin inactivation.142 296 297

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

Vials are for single use only; discard any unused portions.2

Carefully dispose of all used vials, including expired vials and/or equipment used in preparation and administration, as medical waste.2

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).120 229

EMG-guided injections often are recommended to ensure optimal placement of toxin, particularly in patients who have not responded adequately to previous injections, and to minimize adverse effects on nonaffected tissue.120 296 297

Injection into midbelly of larger muscles where motor end plates are located may enhance benefit.296

Clinicians who administer rimabotulinumtoxinB should be familiar with and experienced in the assessment and management of cervical dystonia.2

Total dose administered at each treatment session is given as several injections divided among affected muscles.2 65

Identify affected muscles by careful clinical evaluation, including physical examination (e.g., for areas of hypertrophy, pain) and palpation.9 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

EMG guidance may be useful in delineating involved muscles for injection, particularly in obese patients or for muscles difficult to identify by palpation.37 39 65

Some clinicians suggest that injection procedures be adapted to account for the relatively greater diffusion characteristics of rimabotulinumtoxinB compared with type A.142 157 296 297 301 302

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

Minimize risk of ptosis by avoiding injections near levator palpebrae superioris, especially in individuals with larger brow-depressor complexes.5 142 296 297

Do not treat entire forehead and glabellar lines during a single session; high risk of ptosis.157 296 297

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 hours296 297 following treatment.296 297

When injection sites are marked (e.g., with a ball-point pen) to ensure optimal targeting,296 297 avoid injecting directly into marked areas to prevent tattooing of skin.298

If concurrent cosmetic alteration of the eyebrow† is planned,157 296 297 defer treatment of the lateral eyebrow until after treatment of lateral canthal lines (“crow’s feet”)†; increased diffusion may accomplish sufficient cosmetic alteration of the eyebrow to eliminate the need for further treatment.157 296 297

Dosage

Potency of rimabotulinumtoxinB expressed in units of biologic activity; each unit is equivalent to the median intraperitoneal lethal dose (LD50) in mice.2

Because of differences in assay methods, units of biologic activity of rimabotulinumtoxinB cannot be compared with or converted to units of any other botulinum toxin (e.g., abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA).1 2 5 381 384 403 410

Adults

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.296 297

Patients with a history of tolerating botulinum toxin treatment: Initially, total recommended dose per treatment session is 2500–5000 units divided among affected muscles.2 Total initial doses as high as 10,000 units per treatment session have been used.2 296 297

Toxin treatment-naive patients: Use a lower initial dose.2 296 297 (See Botulinum Toxin-naive Patients under Cautions.)

Duration of response to 5000–10,000 units is generally 12–16 weeks.2 14 16 17

2000 units per axilla, distributed among 25 sites about 2 cm apart, suggested.157 160 296 297

Anhidrosis following rimabotulinumtoxinB injection may occur within 3–5 days, with peak effect in 1–2 weeks and duration 9–16 weeks; duration of response with 2000 or 4000 units per axilla does not appear dose related.160 296 297

7500–9000 units in each palm, distributed among 30–35 sites, suggested.157 261

Duration of muscle weakness (e.g., 2–3 weeks) following treatment with rimabotulinumtoxinB appears similar to that with onabotulinumtoxinA.157

Total dose of 2400–3000 units divided among 6 injection sites used;301 total dose of 2000–3000 units divided among 3 injection sites also suggested.157 296 297 301 302

Injection procedure for rimabotulinumtoxinB may differ from that for onabotulinumtoxinA based on relatively greater diffusion of rimabotulinumtoxinB.142 157 296 297 298 301 302

1500 units divided among 3 injection sites per side (total dosage 3000 units) has been used;310 wrinkle severity was reduced by day 30 and generally had returned to baseline between days 90 and 120.310

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

1000–2500 units on each side of forehead suggested.157 296 Some clinicians suggest that injections be placed slightly higher than the equator of the brow (no lower than 2.5–4 cm above the brow) to account for increased diffusion of rimabotulinumtoxinB.157 296 297

If planning to treat both glabellar and horizontal forehead lines, may treat glabellar facial lines first and reevaluate again in 2 weeks to determine if further treatment needed.157

Prescribing Limits

Adults

Do not exceed recommended dosage or frequency of administration; safety and efficacy of higher dosages not established.2 296

Special Populations

Geriatric Patients

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

Absorption

Bioavailability

No formal pharmacokinetic studies; manufacturer states that drug is not expected to be present in peripheral circulation in measurable concentrations following IM or intradermal injection of recommended doses.2 14

Duration

Duration of response to 5000–10,000 units in cervical dystonia is generally 12–16 weeks.2 14 16 17

• 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

• Inhibits sweat production by blocking release of acetylcholine, which mediates sympathetic neurotransmission in eccrine glands.3 79 157 160 296 297

• Induces neuromuscular blockade via a zinc-dependent endopeptidase, which blocks vesicles containing acetylcholine from fusing with the terminal membrane of the motor neuron.16 31 37 70 79

• Without acetylcholine release, the muscle is unable to contract31 37 70 79 and flaccid paralysis ensues.1 3 5 16 31 32 37

• 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

• Selective chemodenervation is reversible; although muscular atrophy occurs, regeneration of extrajunctional receptors and terminals limits the duration of activity to a few months.3 5 31

• Recovery of neuromuscular activity occurs through neurogenesis of axonal sprouts and motor end plates.32 37 79

• Functional recovery develops in 3–6 months, but sprouting and remodeling may continue for as long as 3 years.37 79

• Response in autonomic disorders involving excessive glandular secretion (e.g., hyperhidrosis) may be longer than in conditions involving overactivity of striated or smooth muscle;296 297 additional study needed to elucidate mechanism in glandular and non-muscle tissue.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time rimabotulinumtoxinB is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take rimabotulinumtoxinB or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to rimabotulinumtoxinB. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

RimabotulinumtoxinB (previously known as botulinum toxin type B) is a neurotoxin produced by Clostridium botulinum, spore-forming anaerobic bacillus. It cleaves synaptic Vesicle Association Membrane Protein (VAMP; synaptobrevin) which is a component of the protein complex responsible for docking and fusion of the synaptic vesicle to the presynaptic membrane. By blocking neurotransmitter release, rimabotulinumtoxinB paralyzes the muscle.

Absorption

Not expected to be present in peripheral blood at recommended doses

Sialorrhea (adults)

The use of botulinum toxin B for decreasing or controlling sialorrhea has demonstrated benefit in randomized controlled trials and meta-analyses in patients with various neurological conditions. EFNS guidelines on the clinical management of ALS recommend botulinum toxin B in patients refractory to first-line therapy, based on a single randomized trial. An AAN report classifies botulinum toxin B as probably safe and effective in Parkinson-related sialorrhea. Additional study is needed to determine the expected duration of response, potential candidates, optimal dosing regimens, and standardization of injection procedures.

Upper limb spasticity (adults)

Based on the American Academy of Neurology practice guidelines on the use of botulinum neurotoxin, rimabotulinumtoxinB may be considered as a treatment option for focal manifestations of adult upper limb spasticity.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site pain, headache, dry mouth, nausea, flu-like signs, joint pain, back pain, dizziness, or neck pain. Have patient report immediately to prescriber signs of infection, blurred vision, change in voice, droopy eyelids, loss of strength and energy, difficulty breathing, difficulty swallowing, difficulty speaking, muscle pain, muscle weakness, vision changes, eye pain, severe eye irritation, urinary incontinence, or diplopia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Initial: The dose should be individualized based on the patient's head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history.

Patients with a prior history of tolerating botulinum toxin injections: 2500 to 5000 units (0.5 to 1.0 mL) divided among affected muscles.

Patients with no history of botulinum toxin type B: use should be at a lower dose, with subsequent dosing based on individual response.

Clinical improvement generally begins within the first two weeks after injection with studies showing the duration of effect to be between 12 and 16 weeks at doses of 5000 units or 10,000 units.