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OnabotulinumtoxinA (botulinum toxin type A)
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The Multiple Sclerosis Emerging Therapies Collaborative includes the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), the MS Coalition, the American Academy of Neurology, and the VA Multiple Sclerosis Centers of Excellence East and West.

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What is the medication?
Generic: OnabotulinumtoxinA (botulinum toxin type A)
Brand name: BOTOX® (Boe-tox)
Has the medication received US Food and Drug Administration (FDA) approval?
Yes –Intradetrusor injection of reconstituted botulinum toxin A (200 units/30 ml) was approved on August 24, 2011.
If so, what are the indications and uses?
OnabotulinumtoxinA is indicated to treat urinary incontinence (UI) caused by detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury [SCI], multiple sclerosis [MS]) in adults who have an inadequate response to or are intolerant of an anticholinergic medication. OnabotulinumtoxinA is also used for a variety of other medical conditions, including the following:
  • Upper-limb spasticity (elbow, wrist, and finger muscles)
  • Chronic migraine
  • Cervical dystonia
  • Primary axillary hyperhidrosis
  • Blepharospasm and strabismus
What were the findings in the pivotal and supportive trials of this medication?
Two pivotal trials with identical study designs and primary endpoints have been completed to date and are described in the product insert. Cruz et al., 2011 reports on the first of those studies. The publication of the second study is pending. Both phase 3 pivotal studies were multicenter, double-blind, randomized, placebo-controlled trials in patients with incontinence caused by detrusor overactivity associated with a neurologic condition, who were either spontaneously voiding or using catheterization.
  • Trial Design: A total of 691 patients with SCI or MS with inadequate response to or intolerance of ≥ 1 anticholinergic medication was enrolled. These patients were randomized to receive 200 units of onabotulinumtoxinA (n=227), 300 units of onabotulinumtoxinA (n=223), or placebo (n=241). Starting at week 12, patients could request retreatment if they desired.
    • Patients included in the pivotal trials were between 18 and 80 years old and had UI as a result of neurogenic detrusor overactivity (NDO) associated with SCI or MS. Patients with SCI had a stable neurologic injury at T1 or below, whereas patients with MS were clinically stable for ≥ 3 months prior to screening and had an Expanded Disability Status Scale (EDSS) score ≤ 6.5.
    • All patients had ≥ 14 episodes of UI weekly, and their NDO was confirmed by urodynamic assessment at screening.
  • Primary Endpoint: The primary efficacy endpoint in both studies was the change from baseline in the weekly frequency of UI episodes at week 6 after the first treatment.
  • Key Secondary Endpoints: The key secondary endpoints in both studies were changes from baseline in the following urodynamic parameters:
    • Maximum cystometric capacity (MCC)
    • Maximum detrusor pressure (MDP) during first involuntary detrusor contraction (IDC)
    • Safety
    • Postvoid residual (PVR) for patients with spontaneous voiding pattern
  • Results:
    • The pivotal trials demonstrated no additional benefit of onabotulinumtoxinA 300 units over 200 units.
    • At week 6, patients treated with onabotulinumtoxinA achieved a mean change of -19.9 and -19.6 weekly UI episodes in studies 1 and 2, respectively, as compared with -0.6 and -10.8, respectively, for placebo (ρ < 0.001 study 1; ρ < 0.003 study 2).
    • At week 6, patients treated with onabotulinumtoxiA had a mean MCC increase from baseline of 135.9 ml and 150.8 ml in studies 1 and 2, respectively, as compared with 12.1 ml and 2.8 ml, respectively, for placebo (ρ <0.001 in both studies).
    • At week 6, patients treated with onabotulinumtoxinA had a mean MDP during first IDC decrease from baseline of 28.1 cm H20 and 28.7 cm H20 in studies 1 and 2, respectively, as compared with 3.7 cm H20 and 2.1 cm H20, respectively, for placebo.
    • On the basis of time to request for retreatment, the median duration of response was 42–48 weeks for onabotulinumtoxinA 200 U as compared with 13–18 weeks with placebo.
    • In patients who were not catheterizing at baseline, mean PVR urine volume increased significantly at week 2 in patients treated with onabotulinumtoxinA 200 U (mean increase of 94.1 mL from a mean baseline of 62.9 mL), compared with placebo (mean increase of 3.3 mL from a mean baseline of 57.3 mL) (ρ<0.001).
    • Among patients who were not catheterizing at baseline, catheterization for urinary retention was initiated in 30.6% of patients following treatment with onabotulinumtoxinA 200 U as compared with 6.7% of those on placebo. The median duration of catheterization for urinary retention was 289 days (range 1 to 530) among patients treated with onabotulinumtoxinA 200 U as compared with 358 days (range 2 to 379) for patients treated with placebo.
What is the mechanism of action and the rationale for the use in MS?
Botulinum toxin is a protein produced by the bacterium Clostridium botulinum and is the most powerful neurotoxin known. There are seven types of botulinum toxin with five subtypes of type A—one of which is onabotulinumtoxinA. OnabotulinumtoxinA is a polypeptide composed of a light chain and a heavy chain. The light chain is a protease that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at the presynaptic part of the neuromuscular junction, preventing synaptic vesicles from anchoring to the presynaptic membrane and releasing the acetylcholine contained within them. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid paralysis. When used as treatment for a spastic bladder onabotulinumtoxinA transiently denervates the detrusor muscle. Function is restored following an interval during which axons within the bladder wall sprout new presynaptic terminals that form new neuromuscular junctions.
What is the delivery route and recommended dosing?
The recommended total dose is 200 units of onabotulinumtoxinA per treatment, delivered as 1-mL (~6.7 units) injections across 30 sites into the bladder.

OnabotulinumtoxinA (200 units/30 mL) is injected into the bladder muscle using a rigid or flexible cystoscope. Prior to injection, a diluted local anesthetic is placed in the bladder along with enough saline to achieve adequate visualization for the injections. Thirty injections of 1 mL (~6.7 units) each are injected into the bladder muscle. The procedure can be performed under local anesthesia with or without sedation or under general anesthesia (per physician practice). After the injections are given, the saline used for bladder wall visualization is drained. The patient is observed for at least 30 minutes postinjection.

Patients should be considered for re-injection when the clinical effect of the previous injection diminishes (median time to qualification for retreatment in the double-blind, placebo-controlled clinical studies was 295–337 days [42–48 weeks]), but no sooner than 12 weeks from the prior bladder injection.
Can this medication be used with other medications?
  • Disease-modifying Therapies (DMT): No formal concurrent disease-modifying therapy interaction studies have been conducted with onabotulinumtoxinA for injection.
  • Other Medications:
    • No formal drug interaction studies have been conducted with onabotulinumtoxinA for injection.
    • Coadministration of onabotulinumtoxinA and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should be performed with caution only, as the effect of the toxin may be potentiated.
    • Use of anticholinergic drugs after administration of onabotulinumtoxinA may potentiate systemic anticholinergic effects.
    • The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown.
    • Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.
    • Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of onabotulinumtoxinA.
How does the expected treatment effect compare with the treatment effect provided by other available medications?
No direct comparisons have been made of DM/QS with any other medications used to treat PBA. Although there have been studies reporting success in treating PBA with other agents, including low doses of amitriptyline, there are no other FDA-approved medications for the treatment of PBA.
What are the possible short-term side effects? What is the range of severity of side effects, and what are the recommended management strategies?
  • Common adverse reactions occurring more frequently than with placebo and affecting more than 5% of patients include the following:
    • Urinary retention can result from intradetrusor injection of onabotulinumtoxinA. In the clinical studies, 17 percent of the treatment group developed urinary retention within 12 weeks of treatment compared with 3 percent of the placebo group. Urinary retention can be monitored by assessing PVR urines and instituting self-catheterization where appropriate. Intradetrusor injection of onabotulinumtoxinA is contraindicated in patients with acute urinary retention who are not routinely performing clean intermittent self-catheterization. In patients who are not catheterizing, PVR urine volume should be assessed within 2 weeks posttreatment and periodically thereafter as medically appropriate for up to 12 weeks. Catheterization should be instituted if PVR urine volume exceeds 200 mL and should be continued until PVR falls below 200 mL. Patients should be instructed to contact their physician if they experience difficulty in voiding, as catheterization may be required.
    • Urinary tract infection may result after manipulation of the urinary tract during the injection of the drug. In the pivotal studies, UTI was defined as: positive urine culture > 105 CFU/mL in association with a leukocyturia > 5/hpf or a positive urine culture that in the investigator's opinion, required antibiotic therapy. In the studies, within 12 weeks of intradetrusor injection of onabotulinumtoxinA, 24 percent of the treatment group developed a UTI compared with 17 percent in the placebo group. Intradetrusor injection of onabotulinumtoxinA is contraindicated in patients who have an acute urinary tract infection. The risk of urinary tract infection can be reduced with pre- and postprocedure prophylactic antibiotic administration (except with aminoglycosides, which can aggravate neuromuscular blockage). Prophylactic antibiotics should be administered 1–3 days pretreatment, on the treatment day, and 1–3 days posttreatment. In addition patients can be instructed regarding the signs and symptoms of urinary tract infections, including cloudy, red, dark, or pungent urine; increased urgency; burning during urination; lower-abdominal or flank pain; fever; worsening of neurologic symptoms; malaise; and generalized weakness.
  • Less-common side effects include the following:
    • Bleeding may occur secondary to cystoscopy. Patients should discontinue antiplatelet therapy at least 3 days before the injection procedure. Patients on anticoagulant therapy need to be managed appropriately to decrease the risk of bleeding.
    • Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further injection of onabotulinumtoxinA should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined.
    • Hematuria, fatigue, and insomnia were reported in ≥2% but <5% of patients in clinical trials and were more common than in placebo groups. The significance of this finding is unknown, and the increased incidence of these symptoms may have occurred by chance.
What are the known long-range health risks (morbidity and mortality)?
  • Long-range risks may occur as a consequence of hypotonia and infection involving the bladder, and could include bladder calculi, possible reflux of urine into ureters with hydronephrosis, pyelonephritis, and renal calculi.
  • The effects of onabotulinumtoxinA may spread from the injection area to produce neuromuscular blockage and weakness. These symptoms have been reported hours to weeks following injection. Swallowing and breathing difficulties can be life threatening. Potential distance spread of toxin effect is probably greatest for pediatric patients and for those with significant baseline weakness.
  • Neutralizing antibodies to onabotulinumtoxinA may develop that would compromise or eliminate the effectiveness of treatment. Patients with neutralizing antibodies may also be at higher risk for an acute allergic reaction to the drug. In a long-term, open-label study evaluating cervical dystonia patients, four (1.2%) had positive antibody tests. All four of these patients responded to onabotulinumtoxinA therapy at the time of the positive antibody test. However, three of these four patients developed clinical resistance after subsequent treatment, whereas the fourth patient continued to respond to onabotulinumtoxinA therapy for the remainder of the study. [NOTE: As of October, 2011, the Botulinum Toxin Type A Antibody Test is currently unavailable from Athena Diagnostics and the company is not accepting any orders for it. Contact the company's Client Services (800-394-4493, option 2) with any questions.]
Has the FDA included any black box warnings about this medication?
Yes – the FDA has included a warning about the distant spread of toxin effect, which is outlined above. Symptoms may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, UI, and breathing difficulties. Swallowing and breathing difficulties can be life threatening, and deaths have been reported.
What training is recommended or required for clinicians or patients before initiating this treatment?
Since onabotulinumtoxinA is delivered by cystoscopy, it is most commonly administered by urologists and neurourologists. Providers should have certified competence in the use of a urinary cystoscope to perform onabotulinumtoxinA injections into the detrusor muscle.
What is the pregnancy rating for this medication, and what is known about possible carcinogenesis, mutagenesis, and impairment of fertility?
  • OnabotulinumtoxinA has a Pregnancy Category C rating: There are no adequate and well-controlled studies in pregnant women. OnabotulinumtoxinA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    At high doses, onabotulinumtoxinA injections into pregnant small mammals have resulted in abortions, early deliveries, and maternal death. Studies of onabotulinumtoxinA injection into small mammals during organogenesis have demonstrated reductions in fetal body weight and decreased fetal skeletal ossification.

    It is not known whether onabotulinumtoxinA is excreted in human milk; therefore caution should be exercised when botulinum toxin is administered to a woman who is breastfeeding.
  • Carcinogenesis: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of onabotulinumtoxinA.
  • Mutagenesis: There was no positive effect for onabotulinumtoxinA in a battery of in vitro (microbial reverse mutation assay, mammalian cell mutation assay, and chromosomal aberration assay) and in vivo (micronucleus assay) genetic toxicologic assays.
  • Impairment of Fertility: In fertility studies of onabotulinumtoxinA in rats, reduced fertility was observed in males at the intermediate and high doses and in females at a dose that is approximately equal to 360 units on a body weight basis (units/kg).
Does this medication interact or interfere with oral contraceptives?
There are no known effects of onabotulinumtoxinA on the efficacy of oral contraceptives.
Has the FDA required a safety-monitoring program?
Providers should give patients a copy of the Medication Guide and review the contents with them. After bladder injections for urinary incontinence, patients should be instructed to contact their physician if they experience difficulties in voiding.
What kind of safety monitoring is recommended (including prescreening, routine checkups, and laboratory tests)?
  • Prior to treatment a complete urinary history and appropriate confirmation of detrusor hyperactivity must be documented. The patient should be evaluated to provide evidence of sufficiently good health to undergo cystoscopy.
  • A urine analysis and, where indicated, a urine culture should be performed prior to the procedure. Findings of a urinary tract infection will delay therapy until the infection is cleared. Prophylactic antibiotics should be administered 1–3 days pretreatment, on the treatment day, and 1–3 days posttreatment.
  • In patients who are not catheterizing, PVR urine volume should be assessed within 2 weeks posttreatment and periodically as medically appropriate up to 12 weeks. Catheterization should be instituted if PVR urine volume exceeds 200 mL and should be continued until PVR falls below 200 mL. Patients should be instructed to contact their physician if they experience difficulty in voiding, as catheterization may be required.
Are there any recommended limits on treatment duration with this medication?
There are no recommended limits on duration of treatment with this medication.
What happens following termination of treatment with this medication?
OnabotulinumtoxinA may be discontinued at any time. Any symptomatic benefits of the medication will abate over weeks or months.
What treatment options are available for patients who have been treated with OnabotulinumtoxinA?

Patients who have been treated with onabotulinumtoxinA may use a variety of oral medications for bladder spasticity. These medications may include anticholinergic/antimuscarinic agents such as oxybutynin, hyoscyamine, or propantheline. Patients may also utilize self-catheterization or indwelling catheters, including suprapubic catheters.

What is the washout period?
The half-life of onabotulinumtoxinA is not known because of the inability to detect onabotulinumtoxinA molecules in the peripheral blood following intramuscular injection at the recommended doses.
How can the provider identify a suboptimal treatment response?

In the clinical trials patient were required to experience a minimum of 14 episodes of UI per week. The average was 32–36 episodes per week in the trial patients. The mean change at week 6 was a reduction of 19.4 episodes per week. Patients who do not have a significant reduction in incontinence episodes may be considered suboptimal responders.

Is the manufacturer/distributor offering any financial assistance program for patients?
Allergan Pharmaceuticals offers Botox Reimbursement Solutions to help manage the reimbursement process. The website is BOTOXReimbursementSolutions.com. Botox Reimbursement Solutions can also be reached by telephone at 1-800-44-BOTOX, option 4. Reimbursement Business Managers are available for on-site education, training, and support. Currently reimbursement strategies directly related to the bladder indication are being developed.
Are there any special considerations with this medication?
There is an FDA black box warning for onabotulinumtoxinA that relates to the distant spread of the toxin effect.
COMMENTARY BY AUTHORS

Botulinum toxin products are not interchangeable. The potency units of Botox are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botunlinum toxin products and, therefore, units of biological activity of Botox cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method.

WEB LINKS PROVIDED IN THIS DOCUMENT

AUTHORS:

Michael Kaufman, MD, Amy Perrin-Ross, APN, MSN, CNRN, MSCN, Michael Kennelly, MD
EDITOR:
Rosalind Kalb, PhD
DISCLAIMER:
The Emerging Therapies Collaborative is proud to be a source of information about multiple sclerosis. Our comments are based on published data and expert opinion, but do not represent individual therapeutic recommendations or prescriptions. For specific information and advice, consult your physician.
FOR DISCLOSURES AND OTHER INFORMATION:
Please visit our website at http://www.ms-coalition.org/emergingtherapies or email us at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .
For additional information, healthcare professionals are invited to email the National MS Society's Professional Resource Center at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .
Last Updated on Monday, 15 April 2013 15:47