Botox (OnabotulinumtoxinA) Now FDA Approved for Overactive Bladder

Special Feature Fifth Annual Payers' Guide to New FDA Approvals March 2014 Volume 7 - Payers' Guide
Loretta Fala
Medical Writer
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Overactive bladder (OAB), a condition characterized by urinary urgency, frequency, nocturia, and urgency incontinence, affects an estimated 33 million people in the United States.1,2 In fact, as many as 30% of US men and 40% of US women experience symptoms of OAB.2 The prevalence of OAB is likely underestimated, given that many individuals suffering from OAB may not seek help because of embarrassment or a lack of knowledge about OAB.2

Many conditions may contribute to the symptoms of OAB, including neurologic disorders (ie, Parkinson’s disease, stroke, multiple sclerosis), elevated urine production (ie, high fluid intake, poor renal function, or diabetes), medications that increase urine production, bladder abnormalities, enlarged prostate, and excess consumption of alcohol or caffeine.3

Although OAB can occur at any age, elderly patients have an increased risk for OAB.3 However, OAB should not be considered a natural and unavoidable consequence of aging.3 Several approaches are currently available to help improve outcomes for patients with OAB.

OAB has a considerable impact on a patient’s comorbid conditions, as well as the physical, social, psychological, and other aspects that affect the patient’s quality of life. Overall, patients with OAB may experience major disruptions in their lives, with an increased risk for emotional distress, depression, sleep disturbances, and interrupted sleep cycles.3

OAB is also associated with substantial healthcare costs and quality-of-life sequelae.4 The results of a 2009 study showed that the total annual direct cost for common symptoms of OAB in the United States was $22.3 billion, and the cost for infrequent symptoms of OAB was $33.5 billion.5 Perhaps surprising, the costs were higher in younger adults aged <65 years compared with older adults aged ≥65 years.5 One claims-based analysis showed a nearly 5-fold greater annual cost for patients with OAB than for patients without the condition ($5018 vs $1767, respectively).4,6

The treatment of OAB generally involves a combination of treatment strategies.3 According to the American Urological Association (AUA) 2012 treatment guideline for nonneurogenic OAB, “Successful treatment of OAB symptoms with behavioral approaches, anti-muscarinic medications, neuromodulation therapies, and onabotulinumtoxinA, balanced against adverse events, costs and ultimately patient compliance, all have been reported to improve patient quality of life.”1 This AUA guideline recommends that providers review the specific discussion section for each of the treatment types mentioned in the guideline.1

Treating OAB at an early stage may improve patient care and reduce overall healthcare resource utilization; more research is needed on long-term costs, as well as the pathogenesis of OAB-related conditions.7

A New Treatment Option for Patients with OAB

On January 18, 2013, the US Food and Drug Administration (FDA) approved an expanded indication for Botox (onabotulinumtoxinA)—an acetylcholine release inhibitor and a neuromuscular blocking agent—for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and frequency in adults who do not tolerate or do not adequately respond to anticholinergic agents.8 The approval of onabotulinumtoxinA was based on 2 clinical trials of 1105 patients who had symptoms of OAB.8

According to Hylton V. Joffe, MD, Director of the Division of Reproductive and Urologic Products at the FDA’s Center for Drug Evaluation and Research, “Clinical studies have demonstrated Botox’s ability to significantly reduce the frequency of urinary incontinence. Today’s approval provides an important additional treatment option for patients with overactive bladder, a condition that affects an estimated 33 million men and women in the United States.”8

OnabotulinumtoxinA was previously approved by the FDA for several other indications in adults, including the treatment of urinary incontinence resulting from detrusor overactivity associated with a neurologic condition, prophylaxis of headaches in patients with chronic migraines, the treatment of upper-limb spasticity, the treatment of cervical dystonia, the treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents, and the treatment of blepharospasm that is associated with dystonia and strabismus in patients aged ≥12 years.9

Mechanism of Action


OnabotulinumtoxinA blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine.9 The injection of onabotulinumtoxinA into the bladder wall (the detrusor muscle) relaxes the bladder, increasing its storage capacity and reducing urinary incontinence episodes.8

Dosing and Administration

OnabotulinumtoxinA is available as single-use, sterile 100-unit or 200-unit vacuum-dried powder for reconstitution only with sterile, nonpreserved 0.9% sodium chloride injection USP before injection.9 The recommended total dose for OAB is 100 units, as 0.5-mL (5 units) injections across 20 sites into the detrusor muscle (ie, bladder wall). A total dose of 360 units should not be exceeded in a 3-month interval.9

The injection of onabotulinumtoxinA is administered via a cystoscope procedure that allows visualization of the bladder interior during the injection. A local anesthetic (with or without sedation) may be used before injection. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.9

Patients must not have a urinary tract infection (UTI) at the time of treatment. Prophylactic antibiotics, except aminoglycosides, should be administered 1 to 3 days before treatment, on the treatment day, and 1 to 3 days after treatment to reduce the risk of procedure-related UTI. Patients receiving antiplatelet therapy should discontinue antiplatelet agents at least 3 days before the administration of onabotulinumtoxinA injection. These patients should also be managed appropriately to decrease the risk of bleeding.9

Clinical Trials

The safety and efficacy of onabotulinumtoxinA for OAB were studied in 2 double-blind, placebo-controlled, 24-week trials with patients with OAB and symptoms of urge urinary incontinence, urgency, or frequency (Studies OAB-1 and OAB-2). These patients, whose symptoms were not adequately managed with anticholinergic therapy (ie, inadequate response or intolerable side effects), were randomized to receive either 100 units of onabotulinumtoxinA (N = 557) or placebo (N = 548). All patients received 20 injections of the study drug (5 units of onabotulinumtoxinA) or placebo, spaced approximately 1 cm apart into the detrusor muscle.9

The results of Study OAB-1 are shown in Table 1. At week 12, patients receiving onabotulinumtoxinA experienced urinary incontinence an average of 1.6 fewer episodes daily than patients who received placebo.9



In Study OAB-2 (Table 2), at week 12, patients in the onabotulinumtoxinA group experienced urinary incontinence an average of 1.9 fewer episodes daily than patients in the placebo group.9



Safety

The most common adverse reactions reported in clinical trials that were reported in ≥5% of the patients using onabotulinumtoxinA (and occurred more often than with placebo) for OAB include UTI, dysuria (ie, painful urination), and urinary retention.9

However, onabotulinumtoxinA is potentially associated with serious risks and must be used with caution, according to the warnings and precautions noted below.

Contraindications
OnabotulinumtoxinA is contraindicated in persons who are hypersensitive to any botulinum toxin preparation or to any of the components in the formulation, or in persons who have an infection at the proposed injection site. In individuals receiving intradetrusor injections, onabotulinumtoxinA is contraindicated in persons with a UTI or with urinary retention.9

Boxed Warning

OnabotulinumtoxinA was approved by the FDA with a boxed warning about the risk for distant spread of toxin effect, noting that this agent may affect areas away from the injection site to produce symptoms consistent with botulinum toxic effects, which have been reported hours to weeks after injection. Swallowing and breathing difficulties associated with this agent can be life-threatening, and there have been reports of death. The risk for symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in patients who have an underlying condition that would predispose them to these life-threatening symptoms.9

Warnings and Precautions


Patients receiving concomitant onabotulinumtoxinA and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like agents), or muscle relaxants, should be observed closely, because the effects of onabotulinumtoxinA may be potentiated.

Swallowing and breathing difficulties caused by the spread of toxin effects can lead to death. Immediate medical attention should be sought if respiratory, speech, or swallowing difficulties occur with the use of this agent.

The potency units of onabotulinumtoxinA are not interchangeable with other preparations of botulinum toxin products.9

Use in Specific Patient Populations

OnabotulinumtoxinA should be used with caution in patients with compromised respiratory function.

The presence of a concomitant neuromuscular disorder may exacerbate the clinical effects of treatment with onabotulinumtoxinA and should be carefully considered.

Because onabotulinumtoxinA increases the incidence of UTI, clinical trials for OAB excluded patients with more than 2 UTIs in the preceding 6 months and patients taking antibiotics chronically for recurrent UTIs. The use of onabotulinumtoxinA for the treatment of OAB in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk.

Postvoid residual urine volume should be monitored in patients who are receiving treatment for OAB or for detrusor muscle overactivity associated with a neurologic condition who do not catheterize routinely, particularly patients with multiple sclerosis or diabetes mellitus.9

Conclusion

Another therapeutic option for OAB became available in 2013 when the FDA approved an expanded indication for onabotulinumtoxinA to treat adults with symptoms of urge urinary incontinence, urgency, or frequency, who have an inadequate response to or are intolerant of anticholinergic agents. OnabotulinumtoxinA is administered via injection into the detrusor muscle.

The safety and effectiveness of onabotulinumtoxinA were demonstrated in 2 clinical trials involving more than 1100 patients with symptoms of OAB. At 12 weeks, patients who received onabotulinumtoxinA had an average of 1.6 to 1.9 fewer urinary incontinence episodes daily than patients receiving placebo. Moreover, patients in the onabotulinumtoxinA group needed to urinate an average of 1 to 1.7 fewer episodes daily and voided an average of approximately 30 mL more urine than patients in the group receiving placebo. The most common adverse events (≥5% and greater than with placebo) associated with the use of onabotulinumtoxinA in the treatment of OAB were UTI, dysuria, and urinary retention.

References

  1. Gormley EA, Lightner DJ, Burgio KL, et al. American Urological Association (AUA) guideline: diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. Approved May 2012. www.auanet.org/common/pdf/education/clinical-guidance/Overactive-Bladder.pdf. Accessed July 18, 2013.
  2. Urology Care Foundation. Overactive bladder (OAB). Updated March 2013. www.urologyhealth.org/urology/index.cfm?article=112. Accessed July 21, 2013.
  3. Mayo Clinic staff. Overactive bladder: treatment and drugs. January 16, 2013. www.mayoclinic.com/health/overactive-bladder/DS00827/DSECTION=treatments- and-drugs. Accessed July 22, 2013.
  4. Mullins CD, Subak LL. New perspectives on overactive bladder: quality of life impact, medication persistency, and treatment costs. Am J Manag Care. 2005;11(4 suppl):S101-S102.
  5. Onukwugha E, Zuckerman IH, McNally D, et al. The total economic burden of overactive bladder in the United States: a disease-specific approach. Am J Manag Care. 2009;15:S90-S97.
  6. Zhou Z, Jensen GA. Insurance claim costs for overactive bladder disorder. Medscape Today News. 2001. www.medscape.com/viewarticle/409985. Accessed July 23, 2013.
  7. Hu TW, Wagner TH. Health-related consequences of overactive bladder: an economic perspective. BJU Int. 2005;96(suppl 1):43-45.
  8. US Food and Drug Administration. FDA approves Botox to treat overactive bladder. Press release. January 18, 2013. Updated January 22, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336101.htm. Accessed July 15, 2013.
  9. Botox (onabotulinumtoxinA) for injection [prescribing information]. Irvine, CA: Allergan, Inc; January 2013.
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