Therapeutics Q&A

August marks the one-year anniversary of FDA's approval of Botox (onabotulinumtoxinA) injection to treat urinary incontinence in people with neurologic conditions, such as spinal cord injury and multiple sclerosis who have overactivity of the bladder. Uninhibited urinary bladder contractions in people with some neurological conditions can lead to an inability to store urine. Traditionally, other therapy options have included medications to relax the bladder and use of a catheter to regularly empty the bladder. Here, Practical Neurology speaks to a urologist and neurologist about the use of the drug.

How does Botox work for the management of incontinence? How long is Botox effective? Is there any limit on how many times the procedure can be repeated?

Botox is approved by the FDA for injection into the bladder muscle to treat leakage of urine (incontinence) in adults 18 years and older with overactive bladder due to a neurologic condition, such as multiple sclerosis (MS) or spinal cord injury (SCI), who still have leakage or experience too many side effects after trying an anticholinergic medication.

“Botox works by decreasing the inappropriate contractions of the detrusor muscle. This limits the force generated by the bladder wall during involuntary, or reflex, contractions of the bladder wall. The benefit lasts 42 to 48 weeks and may be repeated,” said Richard Dubinsky, MD, MPH, Professor of Neurology at the University of Kansas Medical Center in Kansas City.

Michael J. Kennelly, MD, FACS, Director, Charlotte Continence Center, Co-Director, Women's Center for Pelvic Health, Charlotte, NC said Botox works in two ways:

1.) It reduces activity in the bladder muscle by reducing bladder contractions, which can help:

• Reduce leakage episodes
• Increase the amount of urine the bladder can store
• Decrease the pressure in the bladder, as high bladder pressure can cause urine leakage

2.) It is believed to reduce nerve signals coming from the bladder that tell the nervous system that the bladder is full. Calming the hypersensitive nerves may also help reduce leakage episodes.

“Patients should be considered for retreatment with Botox when the clinical effect of the previous treatment wears off. In clinical trials, Botox has been proven to be effective for about 10 months,” Dr. Kennelly said. While a maximum has not been determined on the number of times the Botox procedure can be repeated, the procedure was repeated in the clinical trials and literature has reported approximately seven years of repeat injections with Botox.

When would a urologist consider administering Botox for urinary incontinence, and in light of this, when should neurologists consider referral?

Dr. Kennelly noted there are approximately 2.5 million men and women in the US with a neurologic condition such as MS, SCI, Parkinson's disease, or stroke who have urinary incontinence. A survey, he said, has shown that many patients are undiagnosed and undertreated, “Therefore, these patients generally don't get referred to a urologist who can diagnose and manage urinary incontinence due to overactive bladder in people with neurologic conditions.”

The current standard of care includes anticholinergic medications that need to be taken regularly, “however, it is estimated that 71 percent of people stop taking at least one anticholinergic medication within 12 months, either because the medication is not working for them or they cannot tolerate the side effects,” Dr. Kennelly says. For those patients, other options may be available through a urologist, including Botox.

Botox has been studied for safety and efficacy and can be administered by a urologist directly into the bladder in the doctor's office or a hospital setting, depending on the urologist and patient's preference, Dr. Kennelly said.

What kind of results can patients expect? How does dosing work? When might general anesthesia be required?

“The expected benefit is a decrease in the frequency of urinary incontinence, and the ability to regain a normal period of time between trips to the bathroom for elimination,” Dr. Dubinsky said.

Botox was studied in people living with MS and SCI with urinary incontinence due to detrusor overactivity who still had leakage or experienced too many side effects after trying an anticholinergic medication. “In the Phase III clinical studies, Botox patients had about 22 fewer leakage episodes each week—compared to about 13 fewer for placebo,” Dr. Kennelly said. Before treatment with Botox, patients in these studies had an average of 32 leakage episodes each week, he said, adding that Botox is approved as a 200U dose for patients with urinary incontinence.

The procedure can be performed without anesthesia, under local anesthesia, or under general anesthesia. “General anesthesia might be required when there is hip adductor spasticity so severe that cystoscopy can't be otherwise performed,” Dr. Dubinsky said.

Common adverse events are urinary tract infection and urinary retention. Is there a patient profile that lends itself to be more likely to suffer these side effects, or is there anything physicians can do to better prevent or monitor them?

Dr. Kennelly mentioned that during the clinical trials for Botox, the most common side effects reported within the first 12 weeks were urinary tract infection (24 percent), urinary retention (17 percent), hematuria (four percent), fatigue (four percent), and insomnia (two percent). “These were the most common adverse events seen in the clinical studies, but it's important for patients to talk to their doctor about all the potential side effects to evaluate whether Botox might be an option,” he said. Full Botox Product Information, including Boxed Warning and Medication Guide, can be found at www.botoxforincontinence.com.

In the clinical trials there was a higher incidence of urinary tract infection (UTI) and de novo clean intermittent catheterization in the patients who were not already catheterizing prior to treatment with Botox. “To minimize risk of UTI, urologists give pre- and post-operative antibiotics to help prevent UTI around the time of the Botox procedure. For patients not catheterizing at the time of the Botox procedure, it is important for urologists to follow up within two weeks to observe and monitor the patient for UTI or incomplete bladder emptying,” Dr. Kennelly said.

“To prevent urinary tract infection, non-aminoglycoside antibiotics should be given one to three days before the injections of Botox, the day of injection and one to three days after injection,” according to Dr. Dubinsky. “If there is a large post void residual, intermittent urinary catheterization can be used to more fully empty the bladder, decreasing the risk of urinary tract infection and treating the urinary retention.”

Is Botox used as monotherapy or might other incontinence therapies still be used in combination?

Botox can be used as a monotherapy or in combination with anticholinergic therapy, Dr. Kennelly said. Botox therapy does not preclude anticholinergic therapy for patients. In research trials for Botox, approximately 35 percent of patients were also using anticholinergics.

How are cystoscopic botulinum toxin A (Botox) injections into the bladder billed and reimbursed?

“Botox is generally well covered by public and private payers. The costs to the patient vary depending on health plan coverage,” Dr. Kennelly said.