Oxytrol Switch For OAB Surfaces Questions On Delayed Diagnoses

Merck’s application to switch the overactive bladder drug Oxytrol for Women must prove to FDA’s OTC advisors that women suffering urinary incontinence due to urinary tract infections, diabetes or other conditions appropriately can discontinue treatment and seek medical attention.

FDA appears to accept that women can safely use the proposed transdermal nonprescription overactive bladder drug Oxytrol for Women in an OTC setting, but has concerns that consumers suffering from other underlying conditions may delay seeking treatment.

Sponsor Merck & Co. Inc. now must prove to FDA’s Nonprescription Drugs Advisory Committee that the drug’s users can appropriately discontinue Oxytrol use and seek medical attention should their symptoms fail to improve after the indicated period.

The agency’s briefing materials regarding Merck’s proposed switch of Oxytrol (oxybutynin transdermal system 3.9 mg) acknowledge that female consumers experiencing urinary incontinence may have a urinary tract infection, diabetes or bladder cancer, or may be pregnant.

“However, it is important to note that consumers with these conditions may also have OAB and, therefore, may benefit from use of oxybutynin,” FDA says in the materials posted Nov. 7.

Merck's proposed Oxytrol for Women OTC labeling

Image courtesy of FDA

Merck, which licensed the OTC rights to Oxytrol from Allergan PLC, will present its case for the switch to FDA’s OTC advisory panel Nov. 9 in Silver Spring, Md.

Merck’s proposed label for OTC Oxytrol instructs women to use the drug only after at least three months of OAB-like symptoms, and to see a doctor if they suspect their urinary incontinence may stem from something more serious than OAB. The firm suggests to FDA that this protocol could lead to earlier recognition and diagnosis of such conditions.

UTIs are common among women but associated with more acute and painful symptoms than OAB, which affects an estimated 20 million women in the U.S. In its briefing materials, Merck says of the women who developed UTIs during its three-month, 727-subject actual use trial for OTC Oxytrol, 98% appropriately discontinued use of the drug and sought consultation with a medical professional.

Type 2 diabetes also can be associated with increased urinary frequency. FDA notes that “it is important to determine whether there is a potential risk for delayed diagnosis of diabetes with use of the drug,” but acknowledges that Merck plans to address this issue in Oxytrol’s labeling.

Merck says increasing access to Oxytrol via its proposed OTC switch, along with the company’s planned education program regarding causes of urinary incontinence and behavioral management strategies, offer overall benefits that “outweigh the potential risk of delay in diagnosis of an underlying disease that produces OAB-like symptoms.”

As a transdermal patch, Oxytrol is regarded as better-tolerated than oral delivery forms and has a relatively benign record of adverse event reports. Merck submitted to FDA 604 AERs for the product since its U.S. launch in 2003, with 21% of those categorized as “general and administration site disorders,” 12% psychiatric disorders, 12% nervous system disorders and 8% gastrointestinal disorders.

“The reports do not identify any new safety signals that would prohibit use in the OTC setting,” FDA says.

NDAC Roster Surprises

Though NDAC Chairman Richard Neill is familiar with Merck from the firm’s unsuccessful attempts to switch the cholesterol drug Mevacor Daily, Neill will not attend the Oxytrol meeting, according to FDA’s draft meeting roster (Also see "Merck, NDAC Chair Neill Cross Paths Again For Oxytrol Switch Meeting" - Pink Sheet, 5 Nov, 2012.).

Instead, Marcus Reidenberg, a professor of pharmacology, medicine and public health at Weill Cornell Medical College, will act as chair. Reidenberg, whose research interests include reasons for individual differences in response to medications and barriers to the use of opioids for treating pain, previously served on NDAC from 1992 to 1995 and began his current term in December 2011.

Reidenberg has been a vocal proponent of expanding the availability of affordable OTC asthma products, given the respiratory disease’s prevalence among poor patients (Also see "Asthma Treatment OTC Switches Would Face Tough Barriers" - Pink Sheet, 19 Sep, 2011.).

In addition to five voting members of the standing committee, NDAC will have seven temporary voting members with expertise in urology, gynecology, mathematics and statistics, bringing the committee’s headcount to 12, according to the draft roster.

Up For Discussion

FDA’s draft questions to the committee seek discussion on possible safety concerns relating to delayed diagnosis of conditions with OAB-like symptoms, and the implications of actual use study subjects who used Oxytrol beyond the indicated two-week treatment period when their symptoms either did not improve or worsened.

According to Merck’s data, 14.4% of subjects failed to stop using the drug as directed when their symptoms did not improve, while another 3.4% failed to stop treatment even after their symptoms were mitigated.

Another question asks whether committee members are concerned about Merck’s label comprehension data, generated over the course of six studies, “given that some of the pre-specified endpoints were not met.”

Among normal-literacy subjects, 85.2% understood the label language indicating that consumers should not use Oxytrol unless they have had OAB symptoms for at least three months. Of low-literate subjects, 67.8% understood this part of the label, for an overall average of 84% comprehension – 1 percentage point short of the success threshold Merck had set.

Pregnant women, whom Oxytrol’s label directs to consult a physician before using, demonstrated some issues with label comprehension and self-selection, especially among the low-literacy cohort. While 92% of general population women indicated they would talk to a doctor before using the drug, only 68% of low-literate women did so.

“While low-literate pregnant women did not score well, the sample may have been atypical of low-literate subjects, since comprehension scores among low-literate women in another study were stronger,” Merck suggested.

The company also updated its proposed Oxytrol front-of-package graphics to present a slimmer female silhouette; an earlier, rounder version of the icon may have caused some study subjects to associate the drug with pregnant women, Merck said.

Merck’s label comprehension studies also evaluated men, who are excluded from OTC Oxytrol’s proposed audience since they can suffer incontinence due to enlarged prostate. In a study of 571 men with urinary symptoms, 90% correctly determined that Oxytrol for Women would be inappropriate for them to use, with those who self-selected incorrectly focusing on the label’s urinary symptoms indication rather than the gender-specific product name.

An earlier study of men that tallied just 72% for correct self-selection helped spur Merck to add “for women” to the Oxytrol name.

In light of its compiled study data, Merck estimates that, overall, “the Oxytrol Drug Facts label is about 80% to 95% effective in communicating key messages regarding self-recognition of OAB and product use.”

Campaign For Urinary Health

Ed Hemwall, Merck’s VP of Rx-to-OTC switch for research & development, said the gulf in time between NDAC switch meetings – the most recent being for Mevacor in December 2007 – could mean that “there are going to be people [on the committee] that aren’t familiar with OTC switch studies and the methodologies … and we’ll have a lot of questions and interest in the validity and the overall complexity of these types of studies.”

Hemwall, who also helped lead Merck’s Mevacor switch program, added that the company believes its proposed labeling for OTC Oxytrol will enable consumers to differentiate between symptoms of OAB and other conditions, while its planned web-based education campaign will help all women – even those who do not purchase Oxytrol – to learn more about urinary health.

Market analysts believe Oxytrol could go from an also-ran in the Rx OAB space to a potentially sizable success story as a first-in-class OTC. But Merck sees the switch as a broader boon for public health, helping to manage a condition that costs the U.S. an estimated $65.9 billion annually from lower worker productivity, job loss and early retirement.

The company points out that since the drug is generally well-tolerated and low-risk, adding OTC Oxytrol to existing self-management regimens would not exacerbate the risks related to other conditions associated with OAB-like symptoms.

[Editor’s note: This story was contributed by “The Tan Sheet,” which focuses on nonprescription pharmaceutical and nutritional industry news and provides in-depth coverage of Rx-to-OTC switch issues. For more information call 1-800-332-2181. To register for a free trial, click here – no credit card needed.]