The switch to OTC: Are urologic drugs next?

Roger Dmochowski, MDSwitching a medication from prescription to over-the-counter status comes with challenges and risks, and is not always successful. In this interview, Roger Dmochowski, MD, discusses the pros and cons of OTC medications and explains the hurdles facing potential OTC products for urologic conditions. Dr. Dmochowski is professor of urology and gynecology at Vanderbilt University Medical Center, Nashville, TN. He is a prior member of the FDA Bone, Reproductive and Urologic Drugs Advisory Committee. He was interviewed by Urology Times Emeritus Editorial Consultant Philip M. Hanno, MD, MPH, clinical professor of urology at Stanford University School of Medicine, Stanford, CA.

Please describe your work with the FDA.

For the last 25 years, I have been involved in assessment of phase I trials, phase II and phase III study design and conduct, as well as regulatory assessment and oversight thereof through the FDA. I have kept up with a lot of the recent changes and evolving treatment concepts, especially around benign functional urology, which has to do with symptomatic conditions and how best to measure outcomes from the objective and the patient-reported outcome (PRO) standpoint. I’m happy to say that I was involved in the recent development of a drug, desmopressin nasal spray (Noctiva), where the development process included the use of a novel PRO instrument.

Forty percent of all over-the-counter drugs in the U.S. today were once prescription drugs. Most OTC products are not covered by insurance, resulting in higher out-of-pocket costs. Some of this cost increase is balanced by reduced medical service use and less time away from work. What are your thoughts on this conundrum?

There is relative value to some products being OTC. Certainly, given the current constraints in development and what is asked of a switch from prescription to OTC status, I find the controls to be very interesting, specifically because they are so patient-centric. One of the concerns when anything goes OTC is how it is really going to be used if it’s put into the public domain. Patient safety is critical, as is the importance of patient literacy concerning the condition being treated and also the formulation being taken.

Increases in medical service use following prescription-to-OTC switches may reflect product substitution. The absence of insurance coverage for OTC products may induce some individuals to seek covered prescription substitutes, resulting in more physician visits to obtain new prescriptions or failure to take any medicine at all. What are your thoughts on this?

I think that is a valid concern. One of the things that OTC medications allow is essentially a presumptive trial for management of a person’s condition. As an example, I started using, unfortunately, quite a bit of OTC anti-reflux treatments just because I didn’t want to have an esophagogastroduodenoscopy. I believe the potential for inappropriate use of OTC agents exists and their use potentially could increase costs. But I also think from the standpoint of patient-centric decision-making and patient involvement in care, the OTC availability of some drugs is a very reasonable option.

Next: "Self-selection is one of three cardinal aspects of the OTC switch process"

Let’s focus on urology. An OTC drug has to be safe, effective, and treat a condition that the patient can recognize and manage without the supervision of a licensed health care provider. What urologic conditions lend themselves to these parameters?

The one that we have the most recent experience with is overactive bladder, which is a symptom syndrome that involves urgency frequency and urge incontinence, which are patient-perceived symptoms. We put a lot of regulatory constraints on how we measure that condition when we do trials that result in regulatory approval for prescription branding. But for OTC, those controls are different and then the decision to take a drug defers to the patient to make a decision based upon their symptoms.

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You allude to something that’s a key part of the OTC process, which is the ability to appropriately self-select. Self-selection is one of three cardinal aspects of the OTC switch process and one that essentially gets at the patient’s level of comprehension of symptoms but also their level of medical literacy. Medical health literacy is something that I’ve been very interested in the last several years, mainly as a way to improve informed consent around risks/benefits and potential options.

What we deal with in pelvic medicine are very complicated conditions. Self-selection is a critical aspect of the success and safety of the OTC switch, and there are controls and algorithms in place to not only assess patient literacy but also to assess the individual’s ability to appropriately self-select based upon the labeling of the drug.

The other aspects of the switch process include the ability to understand the label (label comprehension), and lastly, stop or do not use criteria (centering on co-morbidities and other issues that could result in delayed diagnosis that may put the individual at risk).

Let’s discuss the large overactive bladder market. Are there any OTC drugs for overactive bladder currently available in the U.S.?

No. Transdermal oxybutynin, marketed as Oxytrol for Women when it was switched to an OTC drug, is no longer available. OTC Oxytrol for Women was removed from the market because it was not a commercial success. Rightfully so, there were constraints regarding hematuria and how that should be assessed and recurrent urinary tract infections and how that should be assessed, and it became a relatively complicated process.

Despite the efforts of a very experienced group of people who had done multiple OTC switches very successfully in the past and knew the process, the commercial failure was probably due to the complexity of self-selection and also due to the fact that the drug had a just-above-placebo effect and patients probably didn’t perceive enough benefit to stay with it.

I was very much involved in the clinical trials for the regulatory approval of the prescription version of Oxytrol. Statistically, the transdermal delivery system worked. Patients had less dry mouth than those taking the oral formulation, and they separated from placebo. But one of the interesting phenomena that we deal with in functional medicine is that statistical superiority does not necessarily imply clinically meaningful benefit for individuals. This is the conundrum of clinical trials.

Should we be concerned about Brody and Light’s inverse benefit law stating that, as a drug is promoted for milder cases of a disorder or used for unapproved conditions, which can happen in the OTC market, the benefit/harm ratio worsens because effectiveness is diluted but the risks of harm are the same?

That brings up a very interesting part of the OTC process as far as I’m concerned, which is the labeling. Labeling is supposed to inform the individual when to use, when not to use, when to contact a physician, and what aspects of their particular presenting scenario should or shouldn’t be considered for the drug. But, again, you’re giving the individual consumer a box that has labeling at a sixth-grade reading level that they should intellectualize and understand.

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Ultimately, you’re giving them the decision about whether or not they should use it in an unapproved circumstance. It comes down to that decision.

Next: Actual-use studies

One of the other important aspects of OTC switches is the actual-use study, where the compound, although it has been very well studied, is put in various public domains, such as pharmacies or malls. Patients are asked to come back after a 2-week time frame and asked if they used the drug appropriately and, if not, why not?

Overactive bladder is a tricky condition. You can get urgency and frequency associated with urinary tract infection. You can get urgency and frequency associated with dietary ingestion of some liquids and food stuffs in some patients. There probably was some blunting of effect because of dispersal in the general population.

When I look at other available OTC products that are used by patients with overactive bladder, the best are the azo-based products, such as Azo-Gantrisin. Patients take those frequently for urgency/frequency and obviously they have a urinary tract suppression indication, not urgency/frequency.

When I worked at the FDA in 1999, terazosin was considered for an OTC switch for outlet obstruction and it went nowhere. What about the more selective alpha-blockers that are off patent now?

The concern with alpha-blockers is the potential for either postural blood pressure changes and/or hypotensive effects, which are very limited but still in the label, even of the very selective alpha-blockers. Another concern in the general population that may not have been as adequately screened as clinical trial populations relates to patients with more marginal cardiac or vascular status. If one of these drugs enters the OTC world, there is a risk of exacerbation of syncopal episodes and other concerns associated with it, even though these agents are super selective.

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Tamsulosin is probably the closest of these agents to being considered for OTC status. Again, however, from our clinical results with tamsulosin, we know that some patients may have postural hypotension or at least near-syncopal episodes that may or may not be due to hypotension. Ejaculatory dysfunction is also a concern, but is less of a threat.

Are 5-alpha-reductase inhibitors good candidates for OTC?

The overall side effects are relatively low with 5-alpha-reductase inhibitors. Obviously, the more prominent ones are the sexual side effects. There are some issues with fluid retention associated with them. Also, they’re not the most pleasant drugs to take. The potential for onset of gynecomastia associated with them can be very embarrassing. Although those effects are not life or limb threatening, they are not exactly things that people are happy to encounter.

Next: What are the potential roadblocks to OTC status for PDE-5 inhibitors?

The big elephant in the room is the fact that the PDE-5 inhibitors have either come off patient or will be shortly. What is their status and what are the potential roadblocks to OTC status?

The PDE-5 inhibitors all remain prescription drugs. Generic versions of Viagra are being launched. We all know that PDE-5 inhibitors have some potential side effects-visual and auditory side effects-that occur in a very small percentage of patients but could be problematic if exposed to the general population. The real question concerns the stochastic use associated with erectile dysfunction versus a continual daily dose of Cialis, for instance, which is approved for daily-dose use for voiding dysfunction as well as erectile dysfunction.

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We understand the mechanistics of the PDE-5 inhibitors for causing vasodilation, but if you functionally look at how they work, patients subjectively are better but there is no urodynamic correlate to that. Yes, there’s a slight improvement in flow rate, but you see no change in bladder contraction capabilities or bladder emptying. Some very interesting work done recently suggests that the PDE-5 effect, which can be a very significant subjective effect for some individuals, actually results from a spinal cord reflex mechanism (at least in rodents.)

Is there a possibility that they could be pushed for OTC use? Sure. The public certainly is aware of the class and certain agents in the class, and I think the public has had a recently positive experience with the PDE-5 inhibitors. But, again, because of the lack of true understanding of effect and the potential for both visual and auditory concerns, I think it’s going to be a bit of a safety hurdle.

There’s certainly been a lot of education directed to the public, but what about the nitrate issue?

The cardiac issue and the use of these drugs with nitrates is a substantial issue, and I think even experienced patients have trouble understanding that. So there will be a very significant self-selection concern.

Zithromax is available over the counter in the UK and Hiprex is available over the counter in Denmark. Do you see urinary antiseptics or antibiotics for UTI ever going OTC in the U.S.?

I say this self-ashamedly as a urologist, but we haven’t done a good job with institutionalizing treatment for urinary tract infections. A whole generation of physicians coming out of medical school don’t even understand the basics of urinary tract infection. We see a lot of overuse and abuse of antibiotics. We’re in a time of increasing antibiotic stewardship because of concerns related to antibiotic side effects. I personally have encountered quinolone-induced bacterial overgrowth, colonic bacterial overgrowth, and the sequelae of that.

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The antiseptics and acidic agents such as methanamine hippurate may potentially provide a benefit for individuals who are prone to recurrent infections and are trying to self-medicate. The issue with methanamine hippurate concerns renal function and patients’ understanding of that. There are many people who don’t understand how bad the effect on renal functions is, and I think that’s critical.

Next: "To put an anabolic steroid or an agent that has anabolic steroid-like effects in the OTC world would, in my opinion, be a significant risk for patients"

Are there any herbal remedies like saw palmetto or testosterone-like substances that you feel should not be freely available?

Herbal remedies are available and used frequently by patients for urinary tract consideration. The most recent “herbal supplements” getting some play have been the cranberry extracts. Patients ingest them maximally.

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I’ve served on the FDA advisory panels related to testosterone use, and I have grave concern about products that have anabolic effects and the general public’s relative lack of appreciation of those negative effects. Unfortunately, anabolic steroids have received a lot of positive play from the body building community and there’s been a fair amount of promotion of anabolic steroids for male health issues and male andropause.

To put an anabolic steroid or an agent that has anabolic steroid-like effects in the OTC world would, in my opinion, be a significant risk for patients in terms of the downstream effects on the blood, liver, and cardiovascular system.

“Behind the counter” is not a standard classification for drugs in the U.S. but is a category in Canada and the UK. Do you think that in some gray areas, there would be a place for behind-the-counter drugs empowering the pharmacist for some urology medications in the U.S.?

I think that’s coming as we see greater involvement of pharmacists in ambulatory care. We’re seeing that with the advent of the various clinics in the larger pharmacy chains, and more importantly, the empowerment of pharmacists to actually go out from behind the counter and advise and help patients make selections. I think it’s a natural outgrowth of the expansion of registered pharmacists and their perceived role.

Could it be done in a way that’s safe and reasonable? Yes, I think it could be. In essence, we’re already doing that with some of the decongestant medications because of concerns not so much about the medication for individual use but the use of the medication for illicit purposes.

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