Rectal diazepam eases instillation of nadofaragene firadenovec in NMIBC

In a retrospective analysis across Mayo Clinic sites, Mark D. Tyson II, MD, MPH, and colleagues evaluated whether rectal diazepam pretreatment could improve drug retention and reduce bladder spasms during nadofaragene firadenovec (Adstiladrin) instillation for patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC).¹ The study reviewed 88 instillations in 45 patients, 28% of whom received 10-mg rectal diazepam 15 minutes before treatment.

Compared with standard or no pretreatment, rectal diazepam reduced medication leakage by an absolute 25% (from 29% to 4%), corresponding to a 78% relative reduction in retention failure. Bladder spasms decreased from 56% to 32%—a 24% absolute and 68% relative reduction. Both improvements were clinically meaningful, facilitating more consistent one-hour dwell times, fewer interruptions, and reduced drug waste. One mild diazepam-related adverse event (fatigue) was reported, and no cases of oversedation or dizziness occurred.

Although a numerically lower 3-month high-grade recurrence rate (18% vs 38%) was observed among patients who retained the drug, this difference did not reach statistical significance. Tyson emphasized that the study was not powered for oncologic outcomes but suggested that better drug retention may plausibly improve efficacy.

From a workflow standpoint, the protocol is simple: A compounded 10-mg rectal diazepam suppository is administered by nursing staff 15 minutes before instillation. Tyson noted potential advantages in cost efficiency, treatment consistency, and patient experience.

Although the authors do not plan a randomized trial, Tyson said the magnitude of benefit justifies practice adoption for patients with significant spasms or leakage despite anticholinergics, with appropriate safety precautions for older patients or those with comorbidities.

Tyson is a urologic oncologist at Mayo Clinic in Phoenix, Arizona.

Urology Times: Please provide an overview of this paper and its notable findings.

Tyson: We looked at 88 nadofaragene firadenovec instillations in 45 patients with BCG-unresponsive non–muscle invasive bladder cancer across all 3 Mayo Clinic sites. About 28% of those patients had received 10-mg rectal diazepam given 15 minutes prior to the instillation, and the other 72% had received some variation on an alternative, such as an anticholinergic or nothing. Compared with an alternative or no pretreatment, those who received the rectal diazepam had an absolute improvement of about 25% in the ability to retain the medication, and that corresponds to about a 78% relative risk reduction in loss of the medication.

In terms of bladder spasms, those fell from 56% to 32%, which represented a 24% absolute reduction, with a 68% reduction in relative terms. Both of those observations were clinically significant, so those who received rectal diazepam had much less loss of the medication and fewer bladder spasms. We also looked at the 3-month high-grade recurrence rate. That was 22% overall for the whole cohort, and it was numerically higher after the initial retention failure, so 38% in those who were unable to hold the medication vs 18% in those who were. We don't really look at that too critically. There's not enough sample size to say too much about that, and it's also not statistically significant. But the effect size piques our interest.

The last component of this study was safety. There was one diazepam-related patient who had an attributable AE [adverse event], which was fatigue.

Urology Times: How clinically significant were the reductions in bladder spasms and retention failure that you observed, and how might these translate into improved real-world treatment outcomes?

Tyson: Nadofaragene is designed to be in the bladder for an hour, and if you have a spasm or leakage and you lose the medication, that could undermine the exposure and, plausibly, the efficacy. So, cutting the retention rate from 1 in 3 to 1 in 25 is clinically meaningful. I think patients complete that intended dwell time more reliably. Staff aren't troubleshooting leaks, and you're not needing to reprep or discard drug or reorder drug.

There are a number of logistical and operational efficiencies that occur when you can keep the medication in the bladder. Economically, this drug is expensive, and, I think there are questions about cost effectiveness at baseline. [However,] if you're not even able to deliver the drug for the time it needs to be delivered, and efficacy suffers as a result—and that's entirely theoretical, by the way—then I think avoiding waste in that context is not trivial. Lastly, [in the] patient experience, spasms equal pain, [so] fewer spasms means less discomfort and better acceptance of the maintenance therapy that typically goes on for a couple of years.

Urology Times: Were there any notable differences in patient tolerability or workflow logistics when using rectal diazepam compared with standard pretreatment approaches?

Tyson: In general, nadofaragene is well tolerated, [as is] rectal diazepam. We didn't see any oversedation; we didn't see any dizziness. One patient was a little tired the next day, but I would caution us a little on that, too, because this is a retrospective study, and sometimes the AEs are not reported. They're not collected systematically like they would be in a clinical trial. In terms of the workflow logistics, it's a simple, reproducible process. We get a 10-mg suppository gel supplied by the pharmacy. It is compounded. The nurse administers it 15 minutes before instillation. The nurses call the patient 3 or 4 days prior to confirm that they have an interest in the rectal diazepam and that they have a driver, because it's really important not to drive home after receiving a benzodiazepine, such as diazepam. The net effect is that there is minimal impact on the workflow, not a whole lot added to the chair time. It's a smoother instillation process, [with] fewer interruptions, fewer spasms, less leakage. Overall, it's an improved process.

Urology Times: Given that the reduction in 3-month recurrence did not reach statistical significance, how do you interpret that finding in the context of improved drug retention?

Tyson: Cautiously. We did observe a numerically lower recurrence rate when the first dose was retained, 18% vs 38%, but the study wasn't powered for oncologic end points, so my interpretation is that it improves retention. That could plausibly be an intermediary between better outcomes but confirming that causal link would require a larger prospective study with standardized retention assessments, PROs [patient-reported outcomes], and standardized end points.

Urology Times: How might these findings influence current clinical practice, particularly for urologists administering intravesical gene therapy in the outpatient setting?

Tyson: My pragmatic takeaway is that for patients who experience spasm or leak despite anticholinergics, this is a great thing to consider. Consider the 10-mg rectal diazepam preinstillation process. Some pharmacies don't have the ability to make it, so you might have to send the patient with a prescription [that they can] bring to their appointment. [However,] there are a lot of compounding pharmacies that will do this for patients. Our experience with anticholinergics wasn't very good. That's why this whole process was initiated to begin with, because we were noticing a lot of loss in the medication...and there are some prior randomized data with oxybutynin to show limited benefit and more AEs with oxybutynin. We think that the benzodiazepine–mediated smooth muscle relaxation might be helpful in this context. But in terms of implementation, it's easy to pilot. Either talk to your pharmacist about supplying it or ask the patient to go to a compounding pharmacy to bring it to their appointment. Make sure you have the nurses call the patients and discuss [their need to get a ride to and from the procedure]. If you've already done that in the clinic, that may not be necessary. That's our workflow, but that's not necessarily generalizable to others. Also, you have to be careful about sedation in the older population and have a keen eye on dizziness as they're getting up, etc.

Urology Times: What do you see as the next step in validating these findings; for example, a prospective, randomized trial, standardized pretreatment protocols or pharmacologic comparisons?

Tyson: The question is one of cost: Who's going to pay for a randomized trial in this setting? I can tell you that we don't currently have plans to do a randomized trial. The effect size was so large in our experience that we felt like that was enough to justify a change in practice without prospectively confirming the exact effect size. [However,] that would be the next step if you wanted to do that, which would be to characterize the value of rectal diazepam in this setting vs standard anticholinergic or something else. End points in that trial could look like retention failure and spasm incidence, and secondary end points could look like landmark high-grade recurrence rates and PROs, staff interruption, drug waste, etc. For us, we've essentially just harmonized the timing and dosing and monitoring in our own practices without the prospective data.

Urology Times: Are there any safety concerns or patient selection factors that urologists should keep in mind before considering rectal diazepam pretreatment for intravesical therapy?

Tyson: There's certainly no driving the day of treatment. It's usually not the case that people have alcoholic beverages prior to their intravesical therapy, but they shouldn't do that either. You should obviously have some caution if they're on concomitant drugs that might depress their central nervous system. Probably should also avoid using this approach in patients who have benzodiazepine allergies, severe respiratory insufficiency, untreated sleep apnea, hepatic impairment, a history of benzodiazepine misuse, or concomitant anxiolytics. Those might be some cautionary situations. We are also pretty cautious with older patients. Overall, observed safety was favorable, and broader adoption is justified based on what we've observed.

REFERENCE

1. Moyer JA, Durant AM, Nguyen MV, et al. Use of rectal diazepam to prevent bladder spasms and leakage of medication during intravesical administration of nadofaragene firadenovec for Bacillus Calmette-Guérin-unresponsive nonmuscle-invasive bladder cancer. J Urol. 2025;214(4):393-399. doi:10.1097/JU.0000000000004658