Oral pentosan polysulfate (PPS; Elmiron) was approved by the FDA for the treatment of interstitial cystitis in 1996. PPS and intravesical dimethyl sulfoxide (DMSO) remain the only 2 FDA approved treatments of this disorder. At the Emory Eye Center, between May 2015 and October 2017, 6 adults evaluated by a single clinician were noted to have a unique pigmentary maculopathy in the setting of chronic exposure to PPS¹. Thirty-eight patients were identified during that period who reported active use of PPS, the 6 patients constituting 16% of this group. The affected patients reported a median of 186 months of exposure to a standard dosing regimen; their symptoms included difficulty reading and prolonged dark adaptation. Specific fundus and retinal imaging findings were found. Nickel and Moldwin² in a comment on this issue remarked: “It is quite unlikely that urologists treating patients with IC/B PS would ever have made this association… yet the implications are either frightening if our treatment is causing this condition or instructive if this condition is a previously unknown manifestation of IC/BPS”. Philip Hanno, an acknowledged expert in the field of IC, chose the article from Pearce et al on PPS as the major news story of 2018 in his area for the weekly Urology Update Series. The Emory group presented in 2019 at the annual meeting of the AUA, a new study of 10 patients who had been on chronic PPS therapy with similar macular disease, also noting that they had seen 156 patients with IC/BPS who had no PPS exposure and who had no pigmentary maculopathy. Subsequently, many articles, most in the Ophthalmology literature, have appeared on the subject, and the association, however uncomfortable to us as urologists, now seems definite.

Janssen Pharmaceuticals sent a “Dear Healthcare Provider” letter dated July 24, 2020, which stated: “Cases of pigmentary changes have been reported with long-term use of Elmiron. Although most of these cases occurred after 3 years of use or longer, cases have been seen with a shorter duration of use. While the etiology is unclear, cumulative dose appears to be a risk factor. Visual symptoms in the reported cases included difficulty reading, slow adjustment to low or reduced light environment, and blurred vision. These changes may be irreversible, and retinal and vision changes may progress even after cessation of therapy.”

The letter clearly recommended the following:

• A detailed ophthalmological history prior to starting patients on Elmiron.
• For patients with pre-existing ophthalmologic conditions, a comprehensive baseline retinal examination prior to starting therapy.
• Baseline retinal exams for all patients within 6 months of starting therapy and periodically during therapy.
• Using caution in patients with retinal pigment changes from other causes which may confound the appropriate diagnosis.
• For patients with a family history of hereditary pattern dystrophy, genetic testing should be considered.
• Followup retinal examination should be continued given that retinal and vision changes may progress even after cessation of treatment.
• If pigmentary changes in the retina develop, the risks and benefits of continuing treatment should be re-evaluated, since these changes may be irreversible.
• Inform patients that changes in vision should be reported and evaluated.

Mogica and De³ submitted an article for Urology in 2020, reviewing the literature on the subject up until that time. They included original data from 14 articles: 4 case reports, 4 series and 16 cross-sectional studies. They concluded, “Most reports and studies seem to suggest an association exists between long-term PPS exposure and the development of maculopathy.” The association seems to increase the longer the patients were on medication and with the amount of medication ingested. Most patients with PPS maculopathy were found to have a cumulative exposure of over 1,000 g. They cited reviews elsewhere estimating a probability of being diagnosed with this maculopathy of 2.3% and 3.4%, respectively, after 5 years of PPS use. They hypothesize that large cumulative dosages might saturate the pathways accounting for metabolism and excretion.

Multiple articles on this subject continued to appear in Ophthalmology, opining that the association is real. Most recently, Wang et al⁴ compiled data on 100 consenting patients of 741 who were prescribed PPS within a large university database. The prevalence of PPS maculopathy was 16%. It would have been 19% if 3 indeterminate cases were included. They cited other articles reporting a 20% to 23% prevalence. They also cited prior studies of theirs demonstrating that the risk of toxicity was greatest in users with a cumulative dosage of greater than 1,000 g and especially greater than 1,500 g. The minimum cumulative dose at which retinal toxicity was found was 1,533 g, while 15% in the unaffected group reported higher cumulative dosages. The prevalence of toxicity in those with cumulative dosages greater than 1,000 and 1,500 g was 40% and 55%, respectively. Affected and unaffected groups were compared in this most current series; there was no difference in terms of age, sex, smoking history, height, weight, or BMI. The affected group exhibited significantly longer duration of PPS use, higher daily dosage and greater cumulative dose. The mean duration of intake was 19.5 years in the affected group versus 7.1 in the unaffected group (medians, 18 versus 5). The affected group had a higher mean daily dose of 433.9 mg versus 291.6 mg (medians 400 versus 300 mg). The affected group had a greater mean cumulative dose of 3,103.1 g versus 768.4 g (medians 2,737.5 versus 493).

The association seems unmistakable. For the individual urologist, the decision to prescribe or to maintain long-term usage will ultimately depend on his/her estimate of the true efficacy of this compound, the ability to provide complete disclosure for patients and the risk tolerance of patient and practitioner. Another rock in the shoe of potential liability.