Association Between Pentosan Polysulfate Sodium and Retinal Disorders

Key Points

Question  Is pentosan polysulfate sodium (PPS) use associated with maculopathy?

Findings  In this disproportionality analysis, users of PPS were proportionately more likely to report adverse events associated with retinal disorder compared with users of other drugs for interstitial cystitis and bladder pain.

Meaning  These findings add to the growing evidence that PPS is associated with certain retinal disorders.

Importance  Case series have identified a macular condition hypothesized to be associated with the use of pentosan polysulfate sodium (PPS). Observational studies seeking to quantify this association have yielded equivocal results.

Objective  To estimate the association between PPS exposure and maculopathy.

Design, Setting, and Participants  This disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System from January 2013 through June 2020.

Exposure  Adverse event reports for pentosan polysulfate were selected and compared with adverse event reports associated with drugs taken for the following indications: interstitial cystitis, cystitis, bladder disorder, or bladder pain.

Main Outcome Measures  Retinal adverse events were identified using the retinal disorders Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query, which includes conditions associated with retinal damage attributable to blockage of its blood supply, nutritional deficiencies, toxins, and diseases affecting the retina.

Results  There were 2775 reports available for analysis in the PPS group (of which 1966 were for women [70.9%]) and 6833 reports in the other drugs group (of which 4036 [59.1%] were for women). The proportion of adverse events for any macular event relative to all other events was elevated for the users of PPS compared with those using other interstitial cystitis and bladder pain drugs (proportionate reporting ratio [PRR], 1.21 [95% CI, 1.01-1.44]). With respect to specific retinal conditions, macular degeneration (20 [0.8%] vs 15 [0.2%]), maculopathy (83 [3.4%] vs 2 [0.03%]), retinal dystrophy (3 [0.1%] vs 0), retinal injury (5 [0.2%] vs 0), and retinal toxicity (3 [0.1%] vs 0) were proportionately more common among users of PPS compared with those using other interstitial cystitis and bladder pain drugs, respectively.

Conclusions and Relevance  The results of the current study add to the growing evidence that PPS use is associated with an increased risk of maculopathy. Studies that rule out prevalent retinal abnormalities prior to the initiation of PPS would strengthen the current body of literature.

Interstitial cystitis (IC) is a chronic bladder condition that is characterized by bladder pressure and bladder and pelvic pain. It predominantly affects women. It has no known causative mechanism. Estimates of the prevalence of IC vary widely, ranging from fewer than 5 to greater than 100 per 100 000.^1-4 The lack of a universal definition for use in epidemiologic studies is partly the reason for this wide variation in prevalence estimates. The treatment options for IC include lifestyle changes, such as dietary modifications; bladder training; physical therapy; medications; bladder procedures, such as hydrodistension; and in rare cases, surgery. Pharmacological treatment for IC includes over-the-counter drugs (eg, antihistamines, nonsteroidal anti-inflammatories) and prescription medications (eg, tricyclic antidepressants, cyclosporine). The only US Food and Drug Administration–approved pharmacological treatment for IC is pentosan polysulfate sodium (PPS) (Elmiron).

Despite having received FDA approval in 1996, concerns have only recently emerged regarding the association between PPS and maculopathy characterized by difficulty with visual tasks, such as reading; dark adaptation impairment; and unique pathological findings.^5-8 Based on a number of case series, this condition, now termed PPS-associated maculopathy, has been associated with long-term PPS exposure, the median duration of use being at least 15 years, although some patients have reported shorter durations. There have been a number of epidemiologic studies that have evaluated the association between PPS and macular disease, with some reporting positive associations^9-11 and others reporting no association.¹² This study seeks to extend the epidemiologic literature regarding the association between PPS exposure and maculopathy by investigating this association using data from the US FDA Adverse Event Reporting System (FAERS).

This study was reviewed by the University of Alabama at Birmingham Institutional Review Board for Human Use and deemed to be not human subjects research, given the public availability and deidentified nature of the data source. Informed consent was therefore not required.

The data for this study were obtained from the US FAERS, which is a database containing adverse event reports, medication error reports, and product quality complaints that result in adverse events. The FAERS is used by the FDA and other entities for the postmarketing surveillance of medications and biologics. It is also used for research purposes. Adverse event reports are voluntarily submitted to the FAERS by a wide range of entities, including health care professionals, consumers, lawyers, and drug manufacturers. Drug manufacturers who receive adverse event reports from health care professionals and consumers must in turn submit them to the FDA. Individual adverse event reports can contain information on 1 or more drugs and/or adverse events. In the case of multiple adverse events, there is no hierarchy with respect to severity or importance. However, each drug is classified as a primary suspect drug, secondary suspect drug, concomitant, or interacting. Adverse event reports may be incomplete, containing missing information for individual data fields.

The FAERS data are publicly available and updated quarterly. The data for this study covered data for from January 2013 through the second quarter of 2020 (June 2020). These updates include both newly submitted adverse event reports as well as updates to previously submitted reports. Updated reports may include updates to previously submitted information or new information that was previously omitted. The identification of updated reports is facilitated by the use of a unique case identification number. When analyzing FAERS data, the FDA recommends conducting an initial deduplicating process by selecting the most recently updated record for each unique case identification number¹³; this process was used in the current study. The publicly available FAERS data are composed of 7 individual data files corresponding to (1) patient demographic and administrative information; (2) drug/biologic information; (3) adverse event information; (4) patient outcome information; (5) adverse event reporting source; (6) drug/biologic therapy information (eg, drug start date); and (7) indications for use of the reported drugs. With respect to drug information, the name of the product appears verbatim, and therefore any given drug may be identified by its trade or generic name, with and without misspellings and ancillary text strings, such as “omeprazole mylan (non-AZ product).” Adverse events and indications are coded based on the Medical Dictionary for Regulatory Activities (MedDRA) preferred term–level terminology.

For the purposes of the current study, all adverse event reports containing the terms Elmiron or pentosan polysulfate were selected. A comparison group was selected that included adverse events associated with drugs other than those and taken for the following indications: cystitis (interstitial), cystitis, bladder disorder, or bladder pain.

For the aforementioned adverse event reports, all retinal adverse events were identified using the retinal disorders Standardized MedDRA Query (SMQ). This SMQ focuses on retinal disorders with damage of retina attributable to blockage of its blood supply, nutritional deficiencies, toxins, and diseases affecting the retina (eg, macular degeneration).

Adverse events reports associated with PPS were compared with those for other IC drugs. Proportionate reporting ratios (PRRs) and associated 95% CIs were calculated to compare the proportion of all reported adverse events that were for retinal or macular conditions among adverse event reports for PPS to adverse event reports for other IC drugs. Sensitivity analyses were conducted, wherein the analysis was restricted to adverse event reports that had a cystitis or IC indication, those that had an indication of bladder disorder or bladder pain and adverse event reports prior to 2020. We also computed χ² and, where appropriate, Fisher exact tests. All P values of ≤.05 (2-sided) were considered significant. We used SAS version 9.4 (SAS Institute) for all analyses.

For the period from 2013 through the second quarter of 2020 (June 2020), 263 389 records using the MedDRA preferred terms were identified, and from these, 189 254 unique case records remained after the removal of duplicates. For the same period, 3511 records with relevant drug names were identified, and from these, 2775 unique records remained after the removal of duplicates. When joined, there were 9608 reports available for the analysis: 2775 in the PPS group and 6833 in the other drugs group (Table 1). For the PPS group, indications for use included IC and bladder disorders or problems, and these were found in 1032 reports (37.2%) and 83 reports (3.0%), respectively, whereas 3270 reports (47.9%) and 3506 reports (51.3%) for the other drugs group had these indications. The PPS and other drugs groups differed by age (age >64 years, 375 users of PPS [13.5%] vs 2575 nonusers [37.7%]; age unknown, 1465 users of PPS [52.8%] vs 1921 nonusers [28.1%]) and sex distribution (women: 1966 users of PPS [70.9%] vs 4036 nonusers of PPS [59.1%]). A greater proportion of the PPS group (499 reports [18.0%]) than the other drugs group (588 [8.6%]) had reports from 2020. A greater proportion of reporters were consumers in the PPS group vs the other drugs group (1882 reports [67.8%] vs 4046 reports [59.2%]), and fewer were health care professionals (690 reports [24.9%] vs 2194 reports [32.1%]) and lawyers (24 reports [0.9%] vs 95 [1.4%]).

Overall, the proportion of adverse events for any macular event relative to all other events was elevated for the PPS group compared with the other drugs group (PRR, 1.21 [95% CI, 1.01-1.44]; Table 2). Elevated associations were observed for macular degeneration (20 [0.8%] vs 15 [0.2%]; PRR, 3.28 [95% CI, 1.68-6.40]) and maculopathy (83 [3.4%] vs 2 [0.03%]; PRR, 102.19 [95% CI, 25.15-415.14]). Decreased associations, however, were observed for photophobia (PRR, 0.16 [95% CI, 0.04-0.66]), blurred vision (PRR, 0.52 [95% CI, 0.35-0.76]), reduced visual acuity (PRR, 0.13 [95% CI, 0.03-0.54]), visual impairment (PRR, 0.55 [95% CI, 0.34-0.90]), and vitreous floaters (PRR, 0.19 [95% CI, 0.06-0.61]). It was not possible to calculate PRRs for events that occurred in one group but not the other; nonetheless, in the PPS group, there were reports of retinal dystrophy (n = 3; P = .02), retinal injury (n = 5; P = .002), and retinal toxicity (n = 3; P = .02), while in the other drugs group, these events were not reported.

Compared with results from the main analysis, sensitivity analysis restricted to reports for indications of cystitis or IC showed larger associations for any macular event (PRR, 1.94 [95% CI, 1.53-2.44]) and macular degeneration (PRR, 11.25 [95% CI, 3.10-40.78]) and were equivalent for maculopathy (PRR, 94.47 [95% CI, 23.10-386.35]; eTable 1 in the Supplement). In addition, the proportion of reports for eye disorder were elevated (PRR, 4.50 [95% CI, 1.01-20.06]). Decreased associations were observed for photophobia (PRR, 0.26 [95% CI, 0.03-1.98]), blurred vision (PRR, 0.66 [95% CI, 0.37-1.20]), visual impairments (PRR, 0.67 [95% CI, 0.32-1.44]), and vitreous floaters (PRR, 0.17 [95% CI, 0.02-1.26]). There was an increased number of reports for visual acuity in the other drugs group (n = 15; P = .03). Analyses restricted to reports for indications of bladder disorder or bladder pain resulted in an association of similar magnitude for any macular event (PRR, 1.33 [95% CI, 0.69-2.53]) and a larger association for macular degeneration (PRR, 6.59 [95% CI, 1.88-23.06]; eTable 2 in the Supplement). The proportion of reports for eye disorder were elevated (PRR, 3.29 [95% CI, 0.77-14.17]). There were more reports of maculopathy in the PPS group (n = 2; P = .001). In contrast with the main analysis, the proportion of visual field defect reports was elevated (PRR, 26.35 [95% CI, 3.74-185.60]). None of the decreased associations observed in the main analysis were found for photophobia, blurred vision, reduced visual acuity, visual impairment, and vitreous floaters), and there were no event reports for retinal dystrophy, retinal injury, and retinal toxicity. When limited to adverse event reports prior to 2020, elevated associations were preserved for age-related macular degeneration, macular degeneration, maculopathy, and neovascular age-related macular degeneration (eTable 3 in the Supplement). Additionally, most of the reduced associations were also observed.

Maculopathy associated with PPS is a condition characterized by cystoid macular edema, macular neovascularization, and retinal pigment epithelium atrophy that may result in severe visual acuity loss, although in most cases there is minimal to no visual acuity impairment.^5-8 Patients report symptoms including prolonged dark adaptation, nyctalopia, and difficulty reading or blurred vision. The results of this study indicate the users of PPS are more likely to report adverse events for retinal disorders generally than users of other medications for bladder pain. Adverse events for specific macular (eg, macular degeneration, maculopathy) and retinal (eg, retinal toxicity, retinal injury) were more common among those using PPS, whereas visual function adverse events such as blurred vision and reduced visual acuity were less common. While the current study does not address the underlying mechanism for the association between PPS use and maculopathy, a number of hypotheses have been discussed in the literature.^5,9,14,15

The evolving case definition for PPS-associated maculopathy and the understanding of the associated pathophysiology has occurred in parallel with 4 observational studies evaluating the association between PPS and macular disease. In 2019, Jain et al⁹ used a medical claims database to compare the incidence of atypical maculopathy and dry AMD or drusen (ie, AMD) among a cohort of users of PPS compared with an age-matched, sex-matched, and race-matched cohorts of those who had not used it. The authors conducted 2 sets of analyses, one with 5 years of follow-up and the other with 7. Users of PPS had higher odds of both outcomes at both points, although only the association for atypical maculopathy at the 7-year follow-up was significant. A sensitivity analysis limited to patients with an IC diagnosis revealed a significant association between PPS and atypical maculopathy, though only for the 5-year follow-up; the remaining results were inconsistent, which was perhaps attributable to the reduced sample size. Also using a claims database, Ludwig et al¹² selected a cohort of patients with IC and compared the risk of maculopathy between those who used PPS vs those who did not. The authors concluded that while they could not rule out the role of PPS on maculopathy, they did not identify strong, stable, or consistent associations. The authors subsequently acknowledged that their duration of follow-up was likely insufficient to have observed an association, given what is hypothesized as the necessary duration of exposure (ie, approximately 15 years).^16,17 Additionally, it is important to note that the diagnosis codes used to define the outcomes in these 2 studies^9,12 only partially overlapped, impeding a comparison of their results. In a 2019 cross-sectional study by Hanif et al,¹⁰ patients diagnosed with IC were classified as having unspecified pigmentary maculopathy or no pigmentary maculopathy and their use of IC therapies was compared. In contrast with the prior studies, maculopathy cases were defined based on retrospective retinal imaging, rather than diagnosis codes. Eighty percent of patients with unspecified pigmentary maculopathy had used PPS, compared with 30% of those without pigmentary maculopathy. Vora et al¹¹ also used retinal imaging to identify cases of maculopathy among a cohort of people who had used PPS over the long term. The study did not include an unexposed group of patients. The results indicated a dose-response association between PPS dosage and the likelihood of maculopathy. Finally, Wang et al⁸ screened users of PPS for PPS-associated maculopathy, documenting a 20% prevalence. The authors also observed that those with PPS-associated maculopathy had longer durations of PPS use and higher dosages.

The results of the current study are consistent with the aforementioned research. The PRR for any adverse event captured by the retinal-disorder SMQ was significantly elevated. This was largely driven by strong associations for adverse events, including macular degeneration, retinopathy, retinal disorder, and macular fibrosis. Because of the lack of events in the comparison group, PPRs were not estimable for conditions such as retinal drusen, retinal dystrophy, retinal injury, retinal toxicity, retinal pigmentation, although the differences were truly or borderline significant. Collectively, these conditions are consistent with the PPS maculopathy phenotype described in the literature. However, it is important to point out that the heterogeneity of the adverse events is associated with the self-reported nature of the FAERS as well as the use of the MedDRA. The results also demonstrated reduced PRRs for several visual function retinal disorder events in the SMQ, including blurred vision, visual impairment, and reduced visual acuity. While published case series^5,6 describe patients whose visual functions are largely preserved, most patients also report visual symptoms, such as blurred vision. Blurred vision and visual impairment are the most common adverse events among users of PPS after maculopathy, highlighting their importance. It is unclear why the PRRs for these symptoms were reduced when the PRRs for the associated conditions were elevated, although the older age of those in the comparison group may be a partial explanation.

Comparing the results of observational studies evaluating the association between PPS and macular disease, including the current one, is difficult. This is attributable to several factors, including the lack of a consistent definition of macular disease, differing durations of PPS exposure, and choice of comparison groups. These differences are perhaps not surprising, given the rapidly evolving understanding of the disease. Additionally, most observational studies have relied on administrative data, which does not permit the application of the current working definitions of PPS maculopathy, which requires multimodal imaging. Further, these data sources do not permit sufficient retrospective follow-up to capture exposure durations that are consistent with those described in case series (ie, 10-15 years).

The results of this study should be interpreted in light of several limitations, primarily stemming from the well-known limitations of the FAERS data. The FAERS is based on spontaneous reports of adverse events; it does not purport to represent all occurrences of adverse drug events. However, this is not a limitation unique to the FAERS; in fact, it would be rare for any epidemiologic study to enumerate all occurrences of an outcome under investigation. Rather than complete enumeration, epidemiologic studies focus on identifying outcomes in an unbiased manner. Out of a concern that media reports regarding vision problems related to PPS may have biased the results, a sensitivity analysis limited to adverse event reports submitted prior to 2020 was conducted. Although this resulted in a reduction in the number of macular events, most of the elevated associations were maintained compared with the main analysis, suggesting that the inclusion of the 2020 data did not introduce meaningful bias. This is consistent with research suggesting that notoriety bias does not lead to overreporting in the FAERS and has minimal impact on measures of association.¹⁸

All information is self-reported and not subject to validation, and a causal association between the reported medication(s) and adverse event(s) in any given report cannot be inferred. Unlike a cohort study, the lack of a true denominator (ie, the number of persons who are prescribed or use a product) precludes the calculation of incidence rates. However, the calculation of reporting ratios (PRRs and PORs) from pharmacovigilance data as valid estimates of relative risks has been described, and their use is widely accepted.^19,20 Furthermore, the results of disproportionality analyses of the FAERS data has been shown to yield findings that are consistent with the results of population-based studies.^21-25

Finally, the number of reports for many of the specific retinal events is small. This reduces the precision of the many of the measures of association and potentially produces spurious results.

This study adds to the diversity of study designs used to address the association between PPS and macular disease. Although individual observational studies are unable to establish cause-and-effect associations, the growing body of epidemiologic, clinical and pathophysiologic research strengthens the interpretation that PPS use may lead to maculopathy. However, additional research including prospective observational studies of individuals with normal fundi are needed to further elucidate this association.

Accepted for Publication: September 27, 2021.

Published Online: November 18, 2021. doi:10.1001/jamaophthalmol.2021.4778

Corresponding Author: Gerald McGwin Jr, MS, PhD, Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, 1720 University Blvd, Ste 609, Birmingham, AL 35223 (mcgwin@uab.edu).

Author Contributions: Drs McGwin and MacLennan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: McGwin, Owsley.

Acquisition, analysis, or interpretation of data: McGwin, MacLennan.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: McGwin, Owsley.

Statistical analysis: McGwin, MacLennan.

Administrative, technical, or material support: Owsley.

Conflict of Interest Disclosures: Dr McGwin reported personal fees from the Cracken Law Firm PC to review published science in connection with pharmaceuticals and illnesses, but its payments are rarely specific to a pharmaceutical and no specific payments were in connection with pentosan polysulfate. No other disclosures were reported.