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Elmiron and retinal pigmentary maculopathy, from the public record

By Kelsey research · Published

Elmiron (pentosan polysulfate sodium) is an oral capsule approved by the FDA in 1996 for the relief of bladder pain or discomfort associated with interstitial cystitis. Janssen holds the application. Below are the dated public events behind the 2020 retinal warning on its label, each row cited to a primary document. Date types are those of the Analyses page: published, submitted, approved, announced.

Chronology, 1996 to 2020

Date Event Date type Source
Sep 26, 1996 FDA approves the original application, NDA 020193. approved [1]
Dec 12, 2008 Last labeling supplement listed before 2020 (SUPPL-9). Its WARNINGS section reads "None." Its adverse reactions list includes retinal hemorrhage under special senses, and no pigmentary maculopathy. approved [1][2]
May 22, 2018 Pearce, Chen and Jain publish a retrospective case series of six patients with chronic pentosan exposure and a pigmentary maculopathy, online in Ophthalmology. published [3]
Nov 2018 The article appears in the print issue (Ophthalmology 125(11):1793-1802). published [3]
Jun 24, 2019 Janssen files a prior approval supplement (S-014) with a revised package insert and a clinical overview. It proposes adding a warning of retinal pigmentary changes. submitted [4][5]
Mar 24, 2020 Janssen amends the supplement with two literature searches and a search of its global safety database. submitted [5]
Apr 10 to May 18, 2020 FDA proposes labeling revisions (Apr 10). Janssen sends counterproposals (Apr 24). The two hold a teleconference (May 1). Janssen files agreed labeling as the final amendment (May 18). submitted [5]
Jun 16, 2020 FDA approves S-014, revising the Warnings and Post-Marketing sections and the patient labeling. approved [1][4][6]

The 2018 case series of six patients

The article describes six adult patients seen by one clinician between May 1, 2015 and October 1, 2017. All had taken pentosan for interstitial cystitis. Median cumulative exposure was 2,263 g, over a median of 186 months. Four of six named difficulty reading as the most bothersome symptom. The authors describe a "novel and possibly avoidable maculopathy," note that findings suggest a primary injury to the retinal pigment epithelium, and state that "additional investigation is warranted to explore causality further."[3]

The June 2020 Warnings section, "Retinal Pigmentary Changes"

The approved section states that pigmentary changes in the retina, "reported in the literature as pigmentary maculopathy," have been identified with long-term use. It says most cases occurred after three years of use or longer, that cases have been seen with shorter use, and that "cumulative dose appears to be a risk factor." It suggests a baseline retinal examination, including OCT and autofluorescence imaging, within six months of starting treatment and periodically afterward. It says the changes may be irreversible and may progress after treatment stops.[6]

FDA's review file, with 20 FAERS cases and 53 in VigiBase

The approval package for S-014 includes medical and safety reviews.[5] They record:

  • FDA's drug safety office searched the FAERS adverse event database on March 6, 2020. It found 20 retinopathy cases, 8 of which used terms such as maculopathy or pigmentary changes. It noted that many were reported after the 2018 publication, "indicating the possibility of stimulated reporting."
  • A search of the WHO VigiBase found 53 cases, 49 from the United States, 21 of them received after the publication.
  • The reviewers found "preliminary evidence suggesting a dose-response relationship." They also listed limits on causal conclusions, including observational designs, lack of retinal imaging confirmation in claims studies, and confounding.
  • The division recorded that the data "do not support a causal association" between pentosan and retinopathy, and that the new information supported a revision to the label's Warnings and Precautions and Adverse Reactions sections.
  • The applicant's account says its 2019 proposed text stated that causality had not been established and that an eye examination should be considered if vision changed. It also says FDA and Janssen initially disagreed on how to describe the changes.

What the record shows, and what it leaves open

A case series appeared in May 2018. About thirteen months later, on June 24, 2019, the manufacturer filed a supplement proposing a warning. The supplement was amended in 2020 after further literature and case searches, and FDA approved a revised warning on June 16, 2020, just under twelve months after the filing. The pre-2020 label version listed in Drugs@FDA had no retinal warning, and Drugs@FDA lists no labeling supplement between December 2008 and June 2020.

FDA's reviewers saw an association worth labeling, while stating that the data did not establish causation. The final label uses the word "risk factor" for cumulative dose and describes the visual consequences as "not fully characterized."

The record does not show what the manufacturer knew before it filed in 2019, or whether it made earlier internal assessments. The review file redacts some passages. It does not show the content of Janssen's other communications with FDA, any actions by foreign regulators, or how many patients developed the condition. FAERS holds mandatory manufacturer submissions as well as voluntary reports, and a report does not establish causation. The record says nothing about any individual patient or case.

Sources

  1. FDA, Drugs@FDA, Elmiron NDA 020193, approval history and labels. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020193
  2. FDA, Elmiron prescribing information, SUPPL-9, approved December 12, 2008. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020193s009lbl.pdf
  3. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology 2018;125(11):1793-1802. PMID 29801663. DOI 10.1016/j.ophtha.2018.04.026. https://pubmed.ncbi.nlm.nih.gov/29801663/
  4. FDA, supplement approval letter, NDA 020193/S-14 (sNDA "dated and received June 24, 2019"). https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/020193Orig1s014ltr.pdf
  5. FDA, approval package for NDA 020193/S-014, including medical and safety reviews. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/020193Orig1s014.pdf
  6. FDA, Elmiron prescribing information, SUPPL-14, revised June 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020193s014lbl.pdf