ELMIRON

Pentosan polysulfate sodium is a semi-synthetically produced heparin-like macromolecular carbohydrate derivative, which chemically and structurally resembles glycosaminoglycans. It is a white odorless powder, slightly hygroscopic and soluble in water to 50% at pH 6. It has a molecular weight of 4000 to 6000 Dalton with the following structural formula: ELMIRON ® is supplied in white, opaque hard gelatin capsules containing 100 mg pentosan polysulfate sodium, microcrystalline cellulose, and magnesium stearate. It also contains pharmaceutical glaze (modified) in SD-45, synthetic black iron oxide, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, FD&C Blue No. 1 aluminum lake, D&C Yellow No. 10 aluminum lake, n-butyl alcohol, propylene glycol, SDA-3A alcohol, and titanium dioxide. It is formulated for oral use. Chemical Structure

ELMIRON ® (pentosan polysulfate sodium) is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis.

The recommended dose of ELMIRON ® is 300 mg/day taken as one 100 mg capsule orally three times daily. The capsules should be taken with water at least 1 hour before meals or 2 hours after meals. Patients receiving ELMIRON ® should be reassessed after 3 months. If improvement has not occurred and if limiting adverse events are not present, ELMIRON ® may be continued for another 3 months. The clinical value and risks of continued treatment in patients whose pain has not improved by 6 months is not known.

ELMIRON ® is contraindicated in patients with known hypersensitivity to the drug, structurally related compounds, or excipients.

ELMIRON ® was evaluated in clinical trials in a total of 2627 patients (2343 women, 262 men, 22 unknown) with a mean age of 47 [range 18 to 88 with 581 (22%) over 60 years of age]. Of the 2627 patients, 128 patients were in a 3-month trial and the remaining 2499 patients were in a long-term, unblinded trial. Deaths occurred in 6/2627 (0.2%) patients who received the drug over a period of 3 to 75 months. The deaths appear to be related to other concurrent illnesses or procedures, except in one patient for whom the cause was not known. Serious adverse events occurred in 33/2627 (1.3%) patients. Two patients had severe abdominal pain or diarrhea and dehydration that required hospitalization. Because there was not a control group of patients with interstitial cystitis who were concurrently evaluated, it is difficult to determine which events are associated with ELMIRON ® and which events are associated with concurrent illness, medicine, or other factors. Adverse Experience in Placebo-Controlled Clinical Trials of ELMIRON ® 100 mg Three Times a Day for 3 Months Body System/Adverse Experience ELMIRON ® n=128 Placebo n=130 CNS Overall Number of Patients Within a body system, the individual events do not sum to equal overall number of patients because a patient may have more than one event. 3 5 Insomnia 1 0 Headache 1 3 Severe Emotional Lability/Depression 2 1 Nystagmus/Dizziness 1 1 Hyperkinesia 1 1 GI Overall Number of Patients 7 7 Nausea 3 3 Diarrhea 3 6 Dyspepsia 1 0 Jaundice 0 1 Vomiting 0 2 Skin/Allergic Overall Number of Patients 2 4 Rash 0 2 Pruritus 0 2 Lacrimation 1 1 Rhinitis 1 1 Increased Sweating 1 0 Other Overall Number of Patients 1 3 Amenorrhea 0 1 Arthralgia 0 1 Vaginitis 1 1 Total Events 17 27 Total Number of Patients Reporting Adverse Events 13 19 The adverse events described below were reported in an unblinded clinical trial of 2499 interstitial cystitis patients treated with ELMIRON ® . Of the original 2499 patients, 1192 (48%) received ELMIRON ® for 3 months; 892 (36%) received ELMIRON ® for 6 months; and 598 (24%) received ELMIRON ® for one year, 355 (14%) received ELMIRON ® for 2 years, and 145 (6%) for 4 years. Frequency (1 to 4%): Alopecia (4%), diarrhea (4%), nausea (4%), headache (3%), rash (3%), dyspepsia (2%), abdominal pain (2%), liver function abnormalities (1%), dizziness (1%). Frequency (≤ 1%): Digestive: Vomiting, mouth ulcer, colitis, esophagitis, gastritis, flatulence, constipation, anorexia, gum hemorrhage. Hematologic: Anemia, ecchymosis, increased prothrombin time, increased partial thromboplastin time, leukopenia, thrombocytopenia. Hypersensitive Reactions: Allergic reaction, photosensitivity. Respiratory System: Pharyngitis, rhinitis, epistaxis, dyspnea. Skin and Appendages: Pruritus, urticaria. Special Senses: Conjunctivitis, tinnitus, optic neuritis, amblyopia, retinal hemorrhage. Post-Marketing Experience The following adverse reactions have been identified during post approval use of pentosan polysulfate sodium; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: pigmentary changes in the retina (see WARNINGS ). Rectal Hemorrhage ELMIRON ® was evaluated in a randomized, double-blind, parallel group, Phase 4 study conducted in 380 patients with interstitial cystitis dosed for 32 weeks. At a daily dose of 300 mg (n=128), rectal hemorrhage was reported as an adverse event in 6.3% of patients. The severity of the events was described as "mild" in most patients. Patients in that study who were administered ELMIRON ® 900 mg daily, a dose higher than the approved dose, experienced a higher incidence of rectal hemorrhage, 15%. Liver Function Abnormality A randomized, double-blind, parallel group, Phase 2 study was conducted in 100 men (51 ELMIRON ® and 49 placebo) dosed for 16 weeks. At a daily dose of 900 mg, a dose higher than the approved dose, elevated liver function tests were reported as an adverse event in 11.8% (n=6) of ELMIRON ® -treated patients and 2% (n=1) of placebo-treated patients.

Drug-Drug Interactions In a study in which healthy subjects received pentosan polysulfate sodium 100 mg capsule or placebo every 8 hours for 7 days, and were titrated with warfarin to an INR of 1.4 to 1.8, the pharmacokinetic parameters of R-warfarin and S-warfarin were similar in the absence and presence of pentosan polysulfate sodium. INR for warfarin + placebo and warfarin + pentosan polysulfate sodium were comparable. See also PRECAUTIONS on the use of ELMIRON ® in patients receiving other therapies with anticoagulant effects.

Storage Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F). Keep out of reach of children.