PENTOSAN POLYSULFATE: 4,454 Adverse Event Reports & Safety Profile

DESCRIPTION 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

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

DOSAGE AND ADMINISTRATION 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.

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

ADVERSE REACTIONS 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.

WARNINGS Retinal Pigmentary Changes Pigmentary changes in the retina, reported in the literature as pigmentary maculopathy, have been identified with long-term use of ELMIRON ® (see ADVERSE REACTIONS ). 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 environments, and blurred vision. The visual consequences of these pigmentary changes are not fully characterized. Caution should be used in patients with retinal pigment changes from other causes in which examination findings may confound the appropriate diagnosis, follow-up, and treatment. Detailed ophthalmologic history should be obtained in all patients prior to starting treatment with ELMIRON ® . If there is a family history of hereditary pattern dystrophy, genetic testing should be considered. For patients with pre-existing ophthalmologic conditions, a comprehensive baseline retinal examination (including color fundoscopic photography, ocular coherence tomography (OCT), and auto-fluorescence imaging) is recommended prior to starting therapy. A baseline retinal examination (including OCT and auto-fluorescence imaging) is suggested for all patients within six months of initiating treatment and periodically while continuing treatment. If pigmentary changes in the retina develop, then risks and benefits of continuing treatment should be re-evaluated, since these changes may be irreversible. Follow-up retinal examinations should be continued given that retinal and vision changes may progress even after cessation of treatment.

PRECAUTIONS General ELMIRON ® is a weak anticoagulant (1/15 the activity of heparin). At a daily dose of 300 mg (n=128), rectal hemorrhage was reported as an adverse event in 6.3% of patients. Bleeding complications of ecchymosis, epistaxis, and gum hemorrhage have been reported (see ADVERSE REACTIONS ). Patients undergoing invasive procedures or having signs/symptoms of underlying coagulopathy or other increased risk of bleeding (due to other therapies such as coumarin anticoagulants, heparin, t-PA, streptokinase, high dose aspirin, or nonsteroidal anti-inflammatory drugs) should be evaluated for hemorrhage. Patients with diseases such as aneurysms, thrombocytopenia, hemophilia, gastrointestinal ulcerations, polyps, or diverticula should be carefully evaluated before starting ELMIRON ® . A similar product that was given subcutaneously, sublingually, or intramuscularly (and not initially metabolized by the liver) is associated with delayed immunoallergic thrombocytopenia with symptoms of thrombosis and hemorrhage. Caution should be exercised when using ELMIRON ® in patients who have a history of heparin-induced thrombocytopenia. Alopecia is associated with pentosan polysulfate and with heparin products. In clinical trials of ELMIRON ® , alopecia began within the first 4 weeks of treatment. Ninety-seven percent (97%) of the cases of alopecia reported were alopecia areata, limited to a single area on the scalp.

Hepatic

Insufficiency ELMIRON ® has not been studied in patients with hepatic insufficiency. Because there is evidence of hepatic contribution to the elimination of ELMIRON ® , hepatic impairment may have an impact on the pharmacokinetics of ELMIRON ® . Caution should be exercised when using ELMIRON ® in this patient population. Mildly (< 2.5 × normal) elevated transaminase, alkaline phosphatase, γ-glutamyl transpeptidase, and lactic dehydrogenase occurred in 1.2% of patients. The increases usually appeared 3 to 12 months after the start of ELMIRON ® therapy, and were not associated with jaundice or other clinical signs or symptoms. These abnormalities are usually transient, may remain essentially unchanged, or may rarely progress with continued use. Increases in PTT and PT (< 1% for both) or thrombocytopenia (0.2%) were noted. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Patients should take the drug as prescribed, in the dosage prescribed, and no more frequently than prescribed. Patients should be informed that changes in vision should be reported and evaluated. Retinal examinations including optical coherence tomography (OCT) and auto-fluorescence imaging are suggested for all patients within six months of starting ELMIRON ® and periodically during long-term treatment (see WARNINGS ). Patients should be reminded that ELMIRON ® has a weak anticoagulant effect. This effect may increase bleeding times.

Laboratory Test Findings

Pentosan polysulfate sodium did not affect prothrombin time (PT) or partial thromboplastin time (PTT) up to 1200 mg per day in 24 healthy male subjects treated for 8 days. Pentosan polysulfate sodium also inhibits the generation of factor Xa in plasma and inhibits thrombin-induced platelet aggregation in human platelet rich plasma ex vivo (see PRECAUTIONS-Hepatic Insufficiency ). Carcinogenicity, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies of ELMIRON ® in F344/N rats and B6C3F1 mice have been conducted. In these studies, ELMIRON ® was orally administered once daily via gavage, 5 days per week, for up to 2 years. The dosages administered to mice were 56, 168 or 504 mg/kg. The dosages administered to rats were 14, 42, or 126 mg/kg for males, and 28, 84, or 252 mg/kg for females. The dosages tested were up to 60 times the maximum recommended human dose (MRHD) in rats, and up to 117 times the MRHD in mice, on a mg/kg basis. The results of these studies in rodents showed no clear evidence of drug-related tumorigenesis or carcinogenic risk. Pentosan polysulfate sodium was not clastogenic or mutagenic when tested in the mouse micronucleus test or the Ames test ( S. typhimurium ). The effect of pentosan polysulfate sodium on spermatogenesis has not been investigated.

Pregnancy

Reproduction studies have been performed in mice and rats with intravenous daily doses of 15 mg/kg, and in rabbits with 7.5 mg/kg. These doses are 0.42 and 0.14 times the daily oral human doses of ELMIRON ® when normalized to body surface area. These studies did not reveal evidence of impaired fertility or harm to the fetus from ELMIRON ® . Direct in vitro bathing of cultured mouse embryos with pentosan polysulfate sodium (PPS) at a concentration of 1 mg/mL may cause reversible limb bud abnormalities. Adequate and well-controlled studies have not been performed in pregnant women. Because animal studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ELMIRON ® is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

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.