Elmiron

CLINICAL PHARMACOLOGY

General

Pentosan polysulfate sodium is a low molecular weight heparin-like compound. It has anticoagulant and fibrinolytic effects. The mechanism of action of pentosan polysulfate sodium in interstitial cystitis is not known.

Pharmacokinetics

Absorption: In a clinical pharmacology study in which healthy female volunteers received a single oral 300 or 450 mg dose of pentosan polysulfate sodium containing radiolabeled drug as a solution under fasted conditions, maximal levels of plasma radioactivity were seen approximately at a median of 2 hours (range 0.6-120 hours) after dosing. Based on urinary excretion of radioactivity, a mean of approximately 6% of a radiolabeled oral dose of pentosan polysulfate sodium is absorbed and reaches the systemic circulation.

Food Effects: In clinical trials, ELMIRON (pentosan polysulfate sodium capsules) ® was administered with water 1 hour before or 2 hours after meals; the effect of food on absorption of pentosan polysulfate sodium is not known.

Distribution: Preclinical studies with parenterally administered radiolabeled pentosan polysulfate sodium showed distribution to the uroepithelium of the genitourinary tract with lesser amounts found in the liver, spleen, lung, skin, periosteum, and bone marrow. Erythrocyte penetration is low in animals.

Metabolism: The fraction of pentosan polysulfate sodium that is absorbed is metabolized by partial desulfation in the liver and spleen, and by partial depolymerization in the kidney to a large number of metabolites. Both the desulfation and depolymerization can be saturated with continued dosing.

Excretion: Following administration of an oral solution of a 300 or 450 mg dose of pentosan polysulfate sodium containing radiolabeled drug to groups of healthy subjects, plasma radioactivity declined with mean half-lives of 27 and 20 hours, respectively. A large proportion of the orally administered dose of pentosan polysulfate sodium (mean 84% in the 300 mg group and 58% in the 450 mg group) is excreted in feces as unchanged drug. A mean of 6% of an oral dose is excreted in the urine, mostly as desulfated and depolymerized metabolites. Only a small fraction of the administered dose (mean 0.14%) is recovered as intact drug in urine.

Special Populations

The pharmacokinetics of pentosan polysulfate sodium has not been studied in geriatric patients or in patients with hepatic or renal impairment. See also PRECAUTIONS - Hepatic Insufficiency.

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 (pentosan polysulfate sodium capsules) ® in patients receiving other therapies with anticoagulant effects.

Pharmacodynamics

The mechanism by which pentosan polysulfate sodium achieves its effects in patients is unknown. In preliminary clinical models, pentosan polysulfate sodium adhered to the bladder wall mucosal membrane. The drug may act as a buffer to control cell permeability preventing irritating solutes in the urine from reaching the cells.

Clinical Trials

ELMIRON (pentosan polysulfate sodium capsules) ® was evaluated in two clinical trials for the relief of pain in patients with chronic interstitial cystitis (IC). All patients met the NIH definition of IC based upon the results of cystoscopy, cytology, and biopsy. One blinded, randomized, placebo controlled study evaluated 151 patients (145 women, 5 men, 1 unknown) with a mean age of 44 years (range 18 to 81). Approximately equal numbers of patients received either placebo or ELMIRON (pentosan polysulfate sodium capsules) ® 100 mg three times a day for 3 months. Clinical improvement in bladder pain was based upon the patient's own assessment. In this study, 28/74 (38%) of patients who received ELMIRON (pentosan polysulfate sodium capsules) ® and 13/74 (18%) of patients who received placebo, showed greater than 50% improvement in bladder pain (p=0.005).

A second clinical trial, the physician's usage study, was a prospectively designed retrospective analysis of 2499 patients who received ELMIRON (pentosan polysulfate sodium capsules) ® 300 mg a day without blinding. Of the 2499 patients, 2220 were women, 254 were men, and 25 were of unknown sex. The patients had a mean age of 47 years and 23% were over 60 years of age. By 3 months, 1307 (52%) of the patients had dropped out or were ineligible for analysis, overall, 1192 (48%) received ELMIRON (pentosan polysulfate sodium capsules) ® for 3 months; 892 (36%) received ELMIRON (pentosan polysulfate sodium capsules) ® for 6 months; and 598 (24%) received ELMIRON (pentosan polysulfate sodium capsules) ® for one year.

Patients had unblinded evaluations every 3 months forthe patient's rating of overall change in pain in comparison to baseline and for the difference calculated in "pain/discomfort" scores. At baseline, pain/discomfort scores forthe original 2499 patients were severe or unbearable in 60%. moderate in 33% and mild or none in 7% of patients. The extent of the patients' pain improvement is shown in Table 1.

At 3 months, 722/2499 (29%) of the patients originally in the study had pain scores that improved by one or two categories. By 6 months, in the 892 patients who continued taking ELMIRON (pentosan polysulfate sodium capsules) ®, an additional 116/2499 (5%) of patients had improved pain scores. After 6 months, the percent of patients who reported the first onset of pain relief was less than 1.5% of patients who originally entered in the study (see Table 2).

Table 1: Pain Scores in Reference to Baseline in Open Label Physician's Usage Study (N=2499)1

Efficacy Parameter 3 months2 6 months2
Patient Rating of Overall Change in Pain (Recollection of difference between current pain and baseline pain)3 N=1161
Median=3
Mean=3.44
CI: (3.37, 3.51)
N=724
Median=4
Mean=3.91
CI: (3.83, 3.99)
Change in Pain/Discomfort Score (Calculated difference in scores at the time point and baseline)4 N=1440
Median=1
Mean=0.51
CI: (0.45, 0.57)
N=904
Median=1
Mean=0.66
CI: (0.61, 0.71)
1Trial not designed to detect onset of pain relief
2
CI = 95% confidence interval
36-point scale: 1 = worse, 2 = no better; 3 = slightly improved, 4 = moderately improved. 5 = greatly improved, 6 = symptom gone
43-point scale: 1 = none or mild, 2 = moderate, 3 = severe or unbearable

Table 2: Number (%) of Patients with New Relief of Pain/Discomfort1 in the Open-Label Physician's Usage Study (N=2499)

  at 3 months2 (n=1192) at 6 months3 (n=892)
Considering only the patients who continued treatment 722/1192 (61%) 116/892 (13%)
Considering all the patients originally enrolled in the study 722/2499 (29%) 116/2499 (5%)
1First-time Improvement in pain/discomfort score by 1 or 2 categories
2
Number (%) of patients with improvement of pain/discomfort score at 3 months when compared to baseline
3
Number (%) of patients without pain/discomfort improvement at 3 months who had improvement at 6 months

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

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