, Volume 66, Issue 6, pp 821–835

Pentosan Polysulfate

A Review of its Use in the Relief of Bladder Pain or Discomfort in Interstitial Cystitis


    • Adis International Limited
  • Caroline M. Perry
    • Adis International Limited
Adis Drug Evaluation

DOI: 10.2165/00003495-200666060-00006

Cite this article as:
Anderson, V.R. & Perry, C.M. Drugs (2006) 66: 821. doi:10.2165/00003495-200666060-00006



Pentosan polysulfate (pentosan polysulfate sodium; ELMIRON®), a heparin-like, sulfated polysaccharide, is used to manage bladder pain and discomfort in adults with interstitial cystitis (IC). Preliminary clinical models suggest that pentosan polysulfate repairs damaged glycosaminoglycan (GAG) layers lining the urothelium and in vitro data suggest it may provide an anti-inflammatory effect in patients with IC. Pentosan polysulfate shows beneficial effects in a proportion of patients with IC in terms of the improvement of a patient’s overall condition and the relief of pain, and it is a generally well tolerated therapy. It is the only US FDA-approved oral treatment for the relief of bladder pain or discomfort associated with IC, and data support its role as an important option in the treatment of patients with IC.

Pharmacological Properties

Pentosan polysulfate is a semi-synthetic, sulfated polysaccharide, which is chemically and structurally similar to heparin and GAG. One theory is that the drug binds to and repairs the GAG layer on the bladder epithelium, thus reducing permeability in damaged parts of the barrier and preventing toxins from the urine irritating the uroepithelium.

An in vitro study has shown that pentosan polysulfate may also reduce inflammation associated with IC by inhibiting the inflammatory response and by reducing histamine secretion through inhibition of connective tissue and mucosal mast cells.

In animal studies, pentosan polysulfate showed no clear evidence of drugrelated carcinogenic activity in rats; however, carcinogenic activity was observed in mice exposed to the drug.

The bioavailability of pentosan polysulfate is very low (≤3%). The maximum plasma concentration of pentosan polysulfate occurs within ≈2 hours of oral administration. Pentosan polysulfate was distributed in humans to areas including the uroepithelium of the genitourinary tract, bone marrow, lung, liver, periosteum, skin and spleen in a radiolabelling study. The liver and spleen are the sites of desulfation and the kidney is the site of depolymerisation of pentosan polysulfate, although a large amount of unchanged drug is excreted in the faeces (≈52%) and a small amount in the urine. The elimination half-life of pentosan polysulfate, after a single oral <15mg radiolabelled dose supplemented with a 300mg dose, is ≈26.5 hours.

Pentosan polysulfate has no effect on the pharmacokinetics of warfarin and no other drug interactions have been examined.

Therapeutic Efficacy

In well designed, randomised, placebo-controlled trials in patients with moderate or severe IC, pentosan polysulfate was more effective than placebo, with significantly (both p ≤ 0.04) greater proportions of pentosan polysulfate recipients (28% and 32%) than placebo recipients (13% and 16%) showing a substantial overall improvement of their condition.

In a randomised, nonblind study with ciclosporin and a randomised, double-blind pilot study with hydroxyzine in patients who had at least moderate IC symptoms, pentosan polysulfate was shown to be less effective than ciclosporin and not significantly different from hydroxyzine at improving the symptoms of IC.

Noncomparative studies of long-term treatment with pentosan polysulfate showed improvement in IC symptoms (mostly severe) over time. A significant reduction in pain was also observed over time in some patients.

In a small, nonblind study, combination therapy with pentosan polysulfate and heparin was more effective than pentosan polysulfate alone in improving the symptoms of IC. The concomitant use of pentosan polysulfate and hydroxyzine in a pilot study, however, conferred no advantage over either drug alone.


Pentosan polysulfate 100mg three times daily was generally well tolerated, with adverse events usually being mild in severity. In three randomised, double-blind studies and two noncomparative, long-term studies, the most commonly reported adverse events with pentosan polysulfate were nausea, diarrhoea and headache. Alopecia (1–5% incidence) was reported in three studies. In addition, the incidence of rectal haemorrhage was 4% in one dose-ranging study.

Pentosan polysulfate treatment generally had no significant effect on laboratory parameters. In a long-term study (up to 35 months) abnormal liver function tests occurred in 2% of patients.

1. Introduction

Interstitial cystitis (IC) is a chronic lower urinary tract disorder of unknown aetiology, associated with pelvic pain, urinary frequency and urgency and negative urinary cultures.[1,2] In the US, a study published in 1999[3] estimated the number of women to be affected by IC at 52–67/100 000 (≈750 000 women),[2] although it has been suggested that IC is under-diagnosed[4] and the true figure may be at least 10 times higher.[2] A patient’s health-related quality of life can be markedly affected by IC. Indeed, in severe cases, people may become house bound owing to debilitating pain and urinary problems as well as depression and anxiety.[1,5] Both men and women of all ages can have IC, although adult women make up the majority of diagnosed cases. However, IC may be misdiagnosed by physicians because of the similarity of the symptoms to other disorders, and the strict criteria used to make the diagnosis may determine advanced cases of IC but fail to detect mild or moderate cases.[1,2]

The aetiology of IC is not clear, although it is thought a number of factors are involved, which would explain the variation both in the symptoms of the disease and in patient responses to different medications for IC.[6] Pentosan polysulfate (pentosan polysulfate sodium; ELMIRON®)1 is currently the only oral treatment approved by the US FDA for the relief of bladder pain or discomfort associated with IC.

This article provides an overview of the pharmacology of oral pentosan polysulfate and focuses on its clinical profile in adults with IC, particularly in the alleviation of bladder pain and discomfort associated with IC.

2. Pharmacological Properties

2.1 Pharmacodynamic Properties

Pentosan polysulfate is a semi-synthetic, sulfated polysaccharide (figure 1) similar to heparin and resembles the glycosaminoglycans (GAGs) produced by cells in the body, including those lining the bladder.[7] Anticoagulant and fibrinolytic properties are characteristic of pentosan polysulfate, although its anticoagulant activity is 15 times less than that of heparin.[7]
Fig. 1

Chemical structure of pentosan polysulfate.

The exact mechanism of action of pentosan polysulfate is not yet known, although there are several possible ways in which it may provide relief of symptoms and pain of IC. A widely regarded theory is that the drug could replace damaged parts of the GAG layer that lines the bladder (figure 2).[8] The GAG layer is a protective, mucous coating on the transitional epithelium and is thought to play a large role in controlling cell permeability by preventing most solutes from coming into contact with the cell membranes.[8] Therefore, any damage to the GAG barrier would cause the epithelium to become more permeable to substances from the urine, thus potentially leading to the establishment of IC. Exogenous polysaccharides such as pentosan polysulfate and heparin may repair the gaps and reduce the symptoms of IC in patients who have a damaged GAG layer.[8] It has been shown that intravesical pre-treatment with pentosan polysulfate can reduce the damage done by the cytotoxic substance acrolein in transitional cells in the bladder of female rats, which suggests an enhancement of GAG layer properties by pentosan polysulfate.[9] Pentosan polysulfate has also been reported to reduce bladder epithelial permeability in humans based on the potassium sensitivity test.[10] A higher proportion of patients treated with pentosan polysulfate who showed clinical improvement in their IC symptoms, had a reduction in potassium sensitivity in their bladder at study end (compared with baseline) than those who did not improve clinically.[10]
Fig. 2

A putative mechanism of action of pentosan polysulfate. When the glycosaminoglycan (GAG) layer on the bladder endothelium is intact (a), the anionic charge of the proteoglycans traps water between the spaces in the GAG layer, thus creating a barrier to toxins and bacteria and regulating permeability. If a portion of the GAG layer is damaged (b), toxins are allowed to penetrate the epithelial layer. Pentosan polysulfate is thought to aid in repairing the layer and restoring the permeability function of the barrier.[8,11]

It has also been suggested that pentosan polysulfate may have cytoprotective effects resulting in a reduction in the inflammation of the bladder mucosa that occurs in patients with IC.[12] An in vitro study of human uroepithelial cells[12] showed that the nuclear factor-κB, a nuclear transcription factor that mediates the inflammatory response and which is activated in chronic inflammatory diseases such as rheumatoid arthritis,[13] was inhibited by pentosan polysulfate.[12] Activated bladder mast cells occur in increased numbers in patients with IC[14] and in two in vitro studies,[14,15] pentosan polysulfate appeared to inhibit (in a dose-dependent manner) the stimulation of connective tissue mast cells[14,15] and mucosal mast cells.[14] Mast cell inhibition by pentosan polysulfate resulted in a significant (all p ≤ 0.014) reduction in histamine secretion (compared with untreated mast cells),[15] which may be an additional mechanism of action of the drug and play a part in the alleviation of IC symptoms.

2.1.1 Other Effects

In two 2-year studies in rats and mice, no clear evidence of drug-related carcinogenic activity was found in rats, although an increase in carcinogenic activity was observed in male and female mice.[16] In mice exposed to pentosan polysulfate, an increased incidence of liver tumours (haemangiosarcomas) and hepatocellular neoplasms was observed. An increase in the incidence of malignant lymphomas in female mice was also reported.[16] In addition, an increased incidence of non-neoplastic lesions in both rats and mice exposed to the drug was noted, the lesions were found in areas including the liver, lung, mesenteric lymph node, rectum and spleen.[16] No other in vivo studies of the possible carcinogenic effects of pentosan polysulfate have been reported, although an in vitro study using breast cancer cells showed that the growth of the ZR75-1 line was inhibited and the MCF-7 line underwent cellular proliferation, when the cells were exposed to pentosan polysulfate.[17]

2.2 Pharmacokinetic Properties

The pharmacokinetic properties of orally administered pentosan polysulfate have been evaluated in healthy volunteers[18,19] and additional information is reported in the manufacturer’s prescribing information.[7] No investigation in those aged <16 years has been carried out to date.[7] In a study reported by Simon et al.,[18] radiochromatographic techniques were used to obtain a pharmacokinetic profile in healthy women.

In healthy volunteers, pentosan polysulfate 100mg three times daily had no effect on the pharmacokinetics of warfarin, titrated to between 1.4 and 1.8 of the international normalised ratio for each individual.[20] The lack of effect of pentosan polysulfate on the pharmacokinetics of warfarin, was reported to be similar to the concomitant use of placebo and warfarin.[20] No other drug-drug pharmacokinetic interactions have been studied.[7]

2.2.1 Absorption and Distribution

The bioavailability of pentosan polysulfate is very low with studies indicating that absorption of the administered dose is ≈3% (dosage not reported)[7] or ≤1% for an oral, single 1500mg dose[19] or a single radiolabelled plus supplementary dose as described below.[18] The bioavailability of oral pentosan polysulfate 400mg daily at steady state was 0.5–1% (reviewed by Simon et al.[18]).

Pentosan polysulfate was rapidly absorbed following oral administration of a radiolabelled dose 200μCi (<15mg) followed by a supplementary 300mg unlabelled dose (group 1; n = 7) or a radiolabelled dose 300μCi (<15mg) followed by a 450mg unlabelled dose (group 2; n = 8) in healthy women.[18] Peak plasma concentrations for group 1 and 2 were 250 and 358 ng-eq/mL and were reached in 2.1 and 1.8 hours; the area under the plasma concentration-time curve from time 0 to 120 hours (AUC120) was 21 and 33.8 μg-eq ⋅ h/mL for groups 1 and 2.[18] A low trough plasma concentration of 20–50 ng/mL was reached at steady state following oral pentosan polysulfate 400mg daily (reviewed by Simon et al.[18]).

In humans, pentosan polysulfate is distributed to the genitourinary tract uroepithelium, bone marrow, lung, liver, periosteum, skin and spleen. Animal studies showed low erythrocyte penetration.[7] Studies in mice and rats suggest that pentosan polysulfate is distributed by the lymphatic system and blood, possibly within macrophages, to various parts of the body including the liver, mesenteric and mandibular lymph nodes, rectum, lungs and kidneys (rats only) and the spleen (mice only).[21]

The effect of food on the pharmacokinetic properties of pentosan polysulfate has not been evaluated, although the prescribing information indicates that the drug should be taken 1 hour before or 2 hours after meals.[7]

2.2.2 Metabolism and Elimination

In healthy volunteers, the partial desulfation of pentosan polysulfate (68% of the dose) occurs in the liver and spleen and partial depolymerisation takes place in the kidney; with continued pentosan polysulfate administration, the desulfation and depolymerisation of the drug can become saturated.[7] Following the oral administration of 200μCi (<15mg) radiolabelled pentosan polysulfate and a further 300mg of unlabelled pentosan polysulfate to healthy women, ≈6% and 84% of the radioactivity was recovered in the urine and faeces, respectively.[18]

Only a small proportion of the drug is eliminated unchanged in the urine (≈3%),[7] while ≈52% of the administered dose was identified as unchanged pentosan polysulfate in the faeces.[18] Oral pentosan polysulfate had an estimated half-life (t½) of 26.5 hours after the administration of a <15mg radiolabelled dose supplemented with a single 300mg dose.[18]

3. Therapeutic Efficacy

Several randomised, double-blind, parallel-group, multicentre studies have examined the efficacy of pentosan polysulfate in adults with IC compared with placebo[22,23] (section 3.1) and hydroxyzine[24] (section 3.2). A randomised, open-label, multicentre trial has compared the efficacy of pentosan polysulfate with that of ciclosporin (cyclosporine)[25] [section 3.2]. The hydroxyzine study[24] was a pilot clinical trial where determining the efficacy of the active drugs was an objective secondary to the study’s primary objective of evaluating the feasibility of conducting a larger scale trial. Two long-term, noncomparative trials[26,27] have evaluated the long-term efficacy of pentosan polysulfate and these are described in section 3.3. Pentosan polysulfate has also been evaluated in combination with heparin in a randomised, open-label study.[28] The inclusion criteria for the studies[2228] are shown in table I.
Table I

Inclusion criteria in the clinical trials evaluating the efficacy of pentosan polysulfate (PPS) in patients with interstitial cystitis (IC)[2228]

There were numerous exclusion criteria, which included pregnancy and lactation, use of narcotics, anticoagulants and artificial sweeteners, a known allergy to pentosan polysulfate, history or signs of cancer and many other diseases or physiological problems. In addition, an extensive range of previous and concurrent treatments caused patients either to be excluded from a trial or to have their inclusion deferred. Treatments included pentosan polysulfate, reproductive and urinary system surgery and other IC medications.

Primary efficacy outcomes were determined using a patient-rated evaluation questionnaire targeting overall improvement in their condition,[22,23] daily micturition frequency[25] and a patient-reported 7-point global response assessment (GRA).[24,28]

Secondary efficacy outcomes included the evaluation of overall improvement by the investigator,[22,23] pain and urgency scale ratings[22,23] and changes in the O’Leary-Sant Symptom and Problem Indexes,[24,25,28] 6-point scale GRA,[25] University of Wisconsin Symptom score,[24] visual analogue scale (VAS) for pain[25,28] and urgency,[28] frequency of urination,[2224,28] mean volume of urine voided,[22,23,25] changes in functional bladder capacity[28] and the change in nocturia.[22,23,25] For descriptions of some of the rating scales, see table II.
Table II

Description of rating scales used in the clinical trials[2226,28]

A randomised, double-blind, multicentre, dose-ranging, 32-week study (n = 380) compared the efficacy of 300, 600 and 900 mg/day dosages of pentosan polysulfate (administered as 100, 200 and 300mg doses three times daily) in patients with IC.[29] No dose-response relationship was seen. At the 300 mg/day dosage (n = 128), there was a significant (p < 0.001) improvement from baseline in the patients’ O’Leary-Sant Interstitial Cystitis Symptom Index scores. In addition, the proportion of treatment responders (defined as patients with improvement in the Patient’s Overall Rating of Symptom Index of ≥50%) increased from 21.1% after 4 weeks of treatment to 49.6% after 32 weeks of therapy.[29] It appeared that the patient response curve had not yet plateaued by 32 weeks, indicating a possible need for further long-term efficacy trials; however, these results should be viewed with caution as the trial did not include a placebo group.[29] A retrospective analysis of patients with IC who had been treated with pentosan polysulfate is not discussed, as the dosage was not reported.[30]

3.1 Comparisons with Placebo

Pentosan polysulfate was significantly more effective than placebo in relieving the symptoms of patients with moderate[22] or severe[22,23] IC in two placebo-controlled trials (table III).[22,23] In both studies,[22,23] significantly greater proportions of patients with IC showed improvement in their overall condition when treated with pentosan polysulfate versus those receiving placebo, as evaluated by patients (table III). Improvement in the overall conditions of patients with IC, as evaluated by the study investigators, was seen in significantly greater proportions of pentosan polysulfate recipients than in placebo recipients in both studies[22,23] (table III). Assessments of pain and urgency were similar across both studies with higher proportions of patients experiencing a substantial relief in pain and urgency when treated with pentosan polysulfate compared with placebo (table III). The mean reduction from baseline in the pain score was not significantly different between pentosan polysulfate or placebo recipients in the trial reported by Mulholland et al.;[22] although, the reduction in the mean pain score for patients receiving pentosan polysulfate (0.5) was significantly (p = 0.05) different from zero (no change) compared with no significant change in those receiving placebo (0.2).
Table III

Efficacy of pentosan polysulfate (PPS) in placebo (PL)-controlled trials. Primary and secondary efficacy outcomesa in randomised, double-blind, parallel-group, multicentre trials[22,23] comparing oral PPS 100mg three times daily with PL in adults with interstitial cystitis

The voiding profiles of patients in both studies showed that those receiving pentosan polysulfate expelled numerically greater amounts of urine at each voiding session and in the total amount of urine voided per day compared with those receiving placebo; however, the differences between the two groups was not statistically significant.[22,23] There was no significant difference between the groups in both studies[22,23] for changes in nocturia (number of night-time voids), while the difference in the proportion of patients who increased the amount of urine they expelled at each voiding session by at least 20mL (pentosan polysulfate versus placebo recipients) reached significance (p = 0.02) in the trial reported by Parsons et al.[23] (40% vs 24%), but not in the other study (30% vs 20%).[22] In the larger trial,[23] a secondary efficacy outcome looked at the quality of life as reflected by an increase in the frequency of sexual intercourse. At the end of the 3-month trial, the proportion of sexually active subjects receiving pentosan polysulfate with an increased rate of sexual intercourse approached significance compared with placebo recipients (31% vs 18%; p = 0.06).

3.2 Comparison With Other Drugs

Pentosan polysulfate was significantly less effective than ciclosporin and was not significantly different from hydroxyzine, a combination of pentosan polysulfate and hydroxyzine (section 3.4) or placebo at reducing the symptoms of IC in patients.[24,25] In a 6-month study comparing the efficacy of ciclosporin with pentosan polysulfate[25] in patients with IC (from participating Finnish urology clinics) a significantly smaller reduction in the 24-hour urination frequency in pentosan polysulfate recipients than in ciclosporin recipients was observed. The proportion of patients reaching the anticipated primary endpoint of a 50% reduction in frequency in 24 hours in pentosan polysulfate versus ciclosporin recipients was 0% versus 34% (p < 0.001).[25] There was an improvement in the VAS score for pain for both pentosan polysulfate and ciclosporin (−1.6 vs −4.7cm), although pentosan polysulfate showed a significantly smaller reduction in the VAS score compared with ciclosporin (p < 0.001).[25] Ciclosporin may be useful for patients who have not benefited from other IC therapies; however, the tolerability profile of ciclosporin suggests that patients treated with this drug need to be regularly monitored for blood pressure and serum creatinine levels.[25]

Over half of the patients in the ciclosporin study had at least three previous unsuccessful treatments for IC. Altogether, a wide range of treatments had been tried previously by individual patients, although none had been treated with pentosan polysulfate prior to entry into this trial. The mean patient age, at 58 years, was higher than in most of the studies discussed in this section.[25]

In a 6-month pilot study examining the use of hydroxyzine, pentosan polysulfate, a combination of the two drugs or placebo to treat patients with IC, patients had a median age of 45 years and had at least a moderate degree of IC for a minimum of 24 weeks prior to entering the trial.[24] Treatment with hydroxyzine and/or pentosan polysulfate before entering the study was allowed.[24] In the intent-to-treat population, the proportion of GRA responders was numerically greater in the group receiving pentosan polysulfate alone than in the recipients of placebo or hydroxyzine alone. A numerically higher proportion of patients was classified as responders in the combined pentosan polysulfate treatment arms (34%) versus the no pentosan polysulfate treatment groups (18%) [p = 0.064]. In comparison, the difference in the proportion of GRA responders in the combined hydroxyzine arms (31%) versus the no hydroxyzine arms (20%) was not significant.[24]

Because of a possible bias due to patient withdrawals, study design limitations and limited statistical power due to low rates of recruitment,[24] these results should be viewed with caution.

3.3 Long-Term Treatment

Pentosan polysulfate has also shown long-term efficacy in the treatment of patients with IC in two studies.[26,27]

The long-term efficacy of pentosan polysulfate 100mg three times daily for up to 35 months has been evaluated in a large, multicentre, physician’s usage trial (n = 2809).[26] The majority of the patients in the trial had moderate or severe symptoms of IC, the average age of the patients was 46.9 years and over half of the patients had been treated with at least one course of intravesical dimethyl sulfoxide.

Improvements in the symptoms of IC were recorded and patient evaluation showed that the proportion of patients (who had completed at least 3 months of pentosan polysulfate therapy; n = 1416) with at least moderate improvement in their overall assessment of IC symptoms ranged from 42% to 62% depending on the duration of therapy (5–35 months).[26] When the separate global evaluations for pain (n = 1404) and urgency (n = 1409) were examined, the same proportion of patients had a positive response in their pain assessment from baseline to endpoint (42–62%), and improvement in urgency also followed the same trend with 35–56% of patients showing a decline in urgency.[26]

The maximum number of responsive patients was obtained after a long treatment period (≥29 months). In the pain severity scale evaluations (n = 1504), the proportion of positive responders was 50% (for up to 5 months of therapy) to 58% (for all groups with a therapy duration of >17 months), with the greatest reduction in the pain scale of 2 which was reached by 17 months of drug therapy.[26] In the urgency severity scale (n = 1576), 47% of patients were positive responders by 5 months of drug treatment with a maximum of 55% positive responders by 17 months. The greatest reduction of 0.7 in the scale was reached by 11 months.

A noncomparative, single-centre, long-term study[27] followed 97 patients (mean age 45 years) with IC who, after the failure of previous treatments (including pentosan polysulfate), were treated with pentosan polysulfate 100mg three times daily for up to 116 months. A weak correlation was found between the duration of treatment and a reduction in constant pain (p = 0.044), but there appeared to be no other significant trends between baseline parameters, such as bladder, voiding and pelvic pain, urgency, diuria and nocturia, and the length of treatment.[27] Although ≈50% of patients were estimated to have experienced an initial improvement of their symptoms with pentosan polysulfate treatment, it was also estimated that only 6.2–18.7% of patients who were treated with pentosan polysulfate for ≥3 months (n = 75) benefited from the long-term treatment.[27] The majority of patients had abnormal biopsies or had experienced symptoms of IC for an average of 66 months.[27]

3.4 In Combination with Other Drugs

The concomitant use of pentosan polysulfate and heparin was more effective than the use of pentosan polysulfate as monotherapy in a small, open-label study.[28] Two of the 58 participants in the trial received off-label doses of pentosan polysulfate throughout the study and 56 received pentosan polysulfate 300 mg/day. Heparin was administered subcutaneously at a dosage of 5000 units three times daily for 2 days, followed by 5000 units twice daily for 12 days, to 41 patients (mean age 45.6 years) concomitantly with pentosan polysulfate.[28] Heparin was discontinued after the 14-day treatment protocol and repeated if symptoms recurred. An ongoing maintenance dose of heparin 5000 units/day was self-administered if symptoms persisted after the second heparin treatment cycle. Patients were stratified according to their response to 6 months of prior pentosan polysulfate treatment: a minor response group (n = 22), an intermediate response group (n = 8) and a major response group (n = 11). Seventeen patients (mean age 48.8 years) were randomly selected to form the control group; these patients received only pentosan polysulfate throughout the study.[28] A significantly higher proportion of patients in the minor response group were classified as responders compared with those in the other groups (figure 3).
Fig. 3

Efficacy of combined therapy with pentosan polysulfate (PPS) plus heparin in adults with interstitial cystitis. Data presented are from a randomised, open-label, fixed-dose study[28] comparing three groups of patients who had responded (minor [n = 22], intermediate [n = 8] and major [n = 11] response) to previous therapy with PPS. Patients received PPS 100mg three times daily + heparin 5000 units three times daily for 2 days, followed by 5000 units twice daily for 12 days (n = 41) or PPS 100mg three times daily only (n = 17). Heparin treatment was discontinued after the 2-week cycle and repeated if the symptoms recurred; if symptoms persisted, patients self-administered a maintenance dose of 5000 units/day. The proportion of responders (rating of moderately improved or better) in the Global Response Assessment at 3 months (the primary endpoint) is shown. θ = 0% responders; * p ≤ 0.001 vs PPS-only control; p < 0.001 vs major or intermediate response groups.

A significant (p < 0.05) reduction in pain from baseline was seen in the pentosan polysulfate-plus heparin-treated patient group. At 3 months, there was a change in the VAS score from baseline (pentosan polysulfate-plus-heparin vs pentosan polysulfate-only recipients) of −9.9 versus 11.3mm and at 6 months, −8.5 versus 12.5mm.[28] The greatest average reduction in pain score at both 3 and 6 months was seen in the minor response group (11.4 and 9.1mm) compared with the intermediate (both 3mm) and major response groups (1.7 and 1.5mm), respectively (all p < 0.001 vs intermediate or major response groups).[28]

Combination therapy with pentosan polysulfate and hydroxyzine conferred no advantage over either drug alone in a pilot study (see section 3.2).[24] The combined drug treatment of pentosan polysulfate and hydroxyzine gave the highest numerical GRA rating in patients with IC compared with the other monotherapy treatment arms (pentosan polysulfate, hydroxyzine or placebo [study details in section 3.2]). However, there were no significant differences between the combined drug treatment arm and the other monotherapy treatment arms for the primary endpoint.[24] Combined pentosan polysulfate and hydroxyzine treatment resulted in numerically greater improvements in the secondary assessments compared with the other treatment arms, although the only significant difference was seen in the reduced frequency of voiding in the combination therapy group (p = 0.0037).

4. Tolerability

Tolerability data in this section are from three randomised clinical trials,[22,23,29] two randomised drug-comparison studies,[24,25] a long-term analysis study[27] and a physician’s usage trial,[26] all reported in section 3.

Pentosan polysulfate 100mg taken orally three times daily was generally well tolerated in two randomised, double-blind, placebo-controlled, multicentre clinical trials,[22,23] a randomised, double-blind, parallel-group, dose-ranging study,[29] two noncomparative, long-term studies[26,27] and two randomised, double-blind, drug-comparison studies.[24,25] Discontinuation rates due to adverse events were low among pentosan polysulfate recipients (<5%) in three of the trials,[2224] whereas three studies[26,27,29] had a discontinuation rate in the active drug groups due to adverse events ≈5–9 times higher than that seen in the three studies reported above.

The most commonly reported adverse events (with pentosan polysulfate) in five clinical studies included nausea (1.4–7.9%), diarrhoea (1–14.9%) and headache (1–2.9%).[22,23,26,27,29] In two clinical trials,[22,23] the proportion of pentosan polysulfate recipients experiencing the most common adverse events was the same as or numerically lower (with one exception) than the proportion of patients receiving placebo. These adverse events included (pentosan polysulfate vs placebo recipients) nausea (1.4% vs 4.1%[23] and 1.9% vs 0%[22]), diarrhoea (2.7% vs 2.7%[23] and 0% vs 3.6%[22]) and headache (0% vs 1.4%[23] and 1.9% vs 3.6%[22]). In two drug-comparison trials,[24,25] common adverse events in pentosan polysulfate recipients (values not reported) included headache,[25] fatigue,[24,25] drowsiness,[24] pelvic pain[24,25] and gastrointestinal problems.[24,25] The majority of the adverse events in the drug-comparison trials[24,25] were considered mild in nature (no specific values or statistical analyses were reported) which corresponds with the severity of adverse events described in the other clinical trials[22,23,26,29] and prescribing information.[7] In a large dose-ranging study in adults with IC,[29] rectal haemorrhage was reported in 4% of patients receiving pentosan polysulfate 300 mg/day for 32 weeks, and in the majority of subjects the rectal bleeding was considered to be of mild severity.

Alopecia, mostly mild in severity, was experienced by patients receiving pentosan polysulfate 100mg three times daily in a noncomparative physician’s usage trial (3.9%),[26] a long-term study (1%)[27] and the large dose-ranging study (5%).[29] The occurrence of alopecia did not appear to be dose-related as pentosan polysulfate 600 and 900 mg/day was associated with an 11.3% and 2.6% incidence rate.[29] Alopecia has not been reported in four other studies;[2225] however, the prescribing information states that alopecia is associated with the use of pentosan polysulfate.[7]

Cerebral thrombosis was reported[31] in a patient who used low estrogen oral contraceptives and who had been receiving pentosan polysulfate 100mg three times daily for 3 weeks, for a suspected case of IC. Symptoms appeared 2 days after pentosan polysulfate treatment had ceased and it is possible that thrombocytopenia also occurred; however, that event could not be confirmed as there was a delay in evaluating the platelet counts.[31] A case of serious bleeding due to systemic anticoagulation has also been reported.[32] The affected patient had received oral pentosan polysulfate at a dosage escalating from 100mg three times daily to 300mg three times daily over 4 months. Two patients who were treated with intramuscular pentosan polysulfate 100 and 200mg twice daily for 11 and 10 days, respectively, developed thrombocytopenia and venous thrombosis; after discontinuation of pentosan polysulfate, resolution of the thrombocytopenia was observed.[33] An epidural haematoma was reported to have a possible association with pentosan polysulfate in one patient who had been treated with pentosan polysulfate (dosage not reported) in conjunction with gabapentin 300mg three times daily and amitriptyline 25mg once daily for IC,[34] and in a 6-month comparative trial,[25] one patient receiving pentosan polysulfate experienced gross haematuria.

No serious adverse events or deaths were reported in five clinical trials,[2225,29] or the long-term analysis study.[27] The prescribing information showed an analysis of two studies (the physician’s usage trial [n = 2499] and another 3-month trial [n = 258]) in which 1.3% of pentosan polysulfate recipients reported serious adverse events; death occurred in 0.2% of subjects receiving pentosan polysulfate.[7] With no placebo control group, it is unknown which serious adverse events were associated with the use of pentosan polysulfate or if they were due to other reasons; however, the deaths appeared to be due to other factors, apart from one death in which the cause was unknown.[7]

In two large, well designed studies,[22,23] there were no significant differences between the pentosan polysulfate and placebo groups in regard to changes in patients’ laboratory parameters such as urinalysis, complete blood counts, blood chemistries including prothrombin time and partial thromboplastin time and liver and renal function tests. One patient receiving pentosan polysulfate in the Mulholland et al.[22] study had raised liver enzyme AST and ALT readings at 3 months compared with their baseline levels (the significance of which was not reported) and 2% of patients in the physician’s usage trial were reported as having abnormal liver function tests (no further detail provided).[26] In a long-term analysis study,[27] increasing levels of AST were associated with pentosan polysulfate in one patient after 25 months of treatment and possibly in another patient after 5 months. An increase in serum creatinine was also possibly linked with pentosan polysulfate treatment in another patient.[27]

5. Dosage and Administration

Pentosan polysulfate is indicated in the US, Canada, Australia and Argentina for the oral treatment of bladder pain and discomfort associated with interstitial cystitis in adults aged ≥16 years. In the US, the recommended dosage is 100mg three times daily, taken at least 1 hour before food or 2 hours after food.[7] After 3 months of pentosan polysulfate treatment, patients should be reassessed and treatment may continue for a further 3 months if there is no improvement in IC symptoms and no limiting adverse events.[7] The clinical value of continuing treatment for >6 months, in patients whose pain has shown no improvement by that time, is not known.[7]

Pentosan polysulfate should be used with caution in patients with hepatic insufficiency or disorders of the spleen, since pentosan polysulfate is desulfated by the liver and spleen.[7]

Local prescribing information should be consulted for more detailed information, including contraindications and precautions.

6. Place of Pentosan Polysulfate Sodium in the Management of Interstitial Cystitis

Interstitial cystitis is a costly disease[35] that affects a large number of women and men around the world.[36] It is thought that the undiagnosed cases and misdiagnosis of IC (as other gynaecological and urological conditions, such as endometriosis and chronic prostatitis[36]) underestimate the true incidence of IC in the population.[1,36] A previous estimate, reported in 1999, put the incidence of IC at <0.1% of the population.[3] Currently there is no known cure for IC, so the focus has been on the relief of pain and discomfort associated with this condition.

Pentosan polysulfate is currently the only oral US FDA-approved medication for the relief of bladder pain or discomfort associated with IC. However, there is a range of treatments that physicians often use, either separately or as part of a multimodal treatment strategy, owing to a wide variation in the responses of patients to different treatments. Treatments commonly used to alleviate symptoms and the factors commonly thought to have a possible involvement in the aetiology of IC are listed in table IV. Since the pathogenesis of IC could potentially include damage to the bladder epithelial layer, a potassium leak through the uroepithelium causing nerve depolarisation, inflammation with an increase of activated mast cells and histamine release, neurogenic inflammation, autoimmunity disorders and abnormalities in the urine,[2,6,37] the types of therapies that could potentially be used to treat IC are varied (table IV). In conjunction with pentosan polysulfate, oral therapies such as antihistamines, antispasmodics, antidepressants and analgesics have been used as a multimodal approach to aid in the relief of pain and symptoms of IC. Supportive treatments may be suggested when a patient is first diagnosed with IC and therapy that requires direct intervention, such as surgery, are generally considered a last resort.[6,3739]
Table IV

Commonly prescribed treatments used to alleviate the symptoms of interstitial cystitis (IC) and possible factors involved in the aetiology of IC[2,6,3739]

Pentosan polysulfate is a sulfated polysaccharide and preliminary clinical models suggest that pentosan polysulfate acts to repair the GAG layer that lines the bladder and plays a role in controlling the permeability of the uroepithelium.[7,8] In addition, in vitro studies suggest it may have anti-inflammatory effects by inhibiting a mediator for the inflammatory response[12] and by reducing the secretion of histamine by the inhibition of mast cells.[15] When pentosan polysulfate is taken orally it is absorbed quickly and the plasma concentration peaks in ≈2 hours (see section 2.2);[18] however, the bioavailability of pentosan polysulfate is very low (≤3%) and the drug is eliminated from the body with a large amount of the drug unchanged.[18] This pharmacokinetic profile, while indicating that three-times daily administration of pentosan polysulfate is preferable to a single daily dose, does mean that pentosan polysulfate can be taken as an oral formulation; this differentiates it from similar drugs such as heparin, which are administered intravesically in the treatment of IC.

Pentosan polysulfate is effective at improving the overall condition in a proportion of patients with IC and provides relief from pain and discomfort as seen in two large, well designed trials (section 3.1). In two comparative pilot trials (section 3.2), pentosan polysulfate was less effective than ciclosporin and appeared not to be significantly better than placebo or hydroxyzine in relieving the symptoms of IC. However, patients in the ciclosporin comparison study[25] had been undiagnosed for a longer period than those in other studies and approximately half had been unsuccessfully treated previously, while the hydroxyzine study[24] was not primarily designed to examine the efficacy of the drug treatments. Two noncomparative, long-term studies (see section 3.3) have shown improvements in the symptoms of IC which appear to be associated with duration of pentosan polysulfate treatment. It should be noted that the physician’s use study[26] was selective for responders because of the protocol design, although the results still support the findings that pentosan polysulfate can provide symptom relief in a proportion of patients over several years.

Patients receiving pentosan polysulfate 100mg orally three times daily generally tolerated the drug well, experiencing mainly mild adverse events including nausea, diarrhoea, headache and alopecia. Caution is warranted when patients receiving the drug are to undergo invasive procedures[7] and it has been suggested that platelet counts should be regularly monitored for signs of thrombocytopenia and thrombosis.[31,33] Nevertheless, the anticoagulant properties of this drug did not appear to cause any severe bleeding complications when taken orally at the approved dosage.[22,23,26,27,29]

Since it is likely that IC is caused by multiple factors, the ability to treat the cause of IC rather than the symptoms is more difficult. If in a proportion of patients with IC there is a dysfunctional bladder epithelium, the use of medications that treat only the symptoms, such as nerve hyperactivity or inflammation, may allow damage to the bladder to accumulate over time.[40] Recent studies have focused on the use of pentosan polysulfate as part of a multimodal treatment strategy and, although small, one study has had promising results combining pentosan polysulfate with heparin (see section 3.4). By contrast, another study mentioned above[24] examined combination therapy with pentosan polysulfate and hydroxyzine and showed that it was not significantly more effective than either drug alone or placebo. In the clinical setting, pentosan polysulfate is widely used with other agents,[35] although few studies have examined this type of treatment strategy. Although pentosan polysulfate is the only oral therapy approved in this indication, results of a cost, treatment and co-morbidity US study (n = 749) suggest that this drug is more likely to be used in combination with other medications rather than as a first-line monotherapy.[35] Owing to the clinical practice of treating with a combination of drugs and the preliminary results of the heparin study, further evaluation of pentosan polysulfate as a component of a multimodal treatment strategy is warranted.

The progression of IC from mild to severe may occur over several years with the possibility of symptoms flaring up periodically,[2] so by the time treatment is sought patients may have experienced symptoms for up to 7 years.[3] The earlier that therapy can be implemented in the progression of IC, the fewer medications may be needed to provide effective symptom relief (e.g. pentosan polysulfate and hydroxyzine is often sufficient in patients who are treated at an earlier stage of the disease) and the progression of IC may be slowed, as less damage would have been sustained by the bladder.[40]

Pentosan polysulfate as an oral medication is a convenient treatment option; by comparison, intravesically administered drugs (such as dimethyl-sulfoxide) may require clinical visits and can be time consuming. In addition, the pain associated with IC, originating within the bladder and often extending out into the pelvic area,[40] could also make the intravesical administration of medication very painful in these patients. Data from noncomparative studies show that pentosan polysulfate can be effective over a long period (116 months) and patients should be advised that the effects of treatment may take at least 3–6 months to become noticeable. In addition, pentosan polysulfate treatment may need to be continued indefinitely to maintain symptom relief, although the efficacy of treatment for >6 months in patients who have not had an improvement in pain in that time is unknown.[7] It has been suggested that pentosan polysulfate is effective in a subgroup of patients, possibly because of different aetiologies among the IC-affected population and the severity of the disease; however, when it does work there appears to be a substantial relief in pain and discomfort, which positively affects overall well-being and may affect quality of life. With the several different possible mechanisms of providing relief from the symptoms of IC and the possible ability of the drug to repair any damage to the GAG lining of the bladder, pentosan polysulfate may have a useful role as a component of multimodal therapy. As patients experience relief from the symptoms of IC, any additional drugs that may have been used in the treatment strategy can be reduced or eliminated and the dosage of pentosan polysulfate may also be reduced if appropriate. Currently, there is a lack of pharmacoeconomic data concerning the use of pentosan polysulfate and studies examining the cost effectiveness of pentosan polysulfate are needed.

In conclusion, pentosan polysulfate shows beneficial effects in a proportion of patients with IC in terms of the improvement of a patient’s overall condition and the relief of pain, and it is a generally well tolerated therapy. It is the only US FDA-approved oral treatment for the relief of bladder pain or discomfort associated with IC, and data support its role as an important option in the treatment of patients with IC.


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