Key points from the evidence

The content of this evidence summary was up-to-date in April 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

A randomised controlled trial (RCT) published in 2014 found no statistically significant difference between pentosan polysulfate sodium (pentosan) and placebo for the treatment of pain, urinary urgency, frequency and nocturia in people with the chronic bladder condition interstitial cystitis. A meta‑analysis of older RCTs that used inconsistent methods for assessing symptoms found that pentosan was more effective than placebo in reducing some symptoms of interstitial cystitis. There are limited data comparing pentosan to other active treatments for interstitial cystitis.

Regulatory status: unlicensed. This topic was prioritised because there was a high volume of requests from the NHS.

Effectiveness

  • A recent 24‑week RCT (n=369) found no statistically significant difference between pentosan and placebo using a validated questionnaire that assesses pain, urinary urgency, frequency and nocturia.

  • A meta‑analysis of 4 older RCTs found pentosan improved pain (n=398), urinary urgency (n=306) and frequency (n=160) more than placebo. However, improvements in these symptoms were not seen in all of the individual studies. There was no statistically significant difference in nocturia between pentosan and placebo (n=106). The trials included in the meta‑analysis used inconsistent and non‑validated methods for assessing symptoms.

  • Differences in inclusion criteria and how symptoms were assessed may explain the inconsistent results observed in the clinical trials.

Safety

  • Adverse events reported by people taking pentosan in clinical trials include diarrhoea, headache, nausea, rash, alopecia and rectal bleeding.

  • The FDA label for pentosan (Elmiron, Janssen) advises people undergoing invasive procedures or having signs or symptoms of underlying coagulopathy or other increased risk of bleeding should be evaluated for haemorrhage.

Patient factors

  • The FDA label for Elmiron recommends people taking pentosan should be reassessed after 3 months, and if improvement has not occurred and if limiting adverse events are not present, treatment may be continued for another 3 months. The clinical value and risks of continuing treatment in people whose pain has not improved by 6 months is not known.

  • The FDA label for Elmiron advises that people taking pentosan should be reminded that pentosan has a weak anticoagulant effect; this may increase bleeding times.

Resource implications

  • No price is listed for pentosan and the cost will differ depending on the source. The NHS prescription cost analysis for England 2013 reports that the mean cost of pentosan polysulfate sodium 100 mg capsules was £487.14 per item, and the mean quantity per item was 117. This equates to approximately £4.16 per capsule, or £374.40 for 30 days treatment (100 mg 3 times daily).

  • The 30‑day cost of amitriptyline at dose of 10 mg to 150 mg daily is £1.13 to £3.70 (Drug Tariff March 2015).

  • The 30‑day cost of cimetidine at a dose of 400 mg twice daily is £1.82 (Drug Tariff March 2015).

  • The 30‑day cost of ciclosporin at a dose of 100 mg twice a day is £145.14 (MIMS March 2015).

Introduction and current guidance

Interstitial cystitis (also referred to as bladder pain syndrome or chronic pelvic pain syndrome) is a chronic bladder condition characterised by pain, urinary urgency, frequency and nocturia. In clinical practice the diagnosis of interstitial cystitis is often made once specific causes such as infection and malignancy have been ruled out.

There is no NICE guidance on interstitial cystitis.

Guidelines produced by the European Association of Urology (2015) make recommendations on a number of treatments for interstitial cystitis, including patient education, self‑care and behaviour modification, manual physical therapy techniques, multimodal pain management approaches, oral drugs and intravesical treatments.

Full text of introduction and current guidance.

Product overview

Pentosan polysulfate sodium (pentosan) is a low molecular weight heparin‑like compound with anticoagulant and fibrinolytic effects. The mechanism of action of pentosan in interstitial cystitis is unknown; it may act as a buffer to control cell permeability preventing irritating solutes in the urine from reaching the cells (FDA label for Elmiron, Janssen).

Pentosan is not licensed in the UK. Pentosan is licensed in other countries, including the USA, for the relief of bladder pain or discomfort associated with interstitial cystitis.

Full text of product overview.

Evidence review

  • A double‑blind, randomised controlled trial (RCT, n=369) in adults aged 18 or over with interstitial cystitis found no statistically significant difference between pentosan 100 mg 3 times daily and placebo using the Interstitial Cystitis Symptom Index (ICSI), a validated patient questionnaire covering pain, urinary urgency, frequency and nocturia (Nickel et al. 2014). The study was underpowered, randomising only 369 of the required 645 participants. Slow enrolment of participants and an interim analysis of data prompted early termination of the study.

  • A meta‑analysis included 4 RCTs (n=448) comparing pentosan with placebo in adults (Hwang et al. 1997). The meta‑analysis found pentosan statistically significantly improved symptoms of pain, urinary urgency and frequency compared with placebo. There was no statistically significant difference between pentosan and placebo for improvements in nocturia. However, results from the individual studies included in the meta‑analysis were inconsistent, with some trials finding no statistically significant difference between pentosan and placebo for these outcomes. The trials included in the meta‑analysis used a number of different outcome measures, did not use validated tools to measure responses and some trials used multiple methods to assess a single symptom.

  • Differences in inclusion criteria and how symptoms were assessed may explain the inconsistent results seen in the published placebo‑controlled trials involving pentosan.

  • Trials comparing pentosan with other active treatments are limited. A 6‑month, randomised, unblinded trial (n=64) found that after 6 months treatment, a 50% reduction in micturition frequency was achieved in 11 out of 32 people (34.3%) taking ciclosporin, and no people taking pentosan (p<0.001). More people taking ciclosporin reported adverse events compared with those taking pentosan; 94% compared with 56% (Sairanen et al. 2005).

  • A 32‑week, randomised, double‑blind, dose‑ranging study compared 3 different doses of pentosan; 100 mg, 200 mg and 300 mg 3 times daily. At the end of study period the ICSI score for each dose had statistically significantly improved from baseline, although there was no placebo arm for comparison. There was no statistically significant difference in ICSI score between the 3 different doses. The trial was underpowered; only 230 (60.5%) of the 380 participants completed the study.

  • The study found diarrhoea and rectal bleeding were the only adverse events that were dose‑dependent. Statistically significantly more people taking the highest dose discontinued treatment due to adverse events compared with people taking the lowest dose (Nickel et al. 2005).

  • Pentosan is a weak anticoagulant. The FDA label for Elmiron (Janssen) advises that people undergoing invasive procedures, those who may have signs or symptoms of underlying coagulopathy and people with other increased risk of bleeding (for example due to other treatments) should be evaluated for haemorrhage.

  • Adverse events reported by people taking pentosan in clinical trials include diarrhoea, headache, nausea, rash, alopecia and rectal bleeding.

Full text of evidence review.

Context and estimated impact for the NHS

No estimate of the current use of pentosan for interstitial cystitis was identified. No price is listed for pentosan and the cost will differ depending on the source. The NHS prescription cost analysis for England 2013 reports that the mean cost of pentosan polysulfate sodium 100 mg capsules was £487.14 per item, and the mean quantity per item was 117. This equates to approximately £4.16 per capsule, or £374.40 for 30 days treatment (100 mg 3 times daily). In 2013, 400 items of pentosan polysulfate sodium 100 mg were dispensed at a net cost of £214,300. It is not known for which indications these items were prescribed.

Full text of context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for people with interstitial cystitis who are thinking about trying pentosan.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.