Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: bene-Arzneimittel GmbH, Herterichstrasse 1-3, D-81479 Munich, tel: ++49 (0) 89/7 49 87-0, fax: ++49 (0) 89/7 49 87-142, e-mail: contact@bene-arzneimittel.de
Pharmacotherapeutic group: Urologicals, other urologicals
ATC code: G04BX15
The hypothetic mechanism of action of pentosan polysulfate sodium includes a local effect in the bladder after systemic administration and excretion into the urine by binding of glycosaminoglycans to the deficient mucous of the bladder. This binding of glycosaminoglycans to the bladder mucous reduces bacterial adherence to the inner surface of the bladder and in consequence the incidence of infections is reduced as well. It is hypothesized, that a potential barrier function of pentosan polysulfate sodium instead of the damaged urothelial mucus might play a role as well the antiinflammatory activity of pentosan polysulfate sodium.
A total of four randomised placebo-controlled, double-blind clinical studies prospectively enrolling patients with bladder pain syndrome diagnosed via cystoscopic examination with or without bladder hydrodistension evaluating the efficacy of oral treatment with pentosan polysulfate sodium were published in scientific literature. In all of these studies, patients reported a better subjective improvement of bladder pain syndrome under treatment with pentosan polysulfate sodium compared to placebo. In three studies, the observed difference was clearly statistically significant.
The first study was a double-blind, randomized, placebo-controlled study with a planned cross-over design evaluating pentosan polysulfate sodium versus placebo. Depending on which institution the patients attended they were treated with either 3x100 mg or 2x200 mg PPS per day. 75 patients were randomised into the study and 62 of those completed the study. Efficacy of treatment was evaluated based on the patient reported improvement on four typical symptoms of bladder pain syndrome: pain, urgency, frequency, and nocturia, no primary endpoint was defined. A patient was counted as a responder to treatment in case a 50% improvement compared to baseline was reported for a specific symptom after 3 months of treatment. An evaluation of all data generated in the study showed that for all four symptoms statistically significant more patients responded to pentosan polysulfate sodium treatment compared to placebo:
| PPS | Placebo | P-value | |
|---|---|---|---|
| Pain | |||
| No. responders/total (%) | 19/42 (45) | 7/38 (18) | 0.02 |
| Av. % improvement* | 33.0 ± 35 | 15.8 ± 26 | 0.01 |
| Urgency | |||
| No. responders/total (%) | 21/42 (50) | 9/48 (19) | 0.03 |
| Av. % improvement* | 27.6 ± 31 | 14.0 ± 24 | 0.01 |
| Frequency | |||
| No. responders/total (%) | 33/52 (63) | 16/41 (39) | 0.005 |
| Av. % improvement | -5.1 | -0.4 | 0.002 |
| Nocturia | |||
| Av. % improvement* | -1.5 ± 2.9 | -0.5 ± 0.5 | 0.04 |
(*Mean ± SD)
The following two studies were conducted following very comparable double-blind, randomized, placebo-controlled multicentre study designs. The patients in both studies were treated for three months with either 3x100 mg pentosan polysulfate sodium or placebo. The primary efficacy endpoint of the study was the overall improvement as self-reported by the patient after three months of treatment. The patients were asked whether they felt improved overall since the start of treatment, and if so, whether the improvement was “slight” 25%, "moderate "50%, “great” 75% or “complete cure” 100%. Patients who reported at least moderate (50%) improvement were counted as responders. The secondary efficacy endpoints included the investigators evaluation of improvement. The used scale for the investigators assessment included the categories “worse”, “no change”, “fair”, “good”, “very good”, and “excellent”. A responder was defined as a patient assessed to be at least “good” compared to baseline. Furthermore volume voiding profiles over three days and the impact of treatment on pain and urgency were evaluated as secondary endpoints. The impact on pain and urgency was evaluated via the same questionnaire as the primary endpoint with a responder defined as a patient experiencing an at least moderate (50%) improvement compared to baseline. In addition the impact on pain and urgency was evaluated via a 5 score scale, where a responder was defined as a patient experiencing at least a 1-point improvement compared to baseline.
110 patients were enrolled and treated for three months in the first of the two very comparable studies. A statistically significant benefit of pentosan polysulfate sodium over placebo was demonstrated over the primary endpoint, the patients overall-assessment of improvement as well as on the investigators overall assessment. Furthermore a trend for better efficacy of pentosan polysulfate sodium was observed for the patients self-assessment of an improvement of pain and urgency, despite a deviating effect observed for the evaluation of urgency via the scale. In addition positive effects were observed on the voiding profile, although the observed differences were not statistically significant:
| PPS | Placebo | P-value | |
|---|---|---|---|
| Responders based on patients self-evaluation of overall improvement | 28% | 13% | 0.04 |
| Responders based on investigators evaluation of overall improvement | 26% | 11% | 0.03 |
| Responders regarding pain and urgency | |||
| Pain (moderate/50% improvement) | 27% | 14% | 0.08 |
| Pain scale (1-point improvement) | 46% | 29% | 0.07 |
| Pressure to urinate (moderate/50% improvement) | 22% | 11% | 0.08 |
| Urgency scale (1-point improvement) | 39% | 46% | ns |
| Mean reduction in pain score from baseline | 0.5 | 0.2 | ns |
| Changes from baseline voiding characteristics | |||
| Mean volume per void (cc) | 9.8 | 7.6 | ns |
| Increase of ≥20 cc (% pts) | 30 | 20 | ns |
| Total daily urine volume (cc) | +60 | -20 | ns |
| Voids per day | -1 | -1 | ns |
| 3 voids less per day (% pts) | 32 | 24 | ns |
| Nocturia | -0.8 | -0.5 | ns |
The second of the two very comparable studies enrolled 148 patients and demonstrated a statistically significant benefit pentosan polysulfate sodium over placebo was demonstrated on the patient reported overall improvement evaluated as primary endpoint and an the investigator-assessed overall improvement, all evaluations on pain and urgency. A trend for better efficacy under pentosan polysulfate sodium was observed for improved sexual intercourse:
| PPS | Placebo | P-value | |
|---|---|---|---|
| Responders based on patients self-evaluation of overall improvement | 32% | 16% | 0.01 |
| Responders based on investigators evaluation of overall improvement | 36% | 15% | 0.002 |
| Responders regarding pain and urgency | |||
| Pain (moderate/50% improvement) | 38% | 18% | 0.005 |
| Pain scale (1-point improvement) | 66% | 51% | 0.04 |
| Pressure to urinate (moderate/50% improvement) | 30% | 18% | 0.04 |
| Responders regarding pain and urgency | 61% | 43% | 0.01 |
| Improved sexual intercourse | 31% | 18% | 0.06 |
| Changes from baseline voided volume | |||
| Mean volume per void (cc) | +20.4 | -2.1 | ns |
| Increase of ≥20 cc (% pts) | 40 | 24 | 0.02 |
| Total daily urine volume (cc) | +3 | -42 | ns |
The fourth study was following a double-blind, double-dummy, multifactorial design and evaluated the effects of pentosan polysulfate sodium and hydroxyzine in one study. Patients were randomized to four treatment group and were treated for six months with 3x100 mg pentosan polysulfate sodium, 1x50 mg hydroxyzine, both active treatments, or placebo. A responder analysis based on a patientreported Global Response Assessment (GRA) after 24 weeks of treatment was defined as primary endpoint. The GRA assessment was evaluated via a 7-point centred scale, in which the patients can assess their global response compared to baseline as markedly worse, moderately worse, slightly worse, no change, slightly improved, moderately improved or markedly improved. Participants who reported either of the latter two categories were defined as treatment responders. Secondary outcome measures included the O’Leary-Sant IC Symptom and Problem Index, the University of Wisconsin Symptom score, patient reported symptoms of pain/discomfort and urgency, and results of a 24-hour voiding diary. Comparison of those patients receiving pentosan polysulfate sodium with those not receiving pentosan polysulfate sodium (irrespective of treatment with oral hydroxyzine) revealed no statistically significant difference between the two group, but a trend for better efficacy was observed for the primary endpoint in those patients treated with pentosan polysulfate sodium (either alone or in combination with hydroxyzine) (20 of 59, 34%) compared to the those patients not receiving pentosan polysulfate sodium, but who might receive hydroxyzine (11 of 62, 18%, p0.064):
| PPS | Placebo | |
|---|---|---|
| No. randomized | 59 | 62 |
| No. responders (%) | 20 (34) | 11 (18) |
| No. complete secondary end point data (%) | 49 (83) | 47 (76) |
| Mean pain score ± SD (0-9) | -1.2 ± 1.9 | -0.7 ± 1.8 |
| Mean urgency score ± SD (0-9) | -1.2 ± 1.6 | -0.9 ± 1.6 |
| Mean 24-hr frequency ± SD | -0.7 ± 4.8 | -0.9 ± 6.3 |
| Mean IC symptom index ± SD (0-20) | -2.6 ± 3.4 | -1.7 ± 3.5 |
| Mean IC problem index ± SD (0-16) | -2.6 ± 3.5 | -1.9 ± 2.8 |
| Mean Wisconsin IC score ± SD (0-42) | -6.2 ± 8.9 | -6.7 ± 8.2 |
A pooled analysis of the data described above from placebo-controlled clinical studies was conducted to evaluate, whether patients taking oral pentosan polysulfate sodium have clear benefit from the treatment. This pooled analysis showed that the percentage of patients responding to treatment with pentosan polysulfate sodium with a clinically relevant improvement in their overall assessment, pain and urgency was approximately 2-fold higher than the respective responder rates under placebo:
| PPS | Placebo | |
|---|---|---|
| GRA (95% CI) | 33.0% (27.1%-39.4%) | 15.8% (11.6%-21.2%) |
| Pain (95% CI) | 32.7% (26.0%-40.3%) | 14.2% (9.6%-20.6%) |
| Urgency (95% CI) | 27.4% (21.1%-34.8%) | 14.2% (9.6%-20.6%) |
Less than 10% of orally administered pentosan polysulfate sodium are slowly absorbed from the gastrointestinal tract and are available in systemic circulation in the form of unchanged pentosan polysulfate sodium or it’s metabolites. All studies describe very low systemic availability of unchanged pentosan polysulfate sodium after oral administration. Overall, the reported systemic bioavailability after oral administration of pentosan polysulfate sodium is below 1%.
In healthy volunteers, a single parenteral administration of radioactively labelled pentosan polysulfate sodium leads to a progressive up-take of total radioactivity by the liver, spleen, and kidney (50 min after 1 mg/kg i.v.: 60% of the dose in the liver, 7.7% in the spleen; 3 h post dosing: 60% in the liver plus spleen, and 13% in the bladder).
Pentosan polysulfate sodium is metabolised extensively by desulfation in liver and spleen and depolymerisation in the kidney.
The apparent plasma half-life of pentosan polysulfate sodium depends on the route of administration. While pentosan polysulfate sodium is rapidly cleared from circulation of i.v. administration, the apparent plasma half-life after oral administration is in the range of 24-34 hours. Accordingly, oral administration of pentosan polysulfate sodium 3-times daily is expected to lead to accumulation of pentosan polysulfate sodium over the first 7 days of administration (accumulation factor 5-6.7). After oral administration unabsorbed pentosan polysulfate sodium is excreted predominantly unchanged in the faeces. About 6% of the administered dose of pentosan polysulfate sodium were excreted via urine after desulfation and depolymerisation.
Non-clinical data reveal no special hazard for humans based on conventional repeated dose toxicity, genotoxicity and long-term carcinogenicity studies.
The effect of pentosan polysulfate sodium on reproductive and developmental toxicity has not been investigated.
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