pentosan polysulfate sodium: prescribing information – dosing, contraindications, interactions, side effects

elmiron is indicated for the treatment of bladder pain syndrome characterized by either glomerulations or Hunner’s lesions in adults with moderate to severe pain, urgency and frequency of micturition (see section 4.4).

Posology

Adults
The recommended dose of pentosan polysulfate sodium is 300 mg/day taken as one 100 mg capsule orally three times daily.
Response to treatment with pentosan polysulfate sodium should be reassessed every 6 months. In case no improvement is reached 6 months after treatment initiation, treatment with pentosan polysulfate sodium should be stopped. In responders pentosan polysulfate sodium treatment should be continued chronically as long as the response is maintained.

Special populations
Pentosan polysulfate sodium has not been specifically studied in special patient populations like elderly or patients with renal or hepatic impairment (see section 4.4). No dose adjustment is recommended for these patients.

Paediatric population
The safety and efficacy of pentosan polysulfate sodium in children and adolescent below 18 years has not been established.
No data are available.

Method of administration

The capsules should be taken with water at least 1 hour before meals or 2 hours after meals.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Due to the weak anticoagulant effect of pentosan polysulfate sodium, elmiron must not be used in patients who actively bleed. Menstruation is no contraindication.

Summary of the safety profile

The following section lists adverse events reported in the literature from clinical studies with pentosan polysulfate sodium. The potential relatedness between these adverse events and the treatment with pentosan polysulfate sodium was not discussed in the respective publications.

The most common adverse events reported from the clinical studies are headache, dizziness and gastro-intestinal events like diarrhoea, nausea, abdominal pain and rectal bleeding.

The adverse events reported under treatment with pentosan polysulfate sodium were comparable to those reported under treatment with placebo in regards to quality and quantity.

Tabulated summary of adverse events

Adverse events are listed below by MedDRA body system organ class and by frequency. Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

Infections and infestations
Common
Infections, influenza
Blood and lymphatic system disorders
Uncommon
Anaemia, ecchymosis, haemorrhage, leukopenia, thrombocytopenia
Not known
Coagulation disorders
Immune system disorder
Uncommon
Photosensitivity
Not known
Allergic reactions
Metabolism and nutrition disorders
Uncommon
Anorexia, weight gain, weight loss
Psychiatric disorders
Uncommon
Severe Emotional Lability/Depression
Nervous system disorders
Common
Headache, dizziness
Uncommon
Increased sweating, insomnia, hyperkinesia, paraesthesia
Eye disorders
Uncommon
Lacrimation, amblyopia
Ear disorders
Uncommon
Tinnitus
Respiratory, thoracic and mediastinal disorders
Uncommon
Dyspnoea
Gastrointestinal disorders
Common
Nausea, diarrhoea, dyspepsia, abdominal

pain, abdomen enlarged, rectal haemorrhage
Uncommon
Indigestion, vomiting, mouth ulcer, flatulence, constipation
Skin and subcutaneous tissue disorders
Common
Peripheral oedema, alopecia
Uncommon
Rash, increased mole size
Musculoskeletal and connective tissue disorders
Common
Back pain
Uncommon
Myalgia, Arthralgia
Renal and urinary disorders
Common
Urinary frequency
General disorders and administration site conditions
Common
Asthenia, pelvic pain
Investigation
Not known
Liver function abnormalities

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Bladder pain syndrome is a diagnosis of exclusion and other urologic disorders should be eliminated by the prescriber, such as urinary tract infection or bladder cancer.

Pentosan polysulfate sodium is a weak anticoagulant. Patients undergoing invasive procedures or having signs/symptoms of underlying coagulopathy or other increased risk of bleeding (due to treatment with other medicinal products influencing coagulation such as anticoagulants, heparin derivatives, thrombolytic or antiplatelet agents including acetylsalicylic acid, or nonsteroidal anti- inflammatory medicinal products (see section 4.5)) should be evaluated for haemorrhagic events.
Patients who have a history of heparin or pentosan polysulfate sodium induced thrombocytopenia should be carefully monitored when treated with pentosan polysulfate sodium.

Hepatic or renal insufficiency

elmiron has not been studied in patients with hepatic or renal insufficiency. Because there is evidence of hepatic and renal contribution to the elimination of pentosan polysulfate sodium, hepatic or renal impairment may have an impact on the pharmacokinetics of pentosan polysulfate sodium. Patients with relevant hepatic or renal insufficiency should be carefully monitored when treated with pentosan polysulfate sodium.

Rare cases of pigmentary maculopathy have been reported with use of pentosan polysulfate sodium (PPS), especially after long term use. Visual symptoms might include complaints of difficulty when reading, visual distortions, altered colour vision and/or slow adjustment to low or reduced light environments.
All patients should have an ophthalmologic examination after 6 months of use of PPS for early detection of pigmentary maculopathy, and, if there are no pathologic findings, regularly after 5 years of use (or earlier, in case of visual complaints). However, in case of relevant ophthalmologic findings, a yearly examination should be conducted. In such situations, treatment cessation should be considered.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

A study in healthy subjects revealed no pharmacokinetic or pharmacodynamic interactions between therapeutic doses of warfarin and pentosan polysulfate sodium. No further interaction studies have been performed.

Due to the weak anticoagulant effect of pentosan polysulfate sodium, patients, who are concomitantly treated with anticoagulants, heparin derivatives, thrombolytic or antiplatelet agents including acetylsalicylic acid, or nonsteroidal anti-inflammatory medicinal products should be evaluated for any haemorrhagic event in order to adapt the dose if needed (see section 4.4).

Pregnancy

There are no data from the use of pentosan polysulfate sodium in pregnant women. Animal studies with respect to reproductive toxicity were not conducted.

elmiron is not recommended during pregnancy.

Breast-feeding

It is unknown whether pentosan polysulfate sodium or metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Therefore, pentosan polysulfate sodium should not be used during breast-feeding.

Fertility

No information on a potential impact of pentosan polysulfate sodium on fertility is available.

Pentosan polysulfate sodium has no or negligible influence on the ability to drive and use machines.

In the case of an accidental overdose, patients should be evaluated for potential adverse effects of pentosan polysulfate sodium like gastrointestinal symptoms or bleeding. In case of adverse reactions, treatment might be paused until the symptoms abate and treatment should be continued at the recommended dose after a critical balancing of the risks thereafter.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Urologicals, other urologicals, ATC code: G04BX15.

Mechanism of action

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 anti- inflammatory activity of pentosan polysulfate sodium.

Clinical efficacy and safety

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)

Absorption

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 %.

Distribution

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).

Biotransformation

Pentosan polysulfate sodium is metabolised extensively by desulfation in liver and spleen and depolymerisation in the kidney.

Elimination

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.