1. PBS/IC (Painful Bladder Syndrome/Interstitial Cystitis) Unravelling the Enigma PMR-MAY-2009-0239 Date of preparation: May 2009 Slides prepared by Galen Limited as a service to medicine Uracyst® (Chonroitin Sulfate, 2%) Prescribing Information is available on the last slide of this presentation

2. What is PBS/IC? Symptoms and impact of PBS/IC Management of PBS/IC Causes and diagnosis of PBS/IC Uracyst Agenda

3. What is PBS/IC? Symptoms and impact of PBS/IC Management of PBS/IC Causes and diagnosis of PBS/IC Uracyst Agenda

4. Definition of PBS/IC*  Suprapubic pain related to bladder filling  Increased daytime and night-time frequency  Absence of infection or other pathology *The ICS reserves the term interstitial cystitis as being a ‘specific diagnosis and requires confirmation by typical cystoscopic features’.

5. Nomenclature  Interstitial cystitis  Painful Bladder syndrome  Bladder Pain Syndrome  Hypersensitive Bladder Syndrome  Chronic Pelvic Pain Syndrome PBS/IC

6. Prevalence of PBS/IC Females All patients Males 0-1920-2930-3940-4950-5960-6970-79 0 2 4 6 8 10 Incidence/ 100 000 Age group, years Age-specific incidence rates for males, females and all patients with interstitial cystitis 1

7. What is PBS/IC? Symptoms and impact of PBS/IC Management of PBS/IC Causes and diagnosis of PBS/IC Uracyst Agenda

8. Cardinal Symptoms of PBS/IC  Pain  Frequency  Urgency

9. Patient quote “IC affects your family life so much. Even with the simple basic things like taking a shopping trip, you have to realise that you can no longer do what you like, when you like, as you have to plan on finding toilets. My children know that wherever we are ‘Mummy will have to find a toilet soon’.” GALEN WOULD LIKE TO THANK MEMBERS OF THE CYSTITIS AND OVERACTIVE BLADDER FOUNDATION FOR SUPPLYING THESE QUOTES.

10. Patient quote “Having IC has completely changed my working life. I went from working in a full-time, well paid job to being forced to work part-time, local to my home, as I couldn’t travel on public transport anymore.” GALEN WOULD LIKE TO THANK MEMBERS OF THE CYSTITIS AND OVERACTIVE BLADDER FOUNDATION FOR SUPPLYING THESE QUOTES.

11. Patient quote “IC alters your intimate relationships. It’s very difficult to continue to have a fulfilling relationship when you are suffering with so much pain and discomfort.You really do need to have a very understanding partner who realises what you are going through.” GALEN WOULD LIKE TO THANK MEMBERS OF THE CYSTITIS AND OVERACTIVE BLADDER FOUNDATION FOR SUPPLYING THESE QUOTES.

12. Impact on Quality of Life Pain, urinary urgency, and urinary frequency Reduced QoL Limitations on sexual intimacy Curtailed activities Sleep deprivation Reduced ability to work

13. Economic Impact  More data is required  NHS incurs a considerable cost in treating PBS/IC  Clemens et al (US): 1  Direct cost per year per patient = $3,631  Indirect cost to the patient per year = $4,216

14. What is PBS/IC? Symptoms and impact of PBS/IC Management of PBS/IC Causes and diagnosis of PBS/IC Uracyst Agenda

15. Causes of PBS/IC Irritating solutes Urothelium Irritated nerve GAG layer Inflammation

16. Associated conditions

17. Challenges of diagnosis Interstitial cystitis Alone or in different combinations No biological markers Restrictive research-based criteria Painful invasive techniques Issues related to the diagnosis of PBS/IC

18. NIDDK inclusion criteria  Bladder pain or urinary urgency  Glomerulations or Hunner’s ulcer on cystoscopy  Specific findings after hydrodistention

19. Differential diagnosis PBS/IC Urinary Tract Infection Medication Endometriosis Bladder Carcinoma Overactive Bladder

20. What is PBS/IC? Symptoms and impact of PBS/IC Management of PBS/IC Causes and diagnosis of PBS/IC Uracyst Agenda

21. Components of basic assessment Medical History Physical Examination Urine cultures Voiding diary Symptom scales

22. Management of PBS/IC  Diet  Oral therapy  Intravesical therapy

23. Diet

24. Pharmacological management Epithelial insult Activation of C fibres Release of Substance P More inflammation Mast cell activation; histamine release Epithelial layer damage Potassium leak into bladder wall GAG-like therapies Inhibit neurological activity Antihistamines Anti-inflammatory drugs

25. Oral therapy  Amitriptyline  Analgesics  Antihistamines  Anti-inflammatory agents  Anticholinergics

26. Oral Therapy continued  Anticonvulsants  Cimetidine  Immunosuppressive agents  Pentosan polysulfate sodium

27. Intravesical therapy  Chondroitin sulfate  Sodium hyaluronate  Dimethyl sulfoxide

28. Patient perception of intravesical therapy for PBS/IC Agent Total no. of patients Improved Made worse No effect DMSO 159/750 (21.2%) 59 (37.1%) 57 (35.8%) 43 (27.1%) Cystistat 28/750 (3.7%) 15 (53.6%) 3 (10.7%) 10 (35.7%) Heparin sodium 25/750 (3.3%) 16 (64%) 5 (20%) 4 (16%)

29. Surgery  Usually last resort  Bladder augmentation  Urinary diversion  Cystectomy  Pelvic pain may continue even after the bladder is removed

30. What is PBS/IC? Symptoms and impact of PBS/IC Management of PBS/IC Causes and diagnosis of PBS/IC Uracyst Agenda

31. The role of GAGs

32. Uracyst  2% solution of sodium chondroitin sulfate  Medical device  Physically restores the GAG layer  Alleviates symptoms, significantly improving patient quality of life

33. Uracyst may provide the optimum dose of chondroitin sulfate 1

34. Nickel et al 2008 1  Aim  To assess the efficacy and safety of intravesical chondroitin sulfate (Uracyst) in the treatment of patients with a clinical diagnosis of IC  Method  Fifty-three patients with IC were enrolled in a multicentre, community-based, open-label study, and received intravesical instillations of Uracyst once a week for six weeks, then once a month for 16 weeks  Endpoints  The primary endpoint - the percentage of responders to treatment at week 10* * assessed by a Global Response Assessment (GRA) scale

35. Uracyst - 47% response rate after 6 treatments 1 53 patients were treated with Uracyst via urinary catheter Weekly for 6 weeks Then monthly for 16 weeks *Responders to treatment are indicated by a marked or moderate improvement on a seven-point Global Response Assessment (GRA) scale.

36. Uracyst – effectively relieves the symptoms of PBS/IC 1 Pain, urgency and frequency were measured using a 0-10cm visual analogue pain scale

37. Uracyst – significantly improves patient quality of life 1 Symptom and bother scores were measured using the O’Leary-Sant Symptom/Problem Index

38. Instillation of Uracyst Catheter Uracyst in bladder

39. Suggested Uracyst treatment plan  Weekly instillations for 4-6 weeks, then monthly thereafter  Optimum response in 4-6 months  Revert back to weekly treatment in cases of symptom flare-up  More frequent therapy may be required in patients with severe PBS/IC  No adverse effects are expected with Uracyst 2  Pain/discomfort/infection associated with the catheter are possible

40. Supporting the patient 1  Be understanding of the challenges facing the patient  Reassure the patient  Explore treatment options  Support self-care

41. Uracyst Prescribing Information The full Prescribing Information should be consulted prior to use. Uracyst® Abbreviated Prescribing Information. Description: Each ml of Uracyst contains 20mg sodium chondroitin sulfate (400mg of chondroitin sulfate per 20ml vial). Chondroitin sulfate is an acidic mucopolysaccharide and is one of the glycosaminoglycans (GAGs). The luminal surface of the bladder is coated with a layer of GAGs that provide a protective impermeable barrier to the bladder. Damage to this GAG layer may result in deficiencies to its protective barrier, inducing irritations in the bladder wall. Chondroitin sulfate is an important component of the bladder GAGs that can replenish the deficient GAG layer on the bladder epithelium. Indications: For replenishment of the glycosaminoglycan (GAG) layer in the bladder, for patients with damaged or GAG deficient bladder epithelium. Dosage and administration: Instil 20ml into the bladder after any residual urine has been removed. For optimum results, Uracyst should be used full strength without dilution, and retained in the bladder as long as possible (not less than 30 minutes). Repeat the instillation of 20ml weekly for 4 to 6 weeks, then, monthly thereafter until symptoms are relieved. Most patients benefit from 6 weekly 20ml instillations, then monthly instillations thereafter depending on their symptomatic response. Contraindications: Do not administer to patients with known hypersensitivity to the solution. Warnings: For Bladder Instillation only. Uracyst contains neither preservatives nor antimicrobials; therefore, any unused portion must be discarded. Precautions: Bring the contents of vial to room temperature before use. Adverse effects: No known adverse effects. Short-term discomfort may be caused by the catheterisation process. Legal category: Medical device. CE Number: CE 0473. CE Mark Holder: Stellar Pharmaceuticals Inc, 544 Egerton Street, London, Ontario, Canada N5W 3Z8. Package quantities and price: Single-dose glass vial of 20ml. Packages of four: £260 (UK), €300 (Ireland). Storage: Store 2 to 25 o C. Do not freeze. Discard unused portions. Distributed by: Galen Limited. Date of preparation: May 2009. Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA. Galen Ireland, c/o Allphar Services Ltd, 4045 Kingswood Road, Citywest Business Park, Co Dublin, Ireland. Telephone: +44 (0) 28 3833 4974. Fax: +44 (0) 28 3839 1640. Website: www.galen.co.uk. Email: info@galen.co.uk.info@galen.co.uk Adverse incidents should be reported. Reporting forms and information can be found at www.mhra.gov.uk or www.imb.ie. Adverse incidents should also be reported to Galen Limited on +44 (0)28 3833 4974 and select the customer services option, or e-mail info@galen.co.uk. Medical information enquiries should also be directed to Galen Limited.