1. A summary of the rationale and clinical evidence
Uracyst
A summary of the rationale and clinical evidence
Abbreviated Prescribing Information can be found on the last slide of this presentation.
PMR-NOV
Date of Preparation: November 2010.

2. Uracyst 2% solution of sodium chondroitin sulfate Medical device
Indicated for the replenishment of the GAG layer in the bladder, for patients with damaged or GAG deficient bladder epithelium
Available in 20ml vials (400mg of chondroitin sulfate per vial)
Although this will predominantly relate to PBS/IC, a deficit in the bladder GAG layer has also been implicated in a number of other conditions, e.g.:
Radiation cystitis
Chronically-recurring bacterial cystitis
Overactive bladder

3. Instillation of Uracyst
Roadmap
Mode of Action
Cost comparison
Uracyst
Clinical Evidence
Instillation of Uracyst

4. The role of the Glycosaminoglycan layer in PBS/IC
The majority of published literature supports the belief that the symptoms of PBS/IC are associated with abnormal permeability due to deficiencies in the GAG layer of the bladder wall.1,2
A functional deficiency of the GAG layer is related to the underlying cause of as many as 60-70% of PBS/IC cases.3
A leaky urothelium, secondary to a deficient GAG layer, allows urine to enter the deeper layers of the bladder wall, resulting in a wide-spread inflammation which could be responsible for the symptoms of PBS/IC. This latter defect could lead to the absorption of potentially toxic substances across the bladder epithelium and trigger a chronic inflammatory reaction in the subepithelial layers, or expose the bladder to uncommon antigens, so promoting an immune response, mast cell activation and the release of histamine.4
The diagram above helps to explain the normal function of the GAG layer, what happens when it is damaged, and how GAG-like therapies such as Uracyst (chondroitin sulfate) can help to alleviate the symptoms of PBS/IC and initiate bladder healing.
The normal urothelium has a high density of glycosaminoglycans, which are present in the form of proteoglycans, and form the so-called ‘GAG layer’. This impermeable protective layer, prevents the penetration of potentially harmful substances such as potassium ions and urinary proteases from penetrating into the deeper layers of the bladder wall.3,5
When this GAG layer is damaged, the protective impermeability function is lost. Potassium, proteases, and other potentially harmful urinary solutes are allowed to penetrate into the bladder, where they may activate sensory neurones. This will result in inflammation and the characteristic symptoms of PBS/IC such as pain and urinary urgency.2,4
Administration of GAG-like therapies, such as Uracyst, restore the GAG layer, and act as a physical barrier to the penetration of these harmful substances i.e. the impermeable nature of the bladder surface is restored.5 Sensory neurones will no longer be activated and inflammation will be reduced. In clinical terms this means the symptoms associated with PBS/IC will be alleviated, and the bladder will be allowed to heal.
1. Screening, treatment and management of interstitial cystitis/painful bladder syndrome. Clinical Proceedings. Association of Reproductive Health Professionals. April 2008.
2. Rosenberg M , Newman D and Page S. Interstitial cystitis/painful bladder syndrome: Symptom recognition is key to early identification, treatment. Cleveland Clinic Journal of Medicine. 2007; 74 (S3): S54-S62.
3. Hurst RE, Roy J and Parsons C. The role of Glycosaminoglycans in normal bladder physiology and the pathophysiology of interstitial cystitis. Interstitial Cystitis Philadelphia. Lippincott-Raven Publishers.
4. Kelada E and Jones A. Interstitial cystitis. Arch Gynecol Obstet (2007) 275:
5. Hurst RE et al. A deficit of proteoglycans on the bladder uroepithelium in interstitial cystitis. European Urology Supplements. 2 (2003)

5. Hurst et al 19876
GAG replacement therapy has become a mainstay in the management of PBS/IC. An understanding of the location of the different GAGs in the bladder wall, relative to each other, may influence the decision on which GAG-like therapy to use.
In this animal study6 (Hurst et al, 1987), two experiments were carried out to assess the distribution of certain GAGs in the bladder.
In the first experiment, the bladder was damaged with trypsin and 10mM HCL for 10 minutes. The results indicated that chondroitin sulfate is one of the first GAGs to be lost as a result of acid damage (which mimics at least some of the features of PBS/IC).
In the second experiment, trypsin and 10mM HCL were again used to induce bladder damage, this time for a longer period of 16 hours. This experiment virtually deconstructed the bladder wall, and it was demonstrated that increasing amounts of hyaluronate were lost as a result of this more extensive damage.
These results would appear to confirm that chondroitin sulfate is primarily located on the surface of the bladder wall, and so may be lost even after relatively mild bladder damage. Hyaluronate, however, appears to be located deeper in the bladder wall, and so may not be lost until more extensive bladder damage has occurred. It may, therefore, be advantageous to treat PBS/IC patients with chondroitin sulfate earlier than with hyaluronate.
6. Hurst RE et al. Functional and structural characteristics of the glycosaminoglycans of the bladder luminal surface. The Journal of Urology. 1987; 138:

6. Chondroitin sulfate deficit in PBS/IC bladders
The picture on the slide demonstrates that PBS/IC patients not only have a damaged GAG layer, but also have a specific deficit of chondroitin sulfate on the surface of the bladder wall.
The left-hand side shows a normal, control biopsy with a healthy, intact GAG layer, and a clearly detectable layer of chondroitin sulfate. The right-hand side shows a PBS/IC bladder with an obvious deficit of chondroitin sulfate. This deficit may be a significant contribution to the increased permeability of the GAG layer.
It has been observed that PBS/IC patients not only have increased bladder permeability, and decreased levels of urinary GAG, but also have a specific deficit of chondroitin sulfate on the luminal surface of the bladder wall. Chondroitin sulfate, like all GAGs, is composed of repeating units of two simple sugars, namely glucuronic acid and a galactosamine. It also has one negatively charged, hydrophilic, sulphated group.7
Studies have been carried out which have assayed the bladder surface for the presence of chondroitin sulfate. The first of these, in 1996, used tissue sections derived from biopsies of 31 IC patients and 24 control sections. Only 5 out of 31 (16%) IC sections were positive for the presence of chondroitin sulfate, compared to 14 out of 24 (58%) control sections. This difference between IC patients and control subjects was statistically significant and indicative of a large difference in the prevalence of a detectable layer of chondroitin sulfate-containing proteoglycans on the luminal surface of the bladder.5,7
This finding, that a deficit of chondroitin sulfate may be a key feature of the pathology of IC, was supported by a further investigation, carried out in Biopsy specimens from 27 IC patients and 8 controls were used, with all 8 controls showing normal staining. 17 of the 27 IC patients, however, exhibited abnormalities in the amount of detectable chondroitin sulfate present on the luminal surface of the bladder wall.5,7
5. Hurst RE. A deficit of proteoglycans on the bladder uroepithelium in interstitial cystitis. European Urology Supplements 2 (2003)
7. Hurst RE et al. A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology. 1996;48 (5):

7. Mode of action of chondroitin sulfate in PBS/IC
Under normal circumstances, the bladder urothelium has minimal affinity for chondroitin sulfate, and binds it on the surface of the umbrella cells in miniscule quantities only. Experimental animal models, however, have shown that when the urothelium is damaged or destroyed, chondroitin sulfate does not penetrate into the deeper muscle layers of the bladder, but instead binds extensively to the urothelium, demonstrating a high affinity for the damaged area.8,9
This pattern of binding suggests that the main action of chondroitin sulfate is on the bladder surface, and is not due to a pharmacological effect on the body as a whole. The fact that chondroitin sulfate does alleviate the symptoms of PBS/IC in spite of not penetrating into the bladder but remaining on the surface, even in the face of extensive damage, suggests a physical barrier effect is responsible for the clinical efficacy of chondroitin sulfate.8
8. Kyker K, Coffman J and Hurst RE. Exogenous glycosaminoglycans coat damaged bladder surfaces in experimentally damaged mouse bladder. BMC Urology :4
9. Hauser P et al. Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J Urol 2009; 182:
Control bladder
Damaged bladder
Fate of Texas Red labelled chondroitin sulfate after bladder damage with trypsin

8. Chondroitin sulfate restores the barrier effect9
This animal study from demonstrates that when chondroitin sulfate instillations are used to treat a damaged bladder (similar to a PBS/IC damaged bladder) the barrier effect of the GAG layer is restored to normal, healthy levels.
The graph above shows the effect of intravesical chondroitin sulfate on the permeability of rat bladders damaged with 10 mM HCl. Bladder permeability was investigated by measuring serum concentrations of 86Rb (a potassium mimetic), following intravesical instillation :
Negative Control (NC) – undamaged bladder has low permeability to 86Rb.
Positive Control (PC) - Acid damaged bladder (representing PBS/IC) has high permeability, with a four-fold increase in serum 86Rb levels being observed.
Chondroitin sulfate-treated (CT) – acid damaged bladder, treated with intravesical chondroitin sulfate – permeability returns to NC levels.
Statistical comparisons strongly supported the hypothesis that acid damage caused increased permeability. However, chondroitin sulfate treatment immediately restored the permeability barrier to control levels.
9. Hauser P et al. Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J Urol 2009; 182:

9. 400mg chondroitin sulfate may be the optimum dose9
Another animal experiment has demonstrated that bladder instillations of 400mg chondroitin sulfate (as provided by Uracyst) may be the optimum dose in the management of PBS/IC9.
Extrapolating this data from rat bladder to human bladders demonstrated that the damaged bladder achieves saturation point of chondroitin sulfate at an intravesical dose of > 200mg (assuming an IC patient has a bladder capacity of 350ml). The bladder appears to stop binding chondroitin sulfate at around 300mg.
This indicates that the dosage provided by each treatment of Uracyst, i.e. 400mg, may provide the optimum dose of intravesical chondroitin sulfate for damaged bladders. It can be seen that a dose of 400mg is sufficient to achieve saturation point of chondroitin sulfate, whereas 80mg appears to be insufficient.
As can also be seen from the slide, uptake of intravesical chondroitin sulfate by damaged bladder is x2.6 fold greater at a dose of 400mg compared to 80mg.
9. Hauser P et al. Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J Urol 2009; 182:

10. View Dr Robert Hurst’s Presentation

11. Instillation of Uracyst
Roadmap
Mode of Action
Cost comparison
Uracyst
Clinical Evidence
Instillation of Uracyst

12. Study 1 - Nickel et al 200810 Aim Method Endpoints
To assess the efficacy and safety of intravesical 2% 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*
Aim: To assess the efficacy and safety of intravesical chondroitin sulfate 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 chondroitin sulfate 2% once a week for six weeks, then once a month for 16 weeks. In all, patients received a total of ten instillations. The primary efficacy endpoint, carried out at week 10 (i.e. four weeks after the initial six instillations) was the percentage of responders to treatment, as assessed by a Global Response Assessment (GRA) scale. Secondary endpoints included percentage responder rate at week 24 (i.e. after all ten instillations), changes in O’Leary-Sant Symptom/Problem Index scores, and changes in pain, urgency, and frequency scores (as measured on a visual analogue scale), over the course of treatment until the end of the study, compared with baseline.
Results – to follow
There were no significant safety issues during the study. In all, 28 patients (53%) reported 65 adverse events. Of these, 20 may have been related to treatment (genital symptoms, UTIs, and increased bladder symptoms), but were all considered mild.
Conclusions: This multicentre community-based real-life clinical practice study suggests that intravesical chondroitin sulfate may have an important role in the treatment of IC. The authors also noted that one of the major strengths of this study was that the results obtained probably mimic the efficacy that would be seen in real-life clinical practice.
10. Nickel JC et al. A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU International. Epub 3 September 2008.
* assessed by a Global Response Assessment (GRA) scale

13. Study 1 Uracyst - Proven efficacy in the treatment of PBS/IC10
Reminder:
Primary efficacy endpoint
Percentage of responders to treatment, as indicated by a marked or moderate improvement on a seven-point patient Global Response Assessment (GRA) scale, at week 10, 4 weeks after the initial 6 treatments, compared with baseline.
Secondary efficacy endpoints
Durability, based on percentage of responders on the GRA scale after 10 treatments (24 weeks) compared to baseline.
Results
For the primary outcome at 10 weeks (after 6 weekly treatments), the responder rate was 47.2%. The responder rate at 24 weeks (following 6 weekly and 4 monthly treatments) was 60.4%.
10. Nickel JC et al. A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU International. Epub 3 September 2008.

14. Study 1 Uracyst - significantly improves quality of life for patients suffering from PBS/IC10
Other secondary endpoints
Symptom/Problem index scores
O’Leary-Sant Symptom Score decreased by a mean of five points (p<0.001 vs.baseline) or 37% reduction after 6 instillations (6.2 points, 43% after 10 instillations; p<0.001);
O’Leary-Sant Bother Score decreased by a mean of 4.3 points (p<0.001 vs. baseline) or 35% reduction after 6 instillations (5.7 points, 44% after 10 instillations; p<0.001).
Pain, urgency and frequency scores
Pain, urgency, and frequency scores (measured on a visual analogue scale) were also measured over the course of the treatment period. Significant reductions in pain, urgency and frequency (p<0.001) scores were reported after 6 and 10 instillations.
10. Nickel JC et al. A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU International. Epub 3 September 2008.

15. View Dr Curtis Nickel’s Presentation
View an interview with Dr Curtis Nickel

16. Study 2 - Nickel et al 200911 Aim Method Endpoints
To assess the efficacy of 6 similar weekly treatments of Uracyst (2% chondroitin sulfate) versus a placebo control.
Method
Sixty-five patients were randomised to receive either 6 once-weekly treatments of Uracyst or the intravesical placebo control.
Endpoints
The primary efficacy endpoint was the percent responders to treatment. A responder was defined as those subjects who had indicated “markedly improved” or “moderately improved”on a 7 point Global Response Assessment (GRA) scale.
Aim: To assess the efficacy of 6 similar weekly treatments of Uracyst (2% chondroitin sulfate) versus a placebo control.
Method: Sixty-five patients were randomised to receive either 6 once-weekly treatments of Uracyst or the intravesical placebo control.
Results – For the primary outcome at 7 weeks (after 6 weekly treatments), almost twice as many patients reported a clinically significant benefit with Uracyst compared to the control.
Conclusions: The observed difference in treatment effect was not statistically significant. The two studies reported by this presentation (Nickel et al 2008 and Nickel et al 2009) show that Uracyst is effective in the treatment of PBS/IC and represents a promising therapy for these patients.
11. Nickel JC et al. Chondroitin sulfate is a promising therapy for interstitial cystitis/painful bladder syndrome (IC/PBS). Abstract P114 presented at NAUA, October CUAJ 2009; 3(Suppl 3): S170.

17. Study 2 Uracyst demonstrates almost twice the response rate compared to placebo11
Reminder:
Primary efficacy endpoint
The percentage of responders to treatment. A responder was defined as those subjects who had indicated “markedly improved” or “moderately improved” on a 7-point patient Global Response Assessment (GRA) scale.
Results.
For the primary outcome at 7 weeks (after 6 weekly treatments), almost twice as many patients reported a clinically significant benefit with Uracyst compared to the control.
11. Nickel JC et al. Chondroitin sulfate is a promising therapy for interstitial cystitis/painful bladder syndrome (IC/PBS). Abstract P114 presented at NAUA, October CUAJ 2009; 3(Suppl 3): S170.

18. Tolerability
Uracyst is well tolerated with no significant safety issues apparent during either efficacy study10,11
No serious adverse events have been reported with clinical use
Most issues tend to arise from complications with the catheterisation process
10. Nickel JC et al.A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU International. Epub 3 September 2008.
11. Nickel JC et al. Chondroitin sulfate is a promising therapy for interstitial cystitis/painful bladder syndrome (IC/PBS). Abstract P114 presented at NAUA, October CUAJ 2009; 3(Suppl 3): S170.

19. Instillation of Uracyst
Roadmap
Mode of Action
Cost comparison
Uracyst
Clinical Evidence
Instillation of Uracyst

20. Cost comparison – GAG instillations for PBS/IC
Brand
Vial Size
Cost per Vial (list price)
Uracyst
20ml
£65
Gepan
40ml
£68*
Cystistat
50ml
£98**
iAluRil
£88***
*Gepan Business Case, de Smit Medical
** Cystistat advertisement, Pliva
***iAluRil advertisement, Aspire Pharma

21. Instillation of Uracyst
Roadmap
Mode of Action
Cost comparison
Uracyst
Clinical Evidence
Instillation of Uracyst

22. Instillation of Uracyst
in bladder
The suggested method of instillation for Uracyst is:12
The patient should lie on their back
Using standard technique, insert a lubricated urinary catheter (gauge 8 to 12) into the urinary bladder via the urethra
Lower the open end of the catheter so that all urine is drained from the bladder into a receptacle for disposal
Elevate the open end of the catheter, insert a sterile funnel, or sterile syringe with the plunger removed, and pour in Uracyst
Once Uracyst has been instilled, remove the catheter
Instruct the patient to hold Uracyst in the bladder for as long as possible, but for at least 30 minutes
The patient may be released immediately after instillation
Uracyst should not be administered to any patient with known hypersensitivity to the solution. As Uracyst does not contain any preservatives or antimicrobials, any unused portion should be discarded immediately after instillation.13
Please refer to the Uracyst Prescribing Information for further details (available on the final slide of this presentation).
12. Instillation of Uracyst Information Sheet. Stellar Pharmaceuticals Inc. September 2006.
13. Uracyst Package Insert. Stellar Pharmaceuticals. November 2008.
Catheter

23. Suggested Uracyst treatment plan
Weekly instillations for 4-6 weeks, then monthly thereafter
Optimum response within 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
Intravesical instillation of Uracyst should be carried out weekly for four to six weeks, then monthly thereafter14
The time to symptom resolution may vary, but optimum response is usually seen within four to six months14
If a patient experiences any flare-up of their PBS/IC symptoms while on monthly therapy, they should revert to weekly therapy until such time that the symptoms have subsided, then go back to monthly treatments14
More frequent therapy i.e. twice weekly instillations for six weeks, and then monthly thereafter for one year may be required in patients with severe PBS/IC14
14. Interstitial cystitis and Uracyst Patient Information Booklet. Stellar Pharmaceuticals Inc.

24. Summary
PBS/IC patients often have a specific deficit of chondroitin sulfate on the surface of the bladder wall
Intravesical chondroitin sulfate binds extensively to the damaged bladder wall surface, helping to re-establish the GAG layer - the first-line of defence against urine
Uracyst is effective and well tolerated in the treatment of PBS/IC
10. Nickel JC et al. Real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU International. Epub 3 September 2008.
11. Nickel JC et al. Chondroitin sulfate is a promising therapy for interstitial cystitis/painful bladder syndrome (IC/PBS). Abstract P114 presented at NAUA, October CUAJ 2009; 3(Suppl 3): S170.

25. References
1. Screening, treatment and management of interstitial cystitis/painful bladder syndrome. Clinical Proceedings. Association of Reproductive Health Professionals. April 2008.
2. Rosenberg M , Newman D and Page S. Interstitial cystitis/painful bladder syndrome: Symptom recognition is key to early identification, treatment. Cleveland Clinic Journal of Medicine. 2007; 74 (S3): S54-S62..
3. Hurst RE, Roy J and Parsons C. The role of Glycosaminoglycans in normal bladder physiology and the pathophysiology of interstitial cystitis. Interstitial Cystitis Philadelphia. Lippincott-Raven Publishers.
4. Kelada E and Jones A. Interstitial cystitis. Arch Gynecol Obstet. 2007; 275:
5. Hurst RE et al. A deficit of proteoglycans on the bladder uroepithelium in interstitial cystitis. European Urology Supplements. 2 (2003)
6. Hurst RE et al. Functional and structural characteristics of the glycosaminoglycans of the bladder luminal surface. The Journal of Urology. 1987; 138:
7. Hurst RE et al. A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology. 1996;48 (5);
8. Kyker K, Coffman J and Hurst RE. Exogenous glycosaminoglycans coat damaged bladder surfaces in experimentally damaged mouse bladder. BMC Urology. 2005; 5:4
9. Hauser P et al. Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J Urol 2009; 182:
10. Nickel JC et al. A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU International. Epub 3 September 2008.
11. Nickel JC et al. Chondroitin sulfate is a promising therapy for interstitial cystitis/painful bladder syndrome (IC/PBS). Abstract P114 presented at NAUA, October CUAJ 2009; 3(Suppl 3): S170.
12. Instillation of Uracyst Information Sheet. Stellar Pharmaceuticals Inc. September 2006.
13. Uracyst Package Insert. Stellar Pharmaceuticals. November 2008.
14. Interstitial cystitis and Uracyst Patient Information Booklet. Stellar Pharmaceuticals Inc.

26. 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 25oC. 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) Fax: +44 (0) Website:
Adverse incidents should be reported. Reporting forms and information can be found at or Adverse incidents should also be reported to Galen Limited on +44 (0) and select the customer services option, or Medical information enquiries should also be directed to Galen Limited.