1. HYPONATRAEMIA in ONCOLOGY Nick Thatcher, Christie Hospital, Manchester, England Date of Prep-Oct 2012 Prescribing Information at end of this presentation OPUK-1012-SAM-2559 Meeting organised and funded by Otsuka Pharmaceuticals UK Ltd

2. Aetiology and diagnosis of hyponatraemia Why is hyponatraemia clinically important? SIADH Treatment HYPONATRAEMIA * Syndrome of inappropriate secretion of antidiuretic hormone

3. AETIOLOGY OF HYPONATRAEMIA Serum [Na + ] < 130 mmol/L Fenske W, et al. Am J Med. 2010 n = 121 4% 20% 32% 35% 7% 2% 0 10 20 30 40 Absolute numer of patients 0 50 12345 4 22 46 25 6 2 Number of causes

4. DEFINING HYPONATRAEMIA Defined as a serum sodium concentration ([Na + ]) < 135 mmol/L 1,2 –May have low, normal or high total body sodium –Hyponatraemia may be caused by either depletion of body sodium or dilution of body sodium in excess water Onset can be rapid (i.e. acute, which develops in < 48 hours) or gradual (i.e. chronic) 1,2 Patients with hyponatraemia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are euvolaemic 1 1. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. 2. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072.

5. HYPOTONIC HYPONATRAEMIA IS CLASSIFIED ACCORDING TO VOLUME STATUS 1. Schrier RW, Bansal S. Curr Opin Crit Care. 2008;14:627-634. 2. Douglas I. Cleve Clin J Med. 2006;73(3):S4-S12. 3. Verbalis J, et al. Am J Med. 2007; 120(11 Suppl 1): S1-21. Hypervolaemic hyponatraemia Euvolaemic hyponatraemia Hypovolaemic hyponatraemia Total body water (TBW) 1     Total body sodium 1  ↔  Extracellular fluid (ECF) volume 2     Oedema 2 PresentAbsent Cause 1-3 Congestive heart failure, cirrhosis, nephrotic syndrome, renal failure (acute or chronic) SIADH, glucocorticoid deficiency, hypothyroidism Renal solute loss: Diuretic therapy, cerebral salt wasting, mineralocorticoid deficiency, salt wasting nephropathy Extrarenal solute loss: Vomiting, diarrhoea, pancreatitis, third space burns

6. ALGORITHM for DIFFERENTIAL DIAGNOSIS of HYPONATRAEMIA Castillo et al Oncologist 2012

7. Clinical Causes Group Mechanism I. Normal Na balance decreased ECF volume due to disturbed renal handling of Na Adenocortical insuffiency, Excess ANP or BNP - ectopic ANP,cerebral Na wasting Renal salt wasting -platinums IIb Renal solute loss increased or decreased ECF volume,hypo Na not due to disturbed renal handling of Na ↓ true circulating blood volume GI causes- ↓ salt and water intake D and V Third space ↓ effective circulating blood volume heart failure,liver cirrhosis II.Impaired Na balance IIa Renal solute conservation true water excess not due to SIADH Tumour products immunoglobulin paraprtoteins Excess hypotonic solutions 1b Excess intake free water or pseudohyponatraemia as SIADH w. normal ECF volume Excess ADH paraneoplastic, vincas cyclophosphamide Glucocorticoid deficiency Thyroid deficiency 1a Excess ADH TUMOUR RELATED HYPONATRAEMIA Onitilo et al Clin Med Res 2007

8. WHY IS HYPONATRAEMIA CLINICALLY IMPORTANT? Most common electrolyte disorder encountered in clinical practice 1 Associated with increased morbidity and mortality 2-3 Associated with cancer Considerable healthcare burden Increased length of stay 2,5,6 Increased direct medical costs 7 Underdiagnosed and mismanaged 8 1. Upadhyay A, et al. Semin Nephrol. 2009;29(3):227-238. 2. Gill G, et al. Clin Endo. 2006;65:246-249. 3. Sajadieh A,et al. Am J Med. 2009;122:679-686. 4. Waikar SS, et al. Am J Med. 2009;122:857-865. 5. Sherlock M, et al. Clin Endo. 2006;64:250-254. 6. Sherlock M, et al. Postgrad Med J. 2009;85;171-175. 7. Shea AM, et al. J Am Soc Nephrol. 2008;19:764-770. 8. Huda MSB, et al. Postgrad Med J 2006; 82: 216-219.

9. MILD, GRADUAL-ONSET HYPONATRAEMIA IS ASSOCIATED WITH BONE FRACTURES Prevalence of hyponatraemia in patients and controls 1 Variable Patients (n=513) Controls (n=513) Unadjusted odds Ratio Adjusted odds Ratio* % (number) Hyponatr aemia 13.06 (67)3.90 (20) 3.47 (2.09-5.79) p <0.001 4.16 (2.24-7.71) p <0.001 *adjusted for age, sex and covariates Mild asymptomatic hyponatraemia is associated with bone fractures in ambulatory elderly 1 Kengne FG, et al. Q J Med. 2008:101(7);583-588.

10. HYPONATRAEMIA IS A SIGNIFICANT PREDICTOR OF OSTEOPOROSIS 10.01.00.1 Odds ratio (95% CI) total hip (p = 0.043) femoral neck (p = 0.003) Adjusted odds ratio = 2.85 95% CI = 1.03–7.86 Mean serum [Na + ] = 133 mmol/L Adjusted odds ratio = 2.87 95% CI = 1.41–5.81 100.0 Verbalis JG, et al. JBMR. 2010;25(3):554-563 Odds of osteoporosis in the total hip and femoral neck in hyponatraemic relative to normonatraemic adults

11. serum [Na + ] = 124 mmol/L -500-400-300-200-100 -2000 -40 -60 -80 0 -100 -120 140 -20 120 100 80 60 40 20 serum [Na + ] = 130 mmol/L -500-400-300-200-100 -200 80 60 40 20 -20 -40 -60 -80 0 -100 -120 serum [Na + ] = 139 mmol/L 100200 -500-400-300-200-100 80 60 40 20 -20 -40 -60 -80 0 -100 -120 serum [Na + ] = 135 mmol/L 100200 -400-300-200-100 80 60 40 20 -20 -40 -60 -80 0 -100 -120 100 CORRECTION OF HYPONATRAEMIA NORMALISED GAIT IN ASYMPTOMATIC HYPONATRAEMIA. Renneboog B, et al. American J Med. 2006;119:71e1-71e8.

12. INCREASED MORTALITY AFTER HOSPITALISATION WITH MILD, MODERATE AND SEVERE HYPONATRAEMIA Waikar SS, et al. Am J Medicine. 2009;122:857-865. Risk of death 5 years following admission in hyponatraemic patients ([Na + ] < 134 mmol/L), compared with normonatraemic patients 1 Multivariable-adjusted risk of death (%) 0 5 10 15 20 25 30 35 < 120120-124129-125130-134 Serum [Na + ] (mEq/L) P<.001 P.52

13. HYPONATRAEMIA IS FREQUENTLY MISMANAGED, POTENTIALLY INCREASING PATIENT MORTALITY 1 42% of diagnoses were inconsistent with clinical and investigative details available Patients with management errors (n=34) p < 0.002 20 41 Mortality (%) Patients managed appropriately (n=70) Mortality in patients with hyponatraemia (serum [Na + ] < 125 mmol/L) 0 5 10 15 20 25 30 35 40 45. Huda MSB, et al. Postgrad Med J 2006;82:216-219. 20% 41%

14. AT HOSPITAL DISCHARGE, HYPONATRAEMIA MAY NOT BE CORRECTED Prospective case control study of 104 hyponatraemic patients (serum [Na + ] < 125 mmol/L) in a large teaching hospital On average, serum [Na + ] was not corrected by the time the patients were discharged A group of high-risk patients were identified with a serum [Na + ] which fell during admission Mortality was greater in these high-risk patients than in patients who did not experience a further decline in serum [Na + ] (34% vs 16%, p < 0.001) In 73% of cases the cause of hyponatraemia was not recorded Serum [Na + ] during admission in patients admitted with hyponatraemia Serum [Na + ] (mmol/L) Adapted from: Gill G, et al. Clin Endo. 2006;65:246-249. Mean admission serum [Na + ] in normonatraemic patients 110 115 120 125 130 135 140 AdmissionLowestDischarge

15. Patients with severe hyponatraemia Patients with normonatraemia (control) Mean number of days Length of hospital stay in patients with severe hyponatraemia (serum [Na + ] < 125 mmol/L) p = 0.005 16 n=104 13 n=100 INCREASED LENGTH OF HOSPITAL STAY Hyponatraemic patients have significantly longer hospital stays, irrespective of the underlying cause: 1,2 In neurosurgical patients hyponatraemia (plasma [Na+] < 130 mmol/L) is associated with a median 7-day increase in hospital stay vs. normonatraemic patients (p <0.001) 2 1. Gill G, et al. Clin Endo. 2006;65:246-249. 2. Sherlock M, et al. Postgrad Med J. 2009;85;171-175. 0 2 4 6 8 10 12 14 16 18

16. VALUE OF SPECIFIC TREATMENT FOR HYPONATRAEMIA Complete resolution of symptoms with resolution of hyponatraemia 1 Improvement in SF-12 Physical and Mental Component Summary Scores with treatment of hyponatraemia 2,3 Improvement in gait with treatment of hyponatraemia 4 Patients not specifically treated for hyponatraemia have higher mortality than those who are specifically treated (37% vs 13%, p = 0.04) 5 1. Chow KM, et al. J Natl Med Assoc. 2004;96:1305-1309. 2. Schrier RW, et al. N Engl J Med. 2006;355:2099-2112. 3. Verbalis JG, et al. Eur J Endocrinology. 2011;164(5):725-732.4. Renneboog B, et al. Am J Med. 2006;119:71.e1-71.e8. 5. Hoorn EJ, et al. Nephrol Dial Transplant. 2006;21:70-76.

17. SIADH* IS THE MOST FREQUENT CAUSE OF HYPONATRAEMIA 1 Characterised by the inappropriate secretion of, or response to, vasopressin 1 –Vasopressin is secreted despite hypotonicity (low plasma osmolality) 1 In most cases, inappropriate secretion of vasopressin results in: 1,2 –An inability to excrete dilute urine –Retention of water –Modest expansion of ECF volume –Dilution of serum [Na + ] –Ultimately hypotonic (dilutional) hyponatraemia 1. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. 2. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. * Syndrome of inappropriate secretion of antidiuretic hormone

18. DIAGNOSING SIADH: ESSENTIAL CRITERIA Hyponatraemia < 135 mmol/L Plasma hypo-osmolality < 275 mOsm/Kg Urine osmolality > 100 mOsm/Kg Clinical euvolaemia No clinical signs of hypovolaemia (orthostatic decreases in blood pressure, tachycardia, decreased skin turgor, dry mucous membranes) No clinical signs of hypervolaemia (oedema, ascites) Increased urinary sodium excretion with normal salt and water intake > 30 mmol/L Absence of other potential causes of euvolaemic hypo-osmolality Exclude hypothyroidism, hypocortisolism, renal disease and recent diuretics 1. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. 2. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

19. POOR INVESTIGATION LEADS TO UNDER-DIAGNOSIS OF SIADH 1 Significant discrepancies in the number of diagnoses of SIADH in a cohort of 104 hyponatraemic patients 1. Huda MSB, et al. Postgrad Med J. 2006;82:216-219. Retrospective diagnosis p = 0.001 20 32 Diagnosis (%) Initial hospital diagnosis Initial and retrospective expert diagnosis of SIADH 0 5 10 15 20 25 30 35

20. CAUSES of SIADH Ellison and Berl N Engl J Med 2007

21. CANCER ASSOCIATED WITH SIADH Raftopoulos Support Care Cancer 2007

22. DRUGS AND SIADH Drugs that stimulate release of vasopressin or enhance its action Opioids, Chlorpropramide, SSRIs, Tricyclic antidepressants, Clofibrate, Carbamazepine, Vincristine, Nicotine, Narcotics, Antipsychotic drugs, Ifosfamide, Cyclophosphamide, Nonsteroidal anti-inflammatory drugs, MDMA (“ecstasy”) Vasopressin analoguesDesmopressin, oxytocin, vasopressin Mixed or uncertain actionACE inhibitors, Clofibrate, Cyclophosphamide, Colchicine, Vincristine, Carboplatin, Etoposide, Carbamazepine, Oxcarbazepine, Clozapine, Amiodarone, Proton pump inhibitors, SSRIs Adapted from: Ellison DH. Berl T. N Engl J Med. 2007;356:2064-2072. SSRIs = Serotonin reuptake inhibitors; MDMA = 3,4-Methylenedioxymethamphetamine; ACE = Angiotensin converting enzyme

23. CHEMOTHEAPY INDUCED HYPONATRAAEMIA Metastatic testicular ca Bleo etop cis 4 th cycle markers normalised no toxicity but despite fluid restriction Na <117 Yeoh et al BMJ Case Rep 2010

24. SMALL CELL LUNG CANCER PROGNOSTIC GROUPS ManchesterLDH <0.0001 Stage0.0001 Na0.0009 PS0.0121 AP0.0186 (CO 2 )0.0321 Score 1 for each adverse factor Better prognosis <2 – all 2 yr. survivors Worse prognosis >3 – all dead <1yr. Cerny et al, Int J Cancer 1987

25. PROGNOSTIC GROUPS Factors validated – PS, Hyponatraemia, LDH, Stage etc. Rawson and Peto et al, Br J Cancer 1990 Thatcher et al, Semin Rad Oncol 1995 Lung cancer risk factors for treatment related death Na <138 mEq/L p=<0.001 Minami-Shimmyo et al Lung cancer 2012

26. Gross et al Cancer Res 1993 Hansen et al Lung Cancer 2010 SCLC SURVIVAL and SODIUM OS 11.2 mos vs 7.1 p=0.0001 Cox p=0.000 Normalisation of Na - better survival p=0.027

27. Treatment of underlying condition Treatment of acute versus chronic hyponatraemia Treatment with hypertonic saline Treatment with fluid restriction Treatment with demeclocycline Treatment with a V 2 receptor antagonist TREATMENT OF SIADH

28. USING SPEED OF ONSET OF HYPONATRAEMIA SECONDARY TO SIADH TO GUIDE YOUR TREATMENT CHOICE 1 Hyponatraemia Acute Gradual onset 3% saline ± diuretics 3% saline ± diuretics Tolvaptan▼ Fluid restriction If the speed of onset is not known, the hyponatraemia should be treated as though it is gradual onset 1. Verbalis J, et al. Am J Med. 2007;120(11 Suppl 1):S1-21. Figure provided by Dr T. Feldcamp 24–48hr > 48hr Severe symptoms Mild symptoms or asymptomatic

29. RAPID CORRECTION OF GRADUAL-ONSET HYPONATRAEMIA AND OSMOTIC DEMYELINATION SYNDROME 1. Adrogue HJ, Madias NE. N Eng J Med. 2000;342:1581-1589..

30. RAPID-ONSET SYMPTOMATIC HYPONATRAEMIA REQUIRES PROMPT TREATMENT In severe and symptomatic cases, rapid correction of serum [Na + ] is required with hypertonic saline 1,2 –Hypertonic 3% saline solution to raise serum [Na + ] by 1-2 mmol/L/hour 1,2 Serum [Na + ] should not be corrected to normal levels 1 –Correction of no more than 8-10 mmol/L in the first 24 hours 2 –18-25 mmol/L during the first 48 hours 2 Serum [Na + ] should be monitored every 2-4 hours 1 –A loop diuretic may be used to enhance water excretion 1,2 1. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. 2. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072.

31. TREATMENT OF GRADUAL-ONSET HYPONATRAEMIA Fluid restriction has been the treatment of choice of patients with gradual-onset hyponatraemia 1,2 –Rapid correction of serum [Na + ] can precipitate osmotic demyelination Fluid restriction has been used as a treatment for hyponatraemia secondary to SIADH since 1957 3 –However: Even severe water restriction of < 500 ml/day produced correction rates of only 1-2 mmol/L/day 3 5-6 days of fluid restriction required to bring the serum sodium concentration into normal ranges 3 1. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. 2. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. 3. Schwartz WB, et al. Am J Med. 1957;23:529-542.

32. IN PATIENTS WITH A U/P ELECTROLYTE RATIO ≥ 1 THERE IS NO FREE WATER CLEARANCE Example: –Plasma [Na + ] = 120 mmol/L –Urinary [K + ] = 50 mmol/L –Urinary [Na + ] = 70 mmol/L This patient would have a U/P ratio of 1, and would not excrete any free water If there is no free water clearance and no provision to replace sodium and potassium lost in the urine, fluid restriction may result in a short-term worsening of the hyponatraemia 1 Furst H, et al. Am J Med Sci. 2000;319 (4):240-244.

33. DEMECLOCYCLINE CLINICAL SUMMARY

34. VASOPRESSIN –RECEPTOR ANTAGONISTS Ellison and Berl N Engl J Med 2007

35. SAMSCA DIRECTLY TARGETS THE MECHANISM OF SIADH TO PROMOTE FREE WATER CLEARANCE Mechanism of action of Samsca Blood Collecting Duct Principal Cell Collecting Duct Samsca blocks the binding of vasopressin to theV 2 receptors Synthesis & transport of aquaporin-2 proteins is reduced This prevents free water absorption 1. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

36. VASOPRESSIN ANTAGONISTS AN EFFECTIVE MEANS OF CORRECTING HYPONATRAEMIA Reduced need for fluid restriction Correction is predictable, titratable and prompt Well tolerated Reduced hospital stay 1. Schrier RW, et al. N Engl J Med. 2006;355:2099-2112. 2. Verbalis JG, et al. Eur J Endocrinology. 2011;164(5):725-732.

37. SALT-1 AND SALT-2: SERUM [NA + ] NORMALISATION AT ALL TIME POINTS, SIADH SUBGROUP 1. Verbalis JG, et al. Eur J Endocrinology. 2011;164(5):725-732. Proportion of patients with normalised serum [Na + ] SIADH subgroup, all time points Patients with normalised serum [Na + ] (%) 0 80 60 40 20 Day Samscan=485151504745444244 Placebon=545752524847424138 FU302518114321 100 25.0 5.5 33.3 5.2 39.2 8.6 60.0 11.5 68.0 20.8 66.6 23.4 70.4 23.8 68.0 26.8 25.0 26.3 a a a a a a a a BSL; Baseline. FU; 7 day follow up a p < 0.05 Samsca vs placebo group Placebo Tolvaptan

38. TOLVAPTAN IMPROVED SF-12 PHYSICAL AND MENTAL COMPONENT SCORES IN PATIENTS WITH SIADH Placebo (n=39) Tolvaptan (n=41) p=0.019 p=0.051 -0.16 3.64 0 2.5 5 7.5 Physical Component ScoreMental Component Score -0.45 5.47 Changes in SF-12 general health survey scores after 30 days of oral administration 1.Verbalis JG, et al. Eur J Endocrinology. 2011. DOI: 10.1530/EJE-10-1078. 2.Schrier RW, et al. N Engl J Med 2006; 355(20): 2099–2112. (physical function, body pain, general health, physically limited accomplishment) (vitality, social function, calmness, sadness, emotionally limited accomplishment) Change from baseline

39. REDUCED LENGTH OF HOSPITAL STAY IN PATIENTS CLASSIFIED AS SIADH AND “OTHER” TREATED WITH TOLVAPTAN 1 Length of stay in patients with severe hyponatraemia, subgroup analysis 1. Verbalis JG, et al. Eur J Endocrinology. 2011. DOI: 10.1530/EJE-10-1078. Mena length of hospital stay (days) 4.70 ± 3.89 p = 0.045 8.40 ± 9.67 0 1 2 3 4 5 6 7 8 9 TolvaptanPlacebo

40. CONCLUSION Normalisation of serum Na important to improve patients outcomes,reduce hospitalisation Vasopressin receptor antagonist, Tolvaptan has proven efficacy in phase III trials

41. ILLUSTRATIVE PATIENT Male, 62 years,50 pack years PH 1981 pancreatitis →DM, 2009 TIA April 2012 fatigue,SOB, PS 2/3, Na 120. admitted local DGH, tolvaptan 25 /4 Na 126,10/5 Na139 SCLC, LS T2 N2 M0, tolvaptan stopped Admitted Christie 18/7 Na 129, PS 2 tolvaptan for 3 days, Na 137 PS 0/1 July 2012 concurrent CT/RT over 4 months Oct 2012 Na 136, tolvaptan stopped. Restaging PR →PCI Na 139 March 2013 fatigue,Na 118, Liver mets Tolvaptan for 5 days Na 139 → 2 nd line CT tolerated well PS 0/1 17 April 2013 Na 140

42. Prescribing Information Samsca®▼(tolvaptan) Presentation: Tablets containing 15 mg or 30 mg of tolvaptan. Indication: Treatment of adult patients with hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Dosage: To be initiated in hospital due to need for dose titration with close monitoring of serum sodium and volume status. For oral use, 15 mg once daily, increasing to a maximum of 60 mg once daily as tolerated to achieve desired serum sodium correction. No dosage adjustment for elderly or in mild to moderate renal or hepatic impairment. No information is available in severe renal or hepatic impairment. There is no experience in children and adolescents under the age of 18 years. Contraindications: Hypersensitivity to any component of Samsca. Anuria. Volume depletion. Hypovolaemic hyponatraemia. Hypernatraemia. Patients who can not perceive thirst. Pregnancy. Breastfeeding. Warnings and precautions: For patients with urgent need to raise serum sodium acutely, alternative treatment should be considered. Patients must have adequate access to water and not become overly dehydrated. Urinary outflow must be secured.Patients should be closely monitored for serum sodium and volume status, particularly in those with renal and hepatic impairment. Too rapid correction of hyponatraemia can cause permanent neurological sequelae, coma or death. Monitoring of serum sodium should start no later than 4-6 hours after treatment initiation. Over rapid correction should be considered if sodium correction exceeds 6 mmol/l during the first 6 hours of administration or 8 mmol/l during the first 6-12 hours. These patients should be monitored more frequently and administration of hypotonic fluid is recommended. In case serum sodium increases ≥ 12 mmol/l within 24 hours or ≥ 18 mmol/l within 48 hours, tolvaptan treatment is to be interrupted followed by administration of hypotonic fluid. Pseudohyponatraemia should be excluded, particularly in hyperglycaemic patients.Samsca may cause hyperglycaemia, therefore diabetic patients treated with Samsca should be managed cautiously, in particular poorly controlled type II diabetes. Samsca contains lactose as an excipient; patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Caution when driving vehicles or using machines, occasionally dizziness, asthenia or syncope may occur. Drug interactions: Caution with: co-administration with CYP3A4 inhibitors, inducers and substrates, digoxin, and vasopressin analogues. Concomitant use with other treatments for hyponatraemia and medicinal products that increase serum sodium concentration is not recommended. Undesirable effects: The following adverse reactions were reported in clinical trials in hyponatraemia: Very common (>1/10): Thirst, nausea. Common (>1/100 to 1/1000 to <1/100): Dysgeusia. See Summary of Product Characteristics for further details and other undesirable effects. Overdosage: There is no information on overdosage but profuse and prolonged aquaresis is anticipated. Adequate fluid intake must be maintained. Legal category: POM Marketing Authorisation numbers/Basic NHS price: SAMSCA 15 mg (EU/1/09/539/001) £746.80 for blister pack of 10 tablets. SAMSCA 30 mg (EU/1/09/539/003) £746.80 for blister pack of 10 tablets. Marketing Authorisation Holder: Otsuka Pharmaceuticals Europe Ltd., Hunton House, Highbridge Estate, Oxford Road, Uxbridge, Middlesex, UB8 1LX, UK. Further information from: Otsuka Pharmaceuticals (U.K.) Ltd., Tel: 020 8756 3100 Date of preparation of prescribing information: April 2012 Adverse events should be reported. Reporting forms and information can be found at yellowcard.mhra.gov.uk. Adverse events should also be reported to Otsuka Pharmaceuticals (U.K.) Ltd (OPUKSafety@otsuka.co.uk).yellowcard.mhra.gov.uk