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

•Aetiology and diagnosis of hyponatraemia

•Why is hyponatraemia clinically important?

•SIADH

•Treatment

HYPONATRAEMIA

* Syndrome of inappropriate secretion of antidiuretic hormone

AETIOLOGY OF HYPONATRAEMIA Serum [Na+] < 130 mmol/L

Fenske W, et al. Am J Med. 2010

n = 121

4%

20%

32%

35%

7% 2%

Primary polydipsia

Hypervolaemia

Hypovolaemia

SIADH

Diuretic-induced

Adrenal insufficiency

4%

20%

32%

35%

7% 2%

0

10

20

30

40

Ab

so

lute

nu

me

r o

f p

ati

en

ts

0

50

1 2 3 4 5

4

22

46

25

62

Number of causes

DEFINING HYPONATRAEMIA• Defined as a serum sodium concentration ([Na+]) <

135 mmol/L1,2

– 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 euvolaemic1

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.

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 sodium1 ↔

Extracellular fluid (ECF) volume2

Oedema2 Present Absent Absent

Cause1-3

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 nephropathyExtrarenal solute loss: Vomiting, diarrhoea, pancreatitis, third space burns

ClinicalCauses 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 volumeExcess ADH

paraneoplastic, vincas

cyclophosphamide

Glucocorticoid deficiency

Thyroid deficiency

1a Excess ADH

TUMOUR RELATED HYPONATRAEMIA

Onitilo et al Clin Med Res 2007

WHY IS HYPONATRAEMIA CLINICALLY IMPORTANT?

• Most common electrolyte disorder encountered in clinical practice1

• Associated with increased morbidity and mortality2-3 • Associated with cancer• Considerable healthcare burden

Increased length of stay2,5,6

Increased direct medical costs7

• Underdiagnosed and mismanaged8

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.

MILD, GRADUAL-ONSET HYPONATRAEMIA IS ASSOCIATED WITH BONE FRACTURES

Prevalence of hyponatraemia in patients and controls1Variable Patients (n=513)

Controls (n=513) Unadjusted

odds Ratio Adjusted odds

Ratio*% (number)

Hyponatraemia

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 elderly1

Kengne FG, et al. Q J Med. 2008:101(7);583-588.

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 = 2.8595% CI = 1.03–7.86

Mean serum [Na+] = 133 mmol/L

Adjusted odds ratio = 2.8795% 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

serum [Na+] = 124 mmol/L

-500 -400 -300 -200 -100 -100 -2000-40-60-80

0

-100-120

140

-20

12010080604020

serum [Na+] = 130 mmol/L

-500 -400 -300 -200 -100 -100 -200

80

60

40

20

-20

-40

-60

-80

0

-100

-120

serum [Na+] = 139 mmol/L

100 200 200-500 -400 -300 -200 -100

80

60

40

20

-20

-40

-60

-80

0

-100

-120

serum [Na+] = 135 mmol/L

100 200 200-400 -300 -200 -100

8060

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.

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 patients1

Mu

ltiv

aria

ble

-ad

just

ed

risk

of

dea

th (

%)

0

5

10

15

20

25

30

35

< 120 120-124 129-125 130-134

Serum [Na+] (mEq/L)

P<.001

P<.001P<.001

P .52

HYPONATRAEMIA IS FREQUENTLY MISMANAGED, POTENTIALLY INCREASING PATIENT MORTALITY1

• 42% of diagnoses were inconsistent with clinical and investigative details available

Patients with management errors

(n=34)

p < 0.002

20

41

Mo

rtal

ity

(%)

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%

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

Ser

um

[N

a+]

(mm

ol/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

Admission Lowest Discharge

Patients with severe

hyponatraemia

Patients with normonatraemia

(control)

Mea

n n

um

ber

of

day

s

Length of hospital stay in patients with severe hyponatraemia (serum

[Na+] < 125 mmol/L)

p = 0.005

16n=104

13n=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

68

10

12

1416

18

SIADH* IS THE MOST FREQUENT CAUSE OF HYPONATRAEMIA1

• Characterised by the inappropriate secretion of, or response to, vasopressin1

– 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

DIAGNOSING SIADH: ESSENTIAL CRITERIA

• Hyponatraemia < 135 mmol/L

• Plasma hypo-osmolality < 275 mOsm/Kg

• Urine osmolality > 100 mOsm/Kg

• Clinical euvolaemiaNo 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-

osmolalityExclude 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.

POOR INVESTIGATION LEADS TO UNDER-DIAGNOSIS OF SIADH1

• 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

Dia

gn

osi

s (%

)

Initial hospital diagnosis

Initial and retrospective expert diagnosis of SIADH

0

5

10

15

20

25

30

35

CAUSES of SIADH

Ellison and Berl N Engl J Med 2007

CANCER ASSOCIATED WITH SIADH

Raftopoulos Support Care Cancer 2007

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 analogues Desmopressin, oxytocin, vasopressin

Mixed or uncertain action ACE 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

CHEMOTHEAPY INDUCED HYPONATRAAEMIA

• Metastatic testicular ca • Bleo etop cis 4th cycle markers normalised no

toxicity but despite fluid restriction Na <117

Yeoh et al BMJ Case Rep 2010

SMALL CELL LUNG CANCERPROGNOSTIC GROUPS

• Manchester LDH <0.0001Stage

0.0001Na

0.0009PS

0.0121AP

0.0186(CO2)

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

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

Gross et al Cancer Res 1993Hansen 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

• Treatment of underlying condition• Treatment of acute versus chronic

hyponatraemia• Treatment with hypertonic saline• Treatment with fluid restriction• Treatment with demeclocycline• Treatment with a V2 receptor antagonist

TREATMENT OF SIADH

USING SPEED OF ONSET OF HYPONATRAEMIA SECONDARY TO SIADH TO GUIDE YOUR TREATMENT CHOICE1

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

RAPID CORRECTION OF GRADUAL-ONSET HYPONATRAEMIA AND

OSMOTIC DEMYELINATION SYNDROME

1. Adrogue HJ, Madias NE. N Eng J Med. 2000;342:1581-1589..

RAPID-ONSET SYMPTOMATIC HYPONATRAEMIA REQUIRES PROMPT TREATMENT

• In severe and symptomatic cases, rapid correction of serum [Na+] is required with hypertonic saline1,2 – Hypertonic 3% saline solution to raise serum [Na+]

by 1-2 mmol/L/hour 1,2

• Serum [Na+] should not be corrected to normal levels1

– Correction of no more than 8-10 mmol/L in the first 24 hours2

– 18-25 mmol/L during the first 48 hours2

• Serum [Na+] should be monitored every 2-4 hours1

– A loop diuretic may be used to enhance water excretion1,2

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.

TREATMENT OF GRADUAL-ONSET HYPONATRAEMIA

• Fluid restriction has been the treatment of choice of patients with gradual-onset hyponatraemia1,2

– Rapid correction of serum [Na+] can precipitate osmotic demyelination

• Fluid restriction has been used as a treatment for hyponatraemia secondary to SIADH since 19573

– However:• Even severe water restriction of < 500 ml/day produced correction rates of only 1-2 mmol/L/day3

• 5-6 days of fluid restriction required to bring the serum sodium concentration into normal ranges3

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.

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 hyponatraemia1

Furst H, et al. Am J Med Sci. 2000;319 (4):240-244.

DEMECLOCYCLINE CLINICAL SUMMARYAuthor Title & Year of

publicationPatients Measurements Efficacy Results Side effects Length of

Treatment

Troyer Demeclocycline Treatment for SIADH (JAMA)1977

7 males with oat cell carcinoma of lung

Demeclocycline 1,200mg/daySNa range 117-124mEg/Litre

Benefit of demeclocycline seen in 5 pts with all symptoms disappearing.

1 pt had elevated blood urea1 pt had renal function impairmentModerate azotemia seen

7-10 days

Forrest et al

Superiority of Demeclocycline over Lithium in the treatment of chronic SIADH(NEJM)1978

10 Of which 7 had carcinoma of the lung

Demeclocycline 600mg-1,200mg/day3 pts received Lithium prior to demeclocycline treatment. Sna range was 117-130meq/l

Demeclocycline is an effective therapy for the treatment of chronic SIADH where severe fluid restriction fails to control symptoms. Demeclocycline is superior to Lithium as it is a more predictable and less toxic agent.

No serious adverse side effects reported

2weeks to 11 months(1pt)

Perks et al

Demeclocycline in the treatment of SIADH(Thorax)1979

14 patients with malignant disease

Demeclocycline 1,200mg/daySNa range-99-120 mmol/l

SNa returned to normal (>135mmol/l) in all pts.

4 pts urea rose above 20 mmol/l

Up to 12 daysMean 8.6days

Trump Serious Hyponatraemia in Patients with Cancer(Cancer)1981

17 pts with various cancers or aplastic anaemia

Demeclocycline 600-1200mg/dSNa range 114-125meq/l

SNa was on average 130meq/l or greater after 3 days of demeclocycline treatment. Peak Na was attained on average 9 days after demeclocycline administration

3 Pts died after demeclocycline treatmentAzotemia was associated with demeclocycline treatment.

1-7 days

VASOPRESSIN –RECEPTOR ANTAGONISTS

Ellison and Berl N Engl J Med 2007

SAMSCA DIRECTLY TARGETS THE MECHANISM OF SIADH TO PROMOTE FREE WATER CLEARANCE

Mechanism of action of Samsca

Blood Collecting DuctPrincipal Cell

Collecting Duct

Samsca blocks the binding of vasopressin to theV2 receptors

Synthesis & transport of aquaporin-2 proteins is reduced

This prevents freewater absorption

1. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

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.

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

Pat

ien

ts w

ith

no

rmal

ised

seru

m [

Na +

] (%

)

0

80

60

40

20

DaySamsca n= 48 51 51 50 47 45 44 42 44Placebo n= 54 57 52 52 48 47 42 41 38

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 26.3a

aa

a

a aa

a

BSL; Baseline. FU; 7 day follow upa p < 0.05 Samsca vs placebo group

Placebo

Tolvaptan

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 Score Mental 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)

Ch

ang

e fr

om

bas

elin

e

REDUCED LENGTH OF HOSPITAL STAY IN PATIENTS CLASSIFIED AS SIADH AND “OTHER” TREATED WITH

TOLVAPTAN1

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.

Men

a l

eng

th o

f h

osp

ital

sta

y (d

ays)

4.70 ± 3.89

p = 0.045

8.40 ± 9.67

0

1

2

3

4

5

6

7

8

9

Tolvaptan Placebo

CONCLUSION

• Normalisation of serum Na important

to improve patients outcomes ,reduce hospitalisation

• Vasopressin receptor antagonist, Tolvaptan has proven efficacy in phase III trials

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 → 2nd line CT tolerated well PS 0/1• 17 April 2013 Na 140

Prescribing InformationSamsca®▼(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 <1/10): Dry mouth, constipation, polydipsia, dehydration, hyperkalaemia, hyperglycaemia, decreased appetite, orthostatic hypotension, ecchymosis, pruritis, pollakiuria, polyuria, asthenia, pyrexia, increased blood creatinine, rapid correction of hyponatraemia, sometimes leading to neurological symptoms. Uncommon (>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 2012Adverse 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).