Investigation and Treatment of Hyponatremic States

Daniel G. Bichet, M.D.Professeur of Medicine and Physiology,

Université de MontréalHôpital du Sacré-Cœur de Montréal

The speaker has received fees/honoraria and grants from Otsuka Pharmaceutical.

An honorarium from Otsuka Pharmaceutical will also be received related to the present lecture.

Some of the drugs, devices, or treatment modalities mentionedin this presentation are: Samsca (Tolvaptan) from Otsuka Pharmaceutical

Conflict Disclosures

Speaker: D.Bichet M.D. Title Hyponatremia – date Nov 24 2012

At the end of this presentation, the attendee will able to:

• Understand the role of vasopressin secretion and its non-suppression by hyponatremia in most clinically important hyponatremic states

• Distinguish hypovolemic hyponatremia (easily treated with volume repletion) from euvolemic and hypervolemic hyponatremic states

• Recognize the importance and urgency of treating symptomatic hyponatremia where severe neurologic manifestations are related to brain edema

Objectives (2)

• Understand the need to treat chronic hyponatremia slowly to prevent osmotic demylination syndrome

• Understand the value and limitations of indirect treatments such as water restriction, urea, furosemide and sodium compared to direct inhibition of the vasopressin V2 receptor with a V2 receptor antagonist

How cats lap: water uptake by Felis catus

Science. 2010 Nov 26;330(6008):1231-4. Epub 2010 Nov 11. We show that the domestic cat (Felis catus) laps by a subtle mechanism based on water adhesion to the dorsal side of the tongue.

Hyponatremia:PNa<136 mmol/L

Two factors to evaluate: deficit in Na+/K+; excess water

Normal glucose, increased in protein or lipids could decrease the volume of water where Na+ is measured: pseudo-hyponatremia.

Mannitol, maltose or glycine: hyponatremia with hyper-osmolality.Urea is a permeable osmolyte and do not cause hyponatremia

.

serum [Na+] ~Na+

E + K+E

body water

Prevalence of Hyponatremia at Initial Presentation to a Healthcare Provider

Tan Tock Seng Hospital, Singapore.

Data from 303,577 samples on 120,137 patients available for analysis.

Hawkins RC. Clin Chim Acta. 2003;337(1-2):169-172.

Serum [Na+] (mEq/L)

7

Risk Factors for Hyponatremia

Selected Conditions1

• Congestive Heart Failure• Cirrhosis• SIADH• Very young or very old age• Adrenal insufficiency• Hypothyroidism• Renal dysfunction• Central nervous system

impairment• Surgery or injury

Selected Drug Classes• Diuretics1,2

• NSAIDs1,2

• Opiate derivatives1,2

• Antidepressants1,2

• Antipsychotics1,2

• Antiepileptic agents1,2

• Anticancer agents1,2

• Antihypertensive agents2

• Proton-pump inhibitors2

NSAIDS = Nonsteroidal Anti-inflammatory Agents, SIADH = Syndrome of Inappropriate Antidiuretic Hormone.1. Adrogué HJ. Am J Nephrol. 2005;25:240-249. 2. Liamis G, et al. Am J Kidney Dis. 2008;52:144-153. 3. Ellison DH, Berl T. N Engl J Med. 2007;356(20):2064-2072.

[Na+] <135 mEq/L3

8

Falls Are a Common Symptom of Chronic “Asymptomatic” Hyponatremia

21.3

5.3

0

5

10

15

20

25

Fal

ls (%

)

Hyponatremic Patients

126±5 mEq/L

(n=122)

Controls

139±2 mEq/L

(n=244)

Adjusted OR 67.4,95% CI 7.5–607.4, P<.001

Patients with chronic “asymptomatic” hyponatremia were admitted for falls significantly more frequently than patients with normal [Na+] levels

Mean Serum [Na+]:

No. of Patients:

Data based on a case-control study in a general Belgium hospital.Renneboog B, et al. Am J Med. 2006;119(1):71.e1-71.e8. 9

Odds Ratio: probability ratioOdds = The probability of events / the probablity of non-events

Hyponatremia in Patients With Bone Fractures Resulting From Incidental Falls

0

2

4

6

8

10

12

14

Patients (n=513)

Control(n=513)

Patie

nts

With

Hyp

onat

rem

ia (%

)

13.1%

3.9%

Hyponatremia was mild and asymptomaticin all patients (mean serum [Na+] 131 mEq/L) and was found to be associated with bone fracture after incidental fall in ambulatory elderly

Adjusted OR (CI):4.16 (2.24–7.71)P<.001

Gankam Kengne F, et al. QJM. 2008;101(7):583-588.

Case control study of 513 cases of bone fracture after incidental fall in ambulatory patients ≥65 y in general university hospital.

• Rat model SIADH: hyponatremia induced x 3 months - ↓ BMD ~ 30%

• NHANES III survey data: mild hyponatremia ~ Adj-OR 2.85 osteoporosis

Non-Hyponatremic Rats

Hyponatremia Rats

Restrictive Cubic Spline Depicting the Unadjusted Relationship Between Hospital Admission Serum Sodium Concentrations and In-Hospital Mortality

Wald R, et al. Arch Intern Med. 2010;170(3):294-302.

0.20

0.15

0.10

0.05

110 115 120 125 130 135 140 145

Admission Serum [Na+] Concentration (mEq/L)

Pred

icte

d Pr

obab

ility

of

In-H

ospi

tal M

orta

lity

Hyponatremia and Long-term Outcomes

• Prospective cohort study of 98,411 adults hospitalized between 2000 and 2003

• Assessed in-hospital, 1-year, and 5-year mortality• Hyponatremia (serum [Na+] <135 mmol/L) was observed

in 14.5% of patients on initial measurement• Those with hyponatremia were older (67.0 vs 63.1 years)

and had more comorbid conditions (mean Deyo-Charlson index 1.9 vs 1.4)

Waikar SS, et al. Am J Med. 2009;122(9):857-865.

Odds Ratio for Death in Patients With Hyponatremia According to Clinical Subtypes

Waikar SS, et al. Am J Med. 2009;122(9):857-865.

-2.00 -1.50 -1.00 -0.50 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50

Multivariable-Adjusted Odds Ratio

1.47 Overall

1.30 Acute myocardial infarction

1.44 Congestive heart failure1.06 Sepsis

1.00 Pneumonia

1.55 Chronic kidney disease0.91 Liver disease

1.08 Gastrointestinal bleeding

1.21 Volume depletion

2.05 Metastatic cancer

1.34 Circ system: surgical

2.26 Circ system: med

2.31 Musculoskeletal: surg1.45 Nervous system: surg

1.38 Nervous system: med

1.07 Resp system: med

14

Odds Ratio: probability ratioOdds = The probability of events / the probablity of non-events

Persistent Normonatremia

(n = 42,176)

Persistent Hyponatremia

(n = 4524)

Resolved Hyponatremia

(n = 3794)

In-hospital mortality 1 (ref) 2.37 1.26

1-year mortality 1 (ref) 1.55 1.19

5-year mortality 1 (ref) 1.32 1.18

Effect of Resolution of Hyponatremia on Odds Ratio for Mortality

Analysis in patients with at least 2 serum [Na+] determinations (categorizations based on first and final serum [Na+] values). Multivariate analysis adjusted for age, sex, Deyo-Charlson index,and individual diagnoses

Waikar SS, et al. Am J Med. 2009;122(9):857-865.

Two types of hyponatremia

Dilutional hyponatremiaTotal body sodium near normal

Total body water increased

Hypervolemic(edema)

Heart failure*Cirrhosis*

Nephrotic syndrome

Euvolemic(no edema)

SIADH*Hypothyroidism

Secondary adrenal insufficiency

Depletional hyponatremiaHypovolemic

Sodium lostTotal body water reduced

Diarrhea

Vomiting

Burns

Trauma

Pancreatitis

Diuretics

Renal salt wasting

Primary adrenalinsufficiency

*Share underlying pathophysiology of AVP excess.

1. Douglas I. Cleve Clin J Med. 2006;73:S4-S12. 2. Kumar S, et al. Lancet. 1998;352:220-228.

hyponatremia can be caused by dilution from retained water, or by depletion from electrolyte losses in excess of water

Secretion of vasopressin, the antidiuretic hormone, osmoregulatory pathways of the hypothalamus

Wilson Y, et al.: Visualization of functionally activated circuitry in the brain. Proc Natl Acad Sci USA 99:3252-3257, 2002

Sagital section of the ventral brain in a mouse at the level of the third ventricle

MnPO : median preoptic nucleus

Determinants of Vasopressin Secretion

5

4

3

2

1

120 125 130 135 140 145

Plas

ma

Argi

nine

-Vas

opre

ssin

(p

g/m

L)

Plasma Sodium (mEq/L)

Detection Limit

A B

1000

100

10

1

0

Incr

ease

in P

lasm

aAr

gini

ne-V

asop

ress

in

(pg/

mL)

% Fall in Mean ArterialBlood Pressure

10 20 30 40 6050

Cationic channels inactivated by stretch, TRPVs (Transient Receptor Potential Vanilloid channels), are the osmoreceptors of the anterior hypothalamus : thirst

and magnocellular neurons.

Osmosensation in vasopressin neurons: Prager-Khoutorsky M, Bourque CW.Trends Neurosci. 2010 Feb;33(2):76-83.

Hyperosmotic stimuli depolarize these cells via the activation of nonselective cation channels (NSCCs)

Hypoosmolality causes hyperpolarization by inhibiting NSCCs

Non-osmotic stimulation of vasopressin, importance of Angiotensin II

•angiotensin II is inducing an osmoregulatory gain.

•This helps restoration of volume and blood pressure maintenance.

AVP Levels Are Elevated in Patients With Hypo-osmolality and CHF

Szatalowicz VL, Bichet DG et al. N Engl J Med. 1981;305:263-266.

Plasma Osmolality, mOsm/kg of WaterPlasma Osmolality, mOsm/kg of Water

300300

Taking diuretics(n=23)

No diuretics (n=14)

Plas

ma

AVP

(pg/

mL)

Plas

ma

AVP

(pg/

mL)

15.015.0

14.014.0

13.013.0

12.012.0

4.04.0

3.0

2.02.0

1.01.00.50.50.00.0

250250 260260 270270 280280 290290

19.219.2

Nor

mal

Ran

ge

Indirect and Direct Therapies for SIADH, Cirrhosis and CHF

TherapyTarget: AVP

Excess Limitations

Isotonic Saline Ineffective in dilutional hyponatremias Can’t be used in edema-forming disorders No controlled safety database

Hypertonic Saline

No consensus on appropriate infusion rates Overcorrection can cause osmotic demyelination Can’t be used in edema-forming disorders No controlled safety database

Fluid Restriction

Slow to correct; Poorly tolerated due to thirst Ineffective with high AVP levels and urine osmolalities

Demeclocycline Not approved for hyponatremia Slow to correct Nephrotoxic (esp. cirrhosis) and disposed by kidney

Urea No USP formulation Not approved for hyponatremia Poor palatability

Vasopressin antagonists

Conivaptan in USA is IV only (due to CYP3A4 inhibition) Tolvaptan accepted by Health Canada

23

Urine/Plasma electrolyte ratio: UNa+UK/PNa+ PK to guide water restriction

U/P ratio Insensible water losses

Expected net water loss

Recommended water consumption

≥ 1.0 800 mL - 800 mL 0 mL

.5 - 1,0 800 mL -800 to -1300 mL Up to 500 mL

< 0.5 800 mL -1300 to -1800 mL Up to one liter

The Urine/Plasma Electrolyte Ratio: A Predictive Guide to Water Restriction:Furst,… Neilson, Eric American Journal of the Medical Sciences. 319(4):240-244, April 2000.

Molar mass of urea CO(NH2)2 = 60g/mol

Molecular weight calculation ; 12.0107 + 15.9994 + (14.0067 + 1.00794x2)2

60g of urea = 1000 mmol 30g of urea = 500 mmol

“Medicinal urea” 30 g × 1 month will be less than $1.00:

urea 10, NaHCO3 2gCitric Acid 1.5g, sucrose 200 mg

Daily Intake(Solute + Water)

Urinary Osmolality (mOsm/kg)

Urine Volume (Liter/day)

Water Balance (Liter/day)

Normal 500 mmol of solute + 2 liters of water

250 2 liters 0

SIADH 1.

500 mmol of solute + 2 liters of water

500 1 liter(500/500)

+ 1

2. 500 mmol of solute+ 500 mmol of urea+ 2 liters of water

500 2 liters(1000/500)

0

60g of urea=1000 mmol: forcing water excretion , however, bitter taste and necessity to absorb with additional fluid

Editorial,What Is the Role of Vaptans in Routine ClinicalNephrology? Daniel G. Bichet Clin J Am Soc Nephrol 7: 700–703, 2012.

Bichet DG. The posterior pituitary. In: The Pituitary, 3rd Ed. Melmed, S. (ed.), Elsevier Press, Inc., 2011, pp. 261-299.

Vasopressin Makes the Cortical and Medullary Collecting Ducts Permeable

to Water

Tolvaptan

AVP and OPC 21268 (V1a)

Macion-Dazard R, et al. J Pharmacol Exp Ther. 2006.

Binding Sites for Agonists and Antagonists

28

SALT(Study of Ascending Levels of Tolvaptan in Hyponatremia ) Criteria and Restrictions

• Persistent dilutional hyponatremia – Inclusion: serum [Na+] below normal (<135 mEq/L)– Non-reversible etiology (eg, HF, cirrhosis, SIADH)– Exclusion: serum [Na+] <120 mEq/L if neurologic impairment

• Concomitant therapies– “Standard of care” medications permitted– Fluid restriction was not mandatory

• Safety considerations– No confounding disease (eg, recent stroke or MI, recent surgery,

uncontrolled diabetes, etc)

Schrier RW, et al. N Engl J Med. 2006;355(20):2099-2112.

Samsca® (tolvaptan) 15 mg QD initiatedin the hospital

dose if serum [Na+] <136 mEq/L and serum [Na+] increase is <5 mEq/L during prior 24 hrs

Withheld dose, decreased next dose, or increased patient’s fluid intake to mitigate risk of overly rapidcorrection if serum [Na+] was• >145 mEq/L, or• by >12 mEq/L during prior 24 hours, or• by >8 mEq/L during 8 hours on the 1st day

Withheld dose, decreased next dose, or increased patient’s fluid intake to mitigate risk of overly rapidcorrection if serum [Na+] was• >145 mEq/L, or• by >12 mEq/L during prior 24 hours, or• by >8 mEq/L during 8 hours on the 1st day

SALT-1 and SALT-2 Study Design (cont’d)

Schrier RW, et al. N Engl J Med. 2006;355(20):2099-2112.

30 mg/day then 60 mg/day as needed

Titration up to day 4

Mean Change From Baseline in Serum

[Na+] by Hyponatremia Etiology

Samsca® (tolvaptan) (n=213)Placebo (n=203)

Mea

n Ch

ange

Fro

m

Base

line

(mEq

/L)

Day 4 Day 30

*

* *

**

*

Data on file: Protocols 156-02-235 and 156-03-238; Pooled.

Pooled Analysis of SALT-1 and SALT-2; Baseline Serum [Na+] <135 mEq/L

*P<.0001 for Samsca® (tolvaptan) vs placebo, based on Cochran-Mantel-Haenszel (CMH) test.

Samsca® (tolvaptan) 15–60 mg (n=110)Placebo (n=105)

Improved and Maintained Serum [Na+]

(Baseline Serum [Na+] <130 mEq/L)Pooled Analysis of SALT-1 and SALT-2

Mea

n Se

rum

[Na+ ]

(±SD

, mEq

/L)

Treatment DayDay 1

*P<.0001 for all visits during tolvaptan treatment compared to placebo.

*

** * *

7-day follow-up

2 3 4 11 18 25 30 Baseline 8h

*P<.0001 vs placebo

142

138

140

136

132

128

124

120

0

134

130

126

122

*

**

SF-12 Conceptual Framework

Physical ComponentSummary - PCS

Mental ComponentSummary - MCS

In general, is your health …?

Health limit moderate activities?

Health limit climbing several flights?

Accomplish less work (Physical)

Limited in kind of work (Physical)

Has pain interfered with work?

Have lots of energy?

Felt calm and peaceful?

Felt downhearted and blue?

Social activities (Physical/Emotional)

Not as careful at work? (Emotional)

Accomplish less at work? (Emotional)

Items Summary Measures

33

Results in SF-12 Mental (MCS) Status Demonstrate Improvements in Patients With

Hyponatremia (ANCOVA, LOCF)

Moderate ES

Small ES

Large ES

n = 83/71 n = 101/103 n = 184/174

Mental Component Summary Score

P<.05

P<.05

MID

P=NS

ES = effect size; MID = minimally important difference.

Data on file: Protocols 156-02-235 and 156-03-238; Pooled.

Chan

ge F

rom

Bas

elin

eto

Day

30

Samsca® (tolvaptan)Placebo

34

Hyponatremia secondary to SIADH

Severe symptoms (seizures, coma,

respiratory distress)

Moderate symptoms ( nausea, confusion ,

disorientation, unsteady gait)

Mild symptoms or asymptomatic ( mild

neurocognitive symptoms, depression)

Active therapy with hypertonic

saline

Active therapy with either

hypertonic saline or Tolvaptan

Fluid restriction, if it fails or not

tolerated, consider Tolvaptan

Acute Hyponatremia Clinical Features

• Seizures, coma, and respiratory arrests sometimes with little warning

• Neurogenic pulmonary edema (hypoxia may increase severity of brain swelling)

• Cerebral edema with herniation (particularly in young women and children)

Brain CT Scans

Normal Study Fatal Hyponatremia

Causes of Acute HyponatremiaWith Fatal Cerebral Edema

• Self-induced water intoxication– Psychotic patients– Ecstasy (N-Methyl-3,4-methylenedioxyamphetamine)

– Marathon runners– Radio contests

• Post-operative iatrogenic hyponatremia

Consensus Conference on Rx of Acute Hyponatremia in Marathon Runners

Recommended Therapy:

• In the field: 3% saline 100 ml over 10 minutes, repeated x 2 if needed

• In hospital: 3% saline 100 ml or 1 ml/kg bolus followed by 100 ml/hr or 1-2 ml/kg/hr

Hew-Butler, Clin J Sport Med 2008;18:111-121

Therapeutic Hypernatremia for Cerebral Edema

• 30 ml bolus of 23.4% saline (equivalent to 238 ml 3% saline)

• Serum Na = 5 mEq/L• Reversed clinical signs of brain herniation in

most cases• Decreased intracranial pressure by 40%

Koenig, MA. Neurology 70: 1023–1029, 2008

Hypertonic Saline for Seizures, Coma or Cerebral Edema: Data @ ≤ 4 hours

Sterns, Semin Nephrol 29:282-299, 2009

Hypertonic Saline for Seizures, Coma or Cerebral Edema: Data @ ≤ 4 hours

Sterns, Semin Nephrol 29:282-299, 2009

4 to 6 mEq/LIncrease AppearsTo Be“Enough”

Acute vs Chronic Hyponatremia

Patients 14 52Duration < 12 hrs 3 daysSerum Na 112 ± 2 118 ± 1 Stupor or Coma 100% 6%Seizures 29% 4%Mortality 50% 6%Low Na Deaths 36% 0%

Data from Arieff, Medicine 56:121, 1976 (consults at one hospital in one year; Na < 128)

Acute Chronic

Rapid Correction of Chronic Hyponatremia Causes Myelinolysis.

% W

ith M

yelin

olys

is

Maximum Correction Rate (mEq/L/hr) 0 1.0 ± 0.1 2.8 ± 0.2 5.7 ± 0.4

Data from Verbalis KI 1991;39:1274

Inadvertent Overcorrection

• Frequent readjustments of dose of 3%• 10% of patients given D5W or hypotonic

fluid after d/c of 3% saline to offset an unexpected water diuresis

• 1 patient given D5W and DDAVP

Mohmand, et al. Clin J Am Soc Nephrol, 2:1110-7, 2007.

Reversing Overcorrection

Sterns, R. Kidney Int August, 2009

0 12 24 36 48 60 7295

100

105

110

115

120

Ser

um S

odiu

m (

mm

ol/l)

Hours

DDAVP 2 mcg q 6hrs3% NaCl

3% NaClD5W

Urine Osmolality (mOsm/kg)

600 80 700 700 700 700

Treatment of double-digit hyponatremia

Richard H. Sterns,American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp 774-779

Teaching Points for Managing Profound Hyponatremia (1)

• Prompt correction by enough to improve symptoms and reduce the risk of seizures– 4-6 mEq/L is enough correction regardless of the– severity of the hyponatremia– Correct hyponatremia rapidly in the first few hours– and then slow down

• Limited correction to prevent neurologic injury (osmotic demyelination syndrome)– 10 mEq/L in a 24-hour period– 18 mEq/L in a 48-hour period

• Stay well below these limits in patients at high risk ofosmotic demyelination

• Anticipate and manage reversible causes of hyponatremia– Administration of desmopressin (dDAVP) every 6-

8 hours with hypertonic saline solution is an effective strategy to control the rate of correction

– Water intake and hypotonic intravenous fluids (including those containing medications) must be restricted in hyponatremic patients treated with desmopressin

Teaching Points for Managing Profound Hyponatremia (2)

Correction Goals for Severe Chronic Hyponatremia

• Rule of Sixes:

– Six-a-day makes sense for safety– Six in six hours for severe sxs (symptoms) and stop

• Explanation:• For all patients with chronic hyponatremia, the goal is 6• mEq/L during the initial 24 hours. For those with severe• symptoms (seizure, severe delirium, and unresponsiveness),• postponing subsequent efforts to increase serum sodium level

until the next day.

LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression

LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion, disorientation, altered mental status

LEVEL 3 - SEVERE SYMPTOMS: vomiting, seizures, obtundation, respiratory distress, coma

HYPONATREMIA TREATMENT ALGORITHMEUVOLEMIC HYPONATREMIA (SIADH)

fluid restriction, but vaptan under select circumstances:•inability to tolerate fluid restriction or failure of fluid restriction•very low sodium level (<125 mEq/L) with increased risk of developing symptomatic hyponatremia•need to correct serum [Na+] to safer levels for surgery or procedures, or for ICU/hospital discharge•unstable gait and/or high fracture risk•prevention of worsened hyponatremia with increased fluid administration•therapeutic trial for symptom relief

vaptan or hypertonic NaCl administration, followed by fluid restriction

hypertonic NaCl administration, followed by fluid restriction ± vaptan

Dilutional hyponatremia1

total body sodium normal to increasedtotal body water increased

Hypervolemic1

(edema)

heart failurecirrhosis

Euvolemic1

(no edema)

SIADH

[Na+] <125 mEq/L

[Na+] ≥125 mEq/L

may be used as initial therapy at discretion of MD

must be: 1. symptomatic

2. resistant to fluid restriction

Hypovolemic2

DiarrheaVomitingBurnsTrauma

PancreatitisDiuretic excessRenal losses

serious neurological symptoms requiring raising

[Na+] urgently

tolvptan NOT INDICATED

(avoid use of tolvaptan with hypertonic saline)

1. Douglas I. Cleve Clin J Med. 2006;73:S4-S12. 2. Kumar S. et al. Lancet. 1996;352:220-228.

for all patients receiving tolvaptan:• initiate and re-initiate treatment in a hospital• frequently monitor serum sodium

tolvptan CONTRAINDICATED

Depletional hyponatremia2

total body sodium decreasedtotal body water decreased

tolvaptan: patient selection

Dosing Recommendations for Samsca® (tolvaptan)

• Initiate and re-initiate therapy only in a hospital

– Too rapid correction of serum [Na+] can cause serious neurologic sequelae

• During initiation and after titration, frequently monitor for changes in serum electrolytes and volume

• Start with 15 mg tablets once daily without regard to meals

• Increase to 30 mg once daily after 24 hours to a maximum of 60 mg once daily as needed

• Avoid fluid restriction during first 24 hours of therapy• Advise patients that they can and should drink fluid in response to thirst• Fluid restriction with Samsca may increase risk of dehydration and hypovolemia

Recommended dosage

Samsca® (tolvaptan): Drug Interactions

CYP 3A = Cytochrome P450 3A; P-gp = P-glycoprotein.

Agent Effects of Other Drugs on Samsca

Ketoconazole 5-fold in tolvaptan exposure; greater in exposure with higher ketoconazole doses or highest labeled doses of other strong CYP 3A inhibitors

Grapefruit juice 1.8-fold in tolvaptan exposure

P-gp inhibitors tolvaptan dose may be required

Rifampin and other CYP3A inducers

85% in tolvaptan exposure; tolvaptan dose may be required

Lovastatin, digoxin, furosemide, hydrochlorothiazide

Coadministration has no clinically relevant impact on tolvaptan exposure

Effects of Samsca on Other Drugs

Digoxin 1.3-fold in digoxin exposure

Lovastatin lovastatin exposure, but not clinically relevant

Warfarin, amiodarone, furosemide, hydrochlorothiazide

No clinically important pharmacokinetic changes

Summary

• Treatment of hyponatremia depends on the underlying cause, volume status, and duration of onset

• Vasopressin is a key physiological hormone in body water homeostasis and, therefore, hyponatremia

• Vasopressin receptor antagonists (“vaptans”) selectively increase solute-free water excretion by the kidneys

• Tolvaptan is the first and only oral selective vasopressin V2 receptor antagonist to treat clinically significant non-hypovolemic hyponatremia