Investigation and Treatment of
Hyponatremic States
Daniel G. Bichet, M.D.
Professeur of Medicine and Physiology,
Université de Montréal
Hôpital du Sacré-Cœur de Montréal
Conflict Disclosures
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 mentioned
in this presentation are:
Samsca (Tolvaptan) from Otsuka Pharmaceutical
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
serum [Na+] ~
Na+E + K+E
body water
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
Prevalence of Hyponatremia at Initial
Presentation to a Healthcare Provider
30
Percentage (%)
25
28.2
Acute hospital care
Ambulatory hospital care
Community care
21.0
20
15
10
7.2
5
2,60
0,49
0
0,17
0,03
Na <116
0,96
0,14
Na <126
Na <136
Serum [Na+] (mEq/L)
Tan Tock Seng Hospital, Singapore.
Data from 303,577 samples on 120,137 patients available for analysis.
7
Hawkins
RC. Clin Chim Acta. 2003;337(1-2):169-172.
Risk Factors for Hyponatremia
Selected Conditions1
Selected Drug Classes
•
•
•
•
•
•
•
•
Congestive Heart Failure
Cirrhosis
SIADH
Very young or very old age
Adrenal insufficiency
Hypothyroidism
Renal dysfunction
Central nervous system
impairment
•
•
•
•
•
•
•
•
•
•
Surgery or injury
Diuretics1,2
NSAIDs1,2
Opiate derivatives1,2
Antidepressants1,2
Antipsychotics1,2
Antiepileptic agents1,2
Anticancer agents1,2
Antihypertensive agents2
Proton-pump inhibitors2
[Na+] <135 mEq/L3
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.
8
Falls Are a Common Symptom of
Chronic “Asymptomatic” Hyponatremia
25
21.3
Falls (%)
20
Adjusted OR 67.4,
95% CI 7.5–607.4, P<.001
Odds Ratio: probability ratio
Odds = The probability of events /
the probablity of non-events
15
10
5.3
5
0
Mean Serum [Na+]:
No. of Patients:
Hyponatremic Patients
Controls
126±5 mEq/L
139±2 mEq/L
(n=122)
(n=244)
Patients with chronic “asymptomatic” hyponatremia were admitted for falls
significantly more frequently than patients with normal [Na+] levels
Data based on a case-control study in a general Belgium hospital.Renneboog B, et al. Am J
9
Med. 2006;119(1):71.e1-71.e8.
Hyponatremia in Patients With Bone
Fractures Resulting From Incidental Falls
Patients With Hyponatremia (%)
14
13.1%
12
Adjusted OR (CI):
4.16 (2.24–7.71)
P<.001
10
8
6
3.9%
4
Hyponatremia
was mild and
asymptomatic
in all patients
(mean serum [Na+]
131 mEq/L) and was
found to be associated
with bone fracture
after incidental fall in
ambulatory elderly
2
0
Patients
(n=513)
Control
(n=513)
Case control study of 513 cases of bone fracture after incidental fall
in ambulatory patients ≥65 y in general university hospital.
Gankam Kengne F, et al. QJM. 2008;101(7):583-588.
• Rat model SIADH: hyponatremia induced x 3
months - ↓ BMD ~ 30%
• NHANES III survey data: mild hyponatremia ~
Adj-OR 2.85 osteoporosis
Hyponatremia Rats
Non-Hyponatremic Rats
Restrictive Cubic Spline Depicting the Unadjusted
Relationship Between Hospital Admission Serum Sodium
Concentrations and In-Hospital Mortality
Predicted Probability of
In-Hospital Mortality
0.20
0.15
0.10
0.05
110
115
120
125
130
135
140
145
Admission Serum [Na+] Concentration (mEq/L)
Wald R, et al. Arch Intern Med. 2010;170(3):294-302.
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
1.47 Overall
1.30 Acute myocardial infarction
1.44 Congestive heart failure
Odds Ratio: probability
ratio
Odds = The probability of
events / the probablity of
non-events
1.06 Sepsis
1.00 Pneumonia
1.55 Chronic kidney disease
0.91 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: surg
1.45 Nervous system: surg
1.38 Nervous system: med
1.07 Resp system: med
-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
Waikar SS, et al. Am J Med. 2009;122(9):857-865.
14
Effect of Resolution of Hyponatremia on
Odds Ratio for Mortality
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
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 hyponatremia
Total body sodium near normal
Total body water increased
Hypervolemic
Euvolemic
(edema)
Heart failure*
Cirrhosis*
Nephrotic syndrome
(no edema)
SIADH*
Hypothyroidism
Secondary adrenal
insufficiency
Depletional hyponatremia
Hypovolemic
Sodium lost
Total body water reduced
Diarrhea
Pancreatitis
Vomiting
Diuretics
Burns
Renal salt wasting
Trauma
Primary adrenal
insufficiency
*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
Sagital section of the ventral
brain in a mouse at the level of
the third ventricle
MnPO : median
preoptic nucleus
Wilson Y, et al.: Visualization of functionally activated circuitry
in the brain. Proc Natl Acad Sci USA 99:3252-3257, 2002
Determinants of Vasopressin Secretion
B
5
1000
Increase in Plasma
Arginine-Vasopressin
(pg/mL)
Plasma
Arginine-Vasopressin
(pg/mL)
A
4
100
3
10
2
1
Detection Limit
120
125
130
1
0
135
140
Plasma Sodium (mEq/L)
145
10
20
30
40
50
60
% Fall in Mean Arterial
Blood Pressure
Cationic channels inactivated by stretch, TRPVs (Transient Receptor Potential
Vanilloid channels), are the osmoreceptors of the anterior hypothalamus : thirst
and magnocellular neurons.
Hyperosmotic stimuli
depolarize these
cells via the activation
of nonselective cation
channels (NSCCs)
Hypoosmolality causes
hyperpolarization by
inhibiting NSCCs
Osmosensation in vasopressin neurons: Prager-Khoutorsky M,
Bourque CW.Trends Neurosci. 2010 Feb;33(2):76-83.
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
19.2
15.0
No diuretics
(n=14)
14.0
Taking diuretics
(n=23)
Normal Range
Plasma AVP
(pg/mL)
13.0
12.0
4.0
3.0
2.0
1.0
0.5
0.0
250
260
270
280
290
300
Plasma Osmolality, mOsm/kg of Water
Szatalowicz VL, Bichet DG et al. N Engl J Med. 1981;305:263-266.
Indirect and Direct Therapies for
SIADH, Cirrhosis and CHF
Therapy
Target: AVP
Excess
Isotonic Saline
Limitations



Hypertonic
Saline




Fluid
Restriction



Demeclocycline




Urea



Vasopressin
antagonists
23



Ineffective in dilutional hyponatremias
Can’t be used in edema-forming disorders
No controlled safety database
No consensus on appropriate infusion rates
Overcorrection can cause osmotic demyelination
Can’t be used in edema-forming disorders
No controlled safety database
Slow to correct;
Poorly tolerated due to thirst
Ineffective with high AVP levels and urine osmolalities
Not approved for hyponatremia
Slow to correct
Nephrotoxic (esp. cirrhosis) and disposed by kidney
No USP formulation
Not approved for hyponatremia
Poor palatability
Conivaptan in USA is IV only (due to CYP3A4 inhibition)
Tolvaptan accepted by Health Canada
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 2g
Citric Acid 1.5g, sucrose 200 mg
60g of urea=1000 mmol: forcing water excretion , however,
bitter taste and necessity to absorb with additional fluid
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
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
Editorial,What Is the Role of Vaptans in Routine Clinical
Nephrology? Daniel G. Bichet Clin J Am Soc Nephrol 7: 700–703, 2012.
Vasopressin Makes the Cortical and Medullary
Collecting Ducts Permeable to Water
Tolvaptan
Bichet DG. The posterior pituitary. In: The Pituitary, 3rd Ed. Melmed, S. (ed.), Elsevier Press,
Inc., 2011, pp. 261-299.
Binding Sites for Agonists
and Antagonists
AVP and OPC 21268 (V1a)
Macion-Dazard R, et al. J
Pharmacol Exp Ther. 2006.
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.
SALT-1 and SALT-2 Study Design
(cont’d)
Titration up to day 4
Samsca® (tolvaptan) 15
mg QD initiated
in the hospital
 dose if serum [Na+] <136 mEq/L and serum [Na+] increase is <5
mEq/L during prior 24 hrs
 30 mg/day then 60 mg/day as needed
Withheld dose, decreased next dose, or increased patient’s fluid
intake to mitigate risk of overly rapid
correction 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
Schrier RW, et al. N Engl J Med. 2006;355(20):2099-2112.
Mean Change From Baseline in Serum
[Na+] by Hyponatremia Etiology
Pooled Analysis of SALT-1 and SALT-2; Baseline Serum [Na+] <135 mEq/L
Day 30
Day 4
10
9
*
Mean Change From
Baseline (mEq/L)
8
7,4
*
6,6
7
6
5
*
4,8
*
4,2
*
*
3,5
4
3,5
2,4
3
1,5
2
1
Samsca® (tolvaptan)
(n=213)
Placebo
(n=203)
0,2
0,5
1,5
0,4
0
SIADH
HF
Cirrhosis
SIADH
HF
Cirrhosis
*P<.0001 for Samsca® (tolvaptan) vs placebo, based on Cochran-Mantel-Haenszel (CMH)
Data on file: Protocols 156-02-235 and 156-03-238; Pooled.
test.
Improved and Maintained Serum [Na+]
(Baseline Serum [Na+] <130 mEq/L)
Pooled Analysis of SALT-1 and SALT-2
Samsca® (tolvaptan) 15–60 mg (n=110)
Placebo (n=105)
142
Mean Serum [Na+] (±SD, mEq/L)
140
138
136
*
134
*
132
130
*
*
*
*
*
*
128
126
124
122
*P<.0001 vs placebo
120
0
Baseline 8h 2 3
Day 1
4
11
18
25
30
7-day
follow-up
Treatment Day
*P<.0001 for all visits during tolvaptan treatment compared to placebo.
SF-12 Conceptual Framework
Items
Summary Measures
Not as careful at work? (Emotional)
Accomplish less at work? (Emotional)
Have lots of energy?
Felt calm and peaceful?
Mental Component
Summary - MCS
Felt downhearted and blue?
Social activities (Physical/Emotional)
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?
33
Physical Component
Summary - PCS
Results in SF-12 Mental (MCS) Status Demonstrate
Improvements in Patients With Hyponatremia
(ANCOVA, LOCF)
8
Samsca® (tolvaptan)
Placebo
Large ES
P<.05
Change From Baseline
to Day 30
7
P<.05
6
P=NS
Moderate ES
5
4
3
MID
2
Small ES
1
0
SALT-1
n = 83/71
SALT-2
n = 101/103
Mental Component Summary Score
ES = effect size; MID = minimally important difference.
34
Data on file: Protocols 156-02-235 and 156-03-238; Pooled.
Pooled
n = 184/174
Hyponatremia secondary to SIADH
Severe symptoms
(seizures, coma,
respiratory distress)
Active
therapy with
hypertonic
saline
Moderate symptoms
Mild symptoms or
( nausea, confusion ,
disorientation, unsteady
gait)
asymptomatic ( mild
neurocognitive
symptoms, depression)
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 Hyponatremia
With 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
4 to 6
mEq/L
Increase
Appears
To Be
“Enough”
Sterns, Semin Nephrol 29:282-299, 2009
Acute vs Chronic Hyponatremia
Acute
Patients
Duration
Serum Na
Stupor or Coma
Seizures
Mortality
Low Na Deaths
14
< 12 hrs
112 ± 2
100%
29%
50%
36%
Chronic
52
3 days
118 ± 1
6%
4%
6%
0%
Data from Arieff, Medicine 56:121, 1976
(consults at one hospital in one year; Na < 128)
Rapid Correction of Chronic
Hyponatremia Causes Myelinolysis.
100%
80%
60%
40%
20%
0%
0 1.0 ± 0.1 2.8 ± 0.2 5.7 ± 0.4
Maximum Correction Rate (mEq/L/hr)
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
D5W
3% NaCl
3% NaCl
DDAVP 2 mcg q 6hrs
120
Serum Sodium (mmol/l)
115
110
105
Urine Osmolality (mOsm/kg)
100
600
80
700
700
700
700
95
0
12
24
36
Hours
Sterns, R. Kidney Int August, 2009
48
60
72
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 of
osmotic demyelination
Teaching Points for Managing Profound Hyponatremia
(2)
• Anticipate and manage reversible causes of
hyponatremia
– Administration of desmopressin (dDAVP) every 68 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
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.
HYPONATREMIA TREATMENT ALGORITHM
EUVOLEMIC HYPONATREMIA (SIADH)
LEVEL 3 - SEVERE SYMPTOMS:
vomiting, seizures, obtundation,
respiratory distress, coma
hypertonic NaCl administration,
followed by fluid restriction ±
vaptan
LEVEL 2 - MODERATE SYMPTOMS:
nausea, confusion, disorientation, altered
mental status
vaptan or hypertonic NaCl
administration, followed by fluid
restriction
fluid restriction, but vaptan under
select circumstances:
•inability to tolerate fluid restriction or
LEVEL 1 - NO OR MINIMAL SYMPTOMS:
headache, irritability, inability to
concentrate, altered mood, depression
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
tolvaptan: patient selection
Dilutional hyponatremia1
Depletional hyponatremia2
total body sodium normal to increased
total body water increased
total body sodium decreased
total body water decreased
Hypervolemic1
Euvolemic1
(edema)
(no edema)
heart failure
cirrhosis
SIADH
Hypovolemic2
Diarrhea
Vomiting
Burns
Trauma
Pancreatitis
Diuretic
excess
Renal losses
tolvptan CONTRAINDICATED
[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
for all patients receiving tolvaptan:
• initiate and re-initiate treatment in a hospital
• frequently monitor serum sodium
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.
Dosing Recommendations for
Samsca® (tolvaptan)
• Initiate and re-initiate therapy only in
a hospital
Recommended dosage
– 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
Samsca® (tolvaptan): Drug Interactions
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
CYP 3A = Cytochrome P450 3A; P-gp = P-glycoprotein.
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 nonhypovolemic hyponatremia