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HYPONATREMIA
and its management
Hyponatremia

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Definition
Epidemiology
Physiology
Pathophysiology
Types
Clinical Manifestations
Diagnosis
Treatment
Hyponatremia
• Definition:
– It is an electrolyte disturbance in which the sodium
concentration in the plasma is lower than normal,
specifically below 135 mEq/L.
– Hyponatremia represents a relative excess of water in
relation to sodium.
Hyponatremia

Epidemiology:

Frequency





Hyponatremia is the most common electrolyte
disorder
Incidence of approximately 1%
Prevalence of approximately 2.5%
Surgical ward, approximately 4.4%
30% of patients treated in the intensive care unit
Incidence of Hyponatremia



Hyponatremia is a common electrolyte
disorder occurring in up to 15% of
hospitalized patients1
Euvolemic hyponatremia, most often caused
by SIADH, accounts for about 60% of all
types of chronic hyponatremia1
If not treated appropriately, hyponatremia
may lead to significant morbidity and death2,3
1.
Baylis PH. Int J Biochem Cell Biol. 2003;35:1495-1499.
2.
Adrogué HJ. Am J Nephrol. 2005;25:240-249.
3.
Huda MSB et al. Postgrad Med J. 2006;82:216-219.
Annual Cost of Hyponatremia
in the United States



Prevalence-based cost of illness study, including information
from databases, published literature, and an expert physician
panel
Low and high scenarios were estimated and incorporated in a
cost of illness model
Results
 US prevalence for hyponatremia estimated at 3.2
to 6.1 million persons annually
 Estimated 1 million hospitalizations annually with
a principal or secondary diagnosis of
hyponatremia

58%-67% of patients had a longer length of stay due to
symptomatic hyponatremia
Direct costs estimated from $1.6 to $3.6 billion
annually
Boscoe A et al. 
Cost Eff Resour Alloc. 2006;4:1-11.
Hyponatremia

Epidemiology Cont.

Mortality/Morbidity

Acute hyponatremia (developing over 48 h or
less) are subject to more severe degrees of
cerebral edema


sodium level is less than 105 mEq/L, the mortality
is over 50%
Chronic hyponatremia (developing over more
than 48 h) experience milder degrees of
cerebral edema

Brainstem herniation has not been observed in
patients with chronic hyponatremia
Hyponatremia

Epidemiology Cont.

Age

Infants



fed tap water in an effort to treat symptoms of
gastroenteritis
Infants fed dilute formula in attempt to ration
Elderly patients with diminished sense of
thirst, especially when physical infirmity limits
independent access to food and drink
Hyponatremia

Pathophysiology


Hyponatremia can only occur when some
condition impairs normal free water excretion
Acute drop in the serum osmolality:


Neuronal cell swelling occurs due to the water
shift from the extracellular space to the
intracellular space
Swelling of the brain cells elicits 2 responses for
osmoregulation, as follows:


It inhibits ADH secretion and hypothalamic thirst center
immediate cellular adaptation
Hyponatremia

Types

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Hypovolemic hyponatremia
Euvolemic hyponatremia
Hypervolemic hyponatremia
Redistributive hyponatremia
Pseudohyponatremia
Hypovolemic hyponatremia


Deficiencies in both TBW and total body
Na exist, although proportionally more Na
than water has been lost
The Na deficit produces hypovolemia
Hypovolemic hyponatremia


Develops as sodium and
free water are lost and/or
replaced by
inappropriately hypotonic
fluids
Sodium can be lost
through renal or non-renal
routes
www.grouptrails.com/.../0-Beat-Dehydration.jpg
Hypovolemic hyponatremia

Non-Renal loss

GI losses
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Excessive sweating
Third spacing of fluids
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Vomiting, Diarrhea, fistulas, pancreatitis
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Ascites, peritonitis, pancreatitis, and burns
Cerebral salt-wasting syndrome

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Traumatic brain injury, aneurysmal subarachnoid
hemorrhage, and intracranial surgery
Must distinguish from SIADH
Hypovolemic hyponatremia

Renal Loss

Diuretics

Mineralocorticoid deficiency

Osmotic diuresis (glucose, urea, mannitol)

Salt-losing nephropathies (eg, intestitial nephritis,
medullary cystic disease, partial urinary tract
obstruction and polycystic kidney disease)
Euvolemic hyponatremia


In euvolemic (dilutional) hyponatremia,
total body Na and thus ECF volume
are normal or near-normal; however,
TBW is increased
In other words, it is increased TBW
with near-normal total body Na
Euvolemic hyponatremia

Causes


Primary Polydispia, when water intake
overwhelms the kidneys’ ability to excrete
water
Excessive water intake in the presence of
Addison’s disease, hypothyroidism or
nonosmotic ADH release
Euvolemic hyponatremia
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Causes

Certain drugs
like
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Diuretics
Barbiturates
Carbamazepine
Chlorpropamide
Clofibrate
Opioids
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Tolbutamide
Vincristine
Cyclophosphamid
e
NSAIDs
Oxytocin
Euvolemic hyponatremia
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Causes:

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SIADH
Downward resetting of the osmostat
Pulmonary Disease

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Cerebral Diseases
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Small cell, pneumonia, TB, sarcoidosis
CVA, Temporal arteritis, meningitis, encephalitis
Medications

SSRI, Antipsychotics, Opiates, Depakote, Tegratol
Hypervolemic hyponatremia
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
Increased total body Na with a relatively
greater increase in TBW
Can be renal or non-renal

Renal:
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
Acute kidney dysfunction
Chronic kidney disease
Nephrotic syndrome
Non-Renal:
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Cirrhosis
Congestive heart failure
Redistributive hyponatremia

Water shifts from the intracellular to the
extracellular compartment, with a resultant
dilution of sodium. The TBW and total body
sodium are unchanged.


This condition occurs with hyperglycemia
Administration of mannitol
Hyponatremia

Pseudohyponatremia


Spurious hyponatremia or Factitious
Hyponatremia
In this, other substances expand the
serum and dilute the sodium or a blood
constituent leads to the creation of
asodium-free phase in the blood thereby
causing the blood plasma volume to be
overestimated.
Hyponatremia

Clinical Manifestations

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Most patients with a serum sodium concentration
exceeding 125 mEq/L are asymptomatic
Patients with acutely developing hyponatremia are
typically symptomatic at a level of approximately 120
mEq/L
Most abnormal findings on physical examination are
characteristically neurologic in origin
Patients may exhibit signs of hypovolemia or
hypervolemia
Hyponatremia
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Diagnosis
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CT head, EKG, CXR if symptomatic
Repeat Na level
Correct for hyperglycemia
Laboratory tests provide important initial information
in the differential diagnosis of hyponatremia
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Plasma osmolality
Urine osmolality
Urine sodium concentration
Uric acid level
FeNa
Hyponatremia
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Laboratory tests Cont.

Plasma osmolality
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normally ranges from 275 to 290 mosmol/kg
If >290 mosmol/kg :
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If 275 – 290 mosmol/kg :
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Hyperglycemia or administration of mannitol
hyperlipidemia or hyperproteinemia
If <275 mosmol/kg :
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Eval volume status
Hyponatremia
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Laboratory tests Cont.
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Plasma osmolality < 275 mosmol/kg
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Increased volume:
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Euvolemic
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CHF, cirrhosis, nephrotic syndrome
SIADH, hypothyroidism, psychogenic polydipsia,
beer potomania, postoperative states
Decreased volume
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GI loss, skin, 3rd spacing, diuretics
Hyponatremia
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Laboratory tests Cont.
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Urine osmolality
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Normal value is > 100 mosmol/kg
Normal to high:
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Hyperlipidemia, hyperproteinemia, hyperglycemia,
SIADH
< 100 mosmol/kg
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hypoosmolar hyponatremia
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Excessive sweating
Burns
Vomiting
Diarrhea
Urinary loss
Hyponatremia
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Laboratory tests Cont.
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Urine Sodium
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>20 mEq/L
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<20 mEq/L
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cirrhosis, nephrosis, congestive heart failure, GI loss,
skin, 3rd spacing, psychogenic polydipsya
Uric Acid Level
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SIADH, diuretics
< 4 mg/dl consider SIADH
FeNa

Help to determine pre-renal from renal causes
Diagnostic Algorithm for Hyponatremia
Assessment of volume status
Hypovolemia
• Total body water ↓
• Total body Na + ↓↓
U[Na+] >20 mEq/L
Renal losses
Diuretic excess
Mineralocorticoid deficiency
Salt-losing deficiency
Bicarbonaturia with renal
tubal acidosis and
metabolic alkalosis
Ketonuria
Osmotic diuresis
U[Na+] <20 mEq/L
Extrarenal losses
Vomiting
Diarrhea
Third spacing of fluids
Burns
Pancreatitis
Trauma
Euvolemia (no edema)
• Total body water ↑
• Total body Na+ ↔
U[Na+]>20 mEq/L
Glucocorticoid
deficiency
Hypothyroidism
Syndrome of
inappropriate
ADH secretion
- Drug-induced
- Stress
Hypervolemia
• Total body water ↑↑
• Total body Na+ ↑
U[Na+] >20 mEq/L
Acute or chronic
renal failure
U[Na+] <20 mEq/L
Nephrotic syndrome
Cirrhosis
Cardiac failure
Legend: ↑ increase; ↑↑ greater increase; ↓ decrease; ↓↓ greater decrease; ↔ no change.
Adapted from Kumar S, Berl T. In: Atlas of Diseases of the Kidney. 1999:1.1-1.22.
Hyponatremia
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Treatment

Four issues must be addressed
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Asyptomatic vs. symptomatic
acute (within 48 hours)
chronic (>48 hours)
Volume status
1st step is to calculate the total body
water
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total body water (TBW) = 0.6 × body weight
Hyponatremia
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Treatment Cont.

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Next decide what our desired correction rate
should be
Symptomatic
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
Immediate increase in serum Na level by 8 to 10
meq/L in 4 to 6 hours with hypertonic saline is
recommended
Acute hyponatremia
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More rapid correction may be possible

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8 to 10 meq/L in 4 to 8 hours
Chronic hyponatremia
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slower rates of correction

12 meq/L in 24 hours
General Principles in the
Treatment of Acute Hyponatremia
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Neurologic consequences can follow both the failure
to promptly treat as well as the excessively rapid
rate of correction of hyponatremia
Presence or absence of significant neurologic signs
and symptoms must guide treatment
Acuteness or chronicity of hyponatremia impacts the
rate at which serum [Na+] is corrected
If drug-induced SIADH, discontinue the drug
The half-life or offset of effect of the offending drug
should be taken into consideration
Frequent monitoring of serum [Na+] is needed
Kumar S, Berl T. In: Atlas of Diseases of the Kidney. 1999:1.1-1.21; Adrogue HJ,
Madias NE. N Engl J Med. 2000;342:1581-1589.
Traditional Treatments for
Hyponatremia
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Acute
Saline infusion
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isotonic
hypertonic (caution ODS)
Fluid restriction (slow effect)
 Furosemide + NaCl (not in CHF)
 Chronic
 Demeclocycline
 Mineralocorticoids
 Lithium
 Urea
Cawley
M. Ann Pharmacother 2007;41:epub DOI 10.1345/aph.1H502

“Ideal” Therapy for Acute
Hyponatremia
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Prompt but safe correction of [Na+] in 24 to 48 hr:
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≤12 mEq/L in the first 24 hr
≤18 mEq/L in the first 48 hr
Produces increased water excretion without
electrolyte excretion (Na+ and K+) - AQUARESIS
Eliminates or decreases need for fluid restriction
Predictable and reliable action
Quick onset/offset: easily titratable
No unexpected side effects/toxicities
No drug/disease interactions
Cost-effective data available
Hyponatremia
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Symptomatic or Acute

Treatment Cont. - Here comes the
Math!!!
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Estimate SNa change on the basis of the
amount of Na in the infusate
ΔSNa = {[Na + K]inf − SNa} ÷ (TBW + 1)


ΔSNa is a change in SNa
[Na + K]inf is infusate Na and K concentration
in 1 liter of solution
Rx of severe Hyponatremia
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Na deficit = 0.6 X BW [ 120-Na]
Volume of 3% saline required ~ Deficit/500
To rise sodium 1 meq/L, we need 70cc hypertonic
saline
Rate of correction:
Acute (<48 h) or symptomatic: 1-2 meq/L/hr
Chronic (>48 h) or asymptomatic: 0.5 meq/L/hr
Do not exceed 12 meq/L rise on the first day
Rx of Hyponatremia

Hypovolemia
Isotonic Saline

Polydipsia
Water Restriction

SIADH
Water Restriction
Furosemide
Demeclocycline ( toxicity)
V1 V2 R antagonist
(Conivaptan)
Rx of Hyponatremia

When choosing a solution to correct
hyponatremia, aim for negative free water
balance, i.e. the calculated osmolality of the
urine [ 2X (UNa+UK)] should be lower than the
chosen solution’s Osmolality.

IVF osmolality (2 X Na concentration in IVF):
3% saline: 2 x 513 = 1026 mOsm/L
NS: 2 x 154 = 308 mOsm/L
½ NS: 2 x 75 = 150
¼ NS: 2 x 37.5 = 75
NS for Rx of Hyponatremia
A
B (SIADH)
C
UNa (meq/L)
100
90
80
UK (meq/L)
50
90
50
Calculated
UOSM= 2x[UNa+UK]
300
360
260
∆ Na with 1 L NS
(Osm=300)
0
Desalination
phenomeno
n
Free water
balance
0
positive
negative
Hyponatremia

IV Fluids

One liter of Lactated Ringer's Solution
contains:

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

One liter of Normal Saline contains:


130 mEq of sodium ion = 130 mmol/L
109 mEq of chloride ion = 109 mmol/L
28 mEq of lactate = 28 mmol/L
4 mEq of potassium ion = 4 mmol/L
3 mEq of calcium ion = 1.5 mmol/L
154 mEq/L of Na+ and Cl−
One liter of 3% saline contains:

514 mEq/L of Na+ and Cl−
Hyponatremia

Asymptomatic or Chronic

SIADH




Response to isotonic saline is different in the
SIADH
In hypovolemia both the sodium and water
are retained
Sodium handling is intact in SIADH
Administered sodium will be excreted in the
urine, while some of the water may be
retained

possible worsening the hyponatremia
Hyponatremia

Asypmtomatic or Chronic

SIADH

Water restriction



0.5-1 liter/day
Salt tablets
Demeclocycline


Inhibits the effects of ADH
Onset of action may require up to one week
VASOPRESSIN RECEPTORS
Vasopressin Receptor Location &
Functions (KI 2006)
Vasopressin Receptor Antagonists
Receptor
Route of
administration
Tolvaptan*
Lixi-Vaptan
Satavaptan
Conivaptan
V2
V2
V2
V1a/V2
Oral
Oral
Oral
IV
No ∆
No ∆ low Dose
High Dose
No ∆
No ∆
Urine Volume
UOSM
24 h Na
excretion
*SALT I and SALT II Trials.
Vasopressin Receptor Antagonists

Conivaptan is the only FDA approved one for:
Hyponatremia due to SIADH and CHF



V1aR antagonist can cause:
Splanchnic vasodilation and variceal bleeding in
cirrhosis.
Hypotension and decrease in PCWP
V1aR blockade can potentially add to the effect
of beta-adrenergic, RAS, and aldosterone
blockade in CHF.
PureV2R antagonists can theoretically be
deleterious in CHF, as the V1aR remains
unblocked in face of high ADH level.
CONIVAPTAN
Conivaptan

[1,1 Biphenyl]-2-carboxamide,N-[4-[(4,5dihydro-2-methylimidazo[4,5d][1]benzazepin-6(1H)-yl)carbonyl]phenyl],monohydrochloride
Conivaptan
Mechanism of action:
 Conivaptan inhibits AVP by competitively
and reversibly binding to selected AVP
receptors without interacting with the
receptors’s active sites.
 Because of higher affinity for V2,
conivaptan is predominantly used for its
V2-associated aquaretic effect.
Aquaresis


Aquaresis is defined as the solute-free excretion
of water by the kidney
Because electrolytes represent a major component of
urine solutes, aquaresis is also electrolyte-sparing



Measured by increases in EWC and is calculated from the urine
volume and from the plasma and urine [Na+] and [K+]
Typically accompanied by increased urine output and reduced
urine osmolality
Distinguished from diuresis (increased urine output
accompanied by electrolyte excretion)
EWC=effective water clearance.
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill:
Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Conivaptan




Only vasopressin receptor antagonist available in the
U.S.
Non-selective (V2 & V1a): potential for splanchnic
vasodilatation w/ subsequent hypotension or variceal
bleeding b/c of V1a effects (so not tested in cirrhotics)
IV formulation only b/c of potent cyt P450 3A4 inhibition
if given orally (so used only for inpatients)
Approved for euvolemic hyponatremia
Conivaptan – J Clin Endo Metab 2006



74 euvolemic (74%) or hypervolemic (26%)
patients >/= 18 years w/ Na 115-130 mEq/l,
FBG < 275mg/dl, serum osm < 290 mosm/kg
H20, no volume depletion
Excluded patients w/ uncontrolled htn or
arrhythmias, hypotension, untreated thyroid
abnormalities or adrenal insufficiency, CrCl < 20
ml/min, LFTs > 5x normal, signs of liver disease,
HIV, those requiring emergent treatment, those
on meds that cause or treat SIADH
RCT giving oral conivaptan, 40 or 80mg/d, or
placebo, given in 2 divided doses x 5 days
Conivaptan – J Clin Endo Metab 2006





Fluid intake limited to 2L/24 hrs
1* outcome: change from baseline in serum
Na area under the curve
Statistically significant change from baseline
in serum Na AUC w/ both doses (achieved
in a statistically significant shorter amount of
time)
AEs: HA, hypotension, nausea, constipation
Aquaretic effects persisted for at least 6hrs
Conivaptan hydrochloride injection



Conivaptan is indicated for the treatment of
euvolemic hyponatremia (eg, SIADH, or in the
setting of hypothyroidism, adrenal insufficiency,
pulmonary disorders, etc) in hospitalized patients
Conivaptan is also indicated for the treatment of
hypervolemic hyponatremia in hospitalized patients
Not indicated for the treatment of congestive heart
failure (effectiveness and safety have not been
established in these patients)
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill: Astellas Pharma US,
Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Efficacy Endpoints in a Double-Blind
Clinical Trial



29 patients receiving 40 mg iv per day (euvolemic
and hypervolemic)
Fluid restriction 2 L or less per day
Primary


Change in serum [Na+] from baseline during the treatment
phase, as measured by the serum [Na+] AUC (mEq•hr/L)
Secondary




Time from first dose to a confirmed increase in serum [Na+]
≥4 mEq/L from baseline
Total time during the treatment phase that serum [Na+] was
≥4 mEq/L above baseline
Change in serum [Na+] from baseline to end of treatment
Number of patients achieving a confirmed increase in
serum [Na+] ≥6 mEq/L or a normal serum [Na+]
(≥135 mEq/L)
Astellas Pharma US, Inc. Data on file. (087-CL-027 Clinical Study Report dated 22 Dec 2003).
Change From Baseline in Serum [Na+]
Mean (SE) Change from Baseline in Serum [Na+] With Vaprisol 40 mg/d
Change in Serum [Na+] (mEq/L)
10
VAPRISOL 40 mg/d
Placebo
8
6
4
2
0
–2
0
8
16
24
32
40
48
Time (hr)
56
64
72
80
88
96
Evidence of Aquaresis

By day 4, Conivaptan produced a cumulative increase in EWC of more
than 2900 mL, compared with approximately 1800 mL with placebo.
*All values at hour 24 of study day.
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill: Astellas Pharma US,
Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Secondary Efficacy Outcomes
in Open-Label Study 080
Number (%) of patients with 4 mEq/L increase from
baseline in serum [Na+]
Median time to 4 mEq/L increase from baseline in
serum [Na+], hr (95% CI)
Mean±SD total time from first dose to 4 mEq/L
increase in serum [Na+] from baseline, hr
Mean±SD change in serum [Na+] from baseline,
mEq/L
End of treatment
Follow-up day 11
Follow-up day 34
Conivaptan
20 mg/day
n=37
Conivaptan
40 mg/day
n=214
29 (78)
178 (83)
23.8
(12.0, 36.0)
24.0
(24.0, 35.8)
60.6±35.2
9.4±5.32
7.1±8.2
11.5±7.3
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill:
Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
59.5±33.2
8.8±5.43
8.0±6.5
10.7±6.7
Secondary Efficacy Outcomes in Patients
With Hypervolemic Hyponatremia
Placebo
n=8
Number (%) of patients with 4 mEq/L
increase from baseline in serum [Na+]
Median time to confirmed 4 mEq/L
increase from baseline in serum [Na+], hr
(95% CI)
Mean±SD from first dose to 4 mEq/L
increase in serum [Na+] from baseline, hr
Mean±SD change in serum [Na+] from
baseline, mEq/L
Conivaptan Conivaptan
20 mg/day 40 mg/day
n=14
n=66
1 (12.5)
9 (64.3)
53 (80.3)
NE
58.5 (NE)
24.1 (23.8,
37.2)
3.6±10.3 42.9±36.2
54.9±35.6
–0.8±3.3
7.1±4.8
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill:
Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
7.4±5.4
Safety and Efficacy of Conivaptan in
Hypervolemic Hyponatremia


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62% of patients had CHF
IV conivaptan 20, 40, and 80 mg/d
Time to serum Na > 4 mEq/L was 24 hr (40 mg)
Overall change in serum Na 7.4 + 4.8 mEq/L
ADEs: infusion-site reactions, hypokalemia,
vomiting, hypotension
Goldsmith S et al: ACC 2007
Overview of Pharmacokinetics
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Nonlinear pharmacokinetics
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Conivaptan’s inhibition of its own metabolism seems to be the major
factor for nonlinearity
High intersubject variability in clearance (94% CV)
Pharmacokinetics in healthy subjects receiving 20-mg
loading dose of conivaptan followed by a 40-mg/d infusion
for 3 days, the mean clearance was 15.2 L/hr, and the mean
t1/2 was 5 hours
In patients with hyponatremia receiving 20-mg loading dose
of conivaptan followed by a 40-mg/d infusion for 4 days,
the median clearance was 9.5 L/hr, and the median t1/2
was 8.6 hours
CV=coefficient of variation; t1/2=terminal elimination half-life.
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill: Astellas Pharma US, Inc.;
February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Distribution, Metabolism, and Excretion
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Conivaptan is extensively bound to human plasma proteins (99%)
Cmax = 30 mins;
t1/2 = 5 hours
Mass balance study
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83% of dose was excreted in feces, 12% in urine
During the first 24 hours after dosing, about 1% of IV dose was excreted
in urine as intact conivaptan
Conivaptan is a substrate and potent inhibitor of CYP3A4. The
coadministration of conivaptan with potent CYP3A4 inhibitors such
as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir
is contraindicated
CYP3A4 is the sole isoenzyme responsible for metabolism of
conivaptan
CYP=cytochrome P450.
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill: Astellas Pharma US,
Inc.; February 2006.
Pharmacokinetics in Hepatic and Renal
Impairment and in Geriatric patients
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Use with caution in both populations
Little data are available
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill:
Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Precautions: Drug Interactions
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Conivaptan is a substrate of CYP3A4, and
coadministration
of conivaptan and CYP3A4 inhibitors could lead to
an increase in conivaptan concentration
Concomitant use of conivaptan and potent CYP3A4
inhibitors such as ketoconazole, itraconazole,
clarithromycin, ritonavir, or indinavir is
contraindicated
Conivaptan is a potent inhibitor of CYP3A4, and
conivaptan may increase plasma concentrations of
coadministered with drugs that are primarily
metabolized by this isoenzyme
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill:
Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Preparation Guidelines
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Conivaptan should be diluted only with 5% Dextrose
Injection
Conivaptan should not be mixed or administered
with Lactated Ringer’s Injection or 0.9% Sodium
Chloride Injection
Once conivaptan is added to the infusion bag, gently
invert the bag several times to ensure complete
mixing
Compatibility of conivaptan with other drugs has not
been studied
Vaprisol® (conivaptan hydrochloride injection). Prescribing information. Deerfield, Ill:
Astellas Pharma US, Inc.; February 2007; Verbalis JG. J Mol Endocrinol. 2002;29:1-9.
Propylene Glycol
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Propylene glycol is an inactive ingredient
used in the formulation of Vaprisol
Propylene glycol is an FDA-approved
acceptable ingredient in food and drug
products
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Potency and administration methods vary among
products
Maximum potency limits apply
Where Does Conivapan Fit?
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No safety issues with the entire vasopressin
receptor antagonist class
Infusion-site reactions with infusion
Do not use in hypovolemic patient
No data in severe hyponatremia (seizure patient)
Evolving story in CHF patients
One dosing approach: Administer conivaptan 20 mg
IV over 30 minutes, check serum Na in 4-6 hours,
along with urine output, and determine if further
therapy is needed
Summary
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Euvolemic and hypervolemic hyponatremia is a
common electrolyte abnormality
The neurohormone arginine vasopressin plays a key
role in salt and water balance
Treat the primary condition first (i.e., drug-induced,
acute heart failure)
Conivaptan blocks the V2 receptors in the collecting
ducts of the kidneys, it gets rid of what patients have
in excess–H2O
The role of conivaptan in the overall management of
euvolemic and hypervolemic patient with
hyponatremia is evolving
Clinical and economic outcomes data are needed