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Effects of oxcarbazepine on sodium concentration and water handling.

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Effects of Oxcarbazepine on Sodium
Concentration and Water Handling
Rajesh C. Sachdeo, MD,1 Alan Wasserstein, MD,2 Peter J. Mesenbrink, PhD,3 and Joseph D’Souza, PhD3
Oxcarbazepine, a keto-analogue of carbamazepine, was recently approved in the United States for the treatment of
seizures of partial onset. Some patients treated with oxcarbazepine showed the development of hyponatremia, which in
most instances was asymptomatic. Understanding the mechanisms by which oxcarbazepine can lead to a reduction of
serum sodium levels could have therapeutic implications for the few patients in whom symptomatic hyponatremia develops. In this study, we evaluated sodium and water handling in patients with epilepsy and in healthy subjects titrated
over 3 weeks to a maximum daily oxcarbazepine dose of 2,400mg. All subjects were evaluated in a hospital setting after
an overnight fast and after an acute water-load test performed before oxcarbazepine exposure and after maintenance on
the medication for 3 weeks. Before oxcarbazepine exposure, the percentage of water load excreted was normal as both
groups excreted more than 80% of the administered water load. After the intake of oxcarbazepine, the water load resulted
in a reduction of the serum sodium and free water clearance without a concomitant increase in the arginine vasopressin
serum levels. Most subjects in both groups failed to excrete 80% or more of the water load, suggesting that the effect of
oxcarbazepine is physiological. We found that, after the water load, serum sodium and free water clearance were diminished in both groups without a concomitant increase in the arginine vasopressin serum levels. These findings indicate
that oxcarbazepine-induced hyponatremia is not attributable to the syndrome of inappropriate secretion of antidiuretic
hormone. Possible mechanisms include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement
of their responsiveness to circulating antidiuretic hormone.
Ann Neurol 2002;51:613– 620
Oxcarbazepine (OXC; 10,11-dihydro-10-oxo-carbamazepine), a keto-analogue of carbamazepine (CBZ), was
recently approved in the United States for the treatment
of seizures of partial onset.1,2 Although structurally related to CBZ, OXC has several clinically relevant advantages over the former, including a more favorable pharmacokinetic profile and better tolerability. Unlike CBZ,
which is oxidized to the 10,11-epoxide, OXC is rapidly
reduced by cytosolic enzymes to the monohydroxy derivative (MHD), which is the pharmacologically active
substance. Because the metabolism of OXC follows nonoxidative pathways, it has a lower propensity to induce
hepatic oxidative enzymes3 and a reduced potential for
drug–drug interactions. In addition, OXC does not undergo autoinduction and was significantly better tolerated than CBZ in an active control, double-blind, comparative trial in patients with newly diagnosed epilepsy.4
As with CBZ,5,6 the serum sodium levels were low
in some patients treated with OXC.7–10 In most patients, the hyponatremia was asymptomatic and only
rarely resulted in morbidity or led to discontinuation
of OXC therapy.2,9 A number of factors, including the
absolute serum sodium level and the rate of reduction,
are important determinants of the symptoms associated
with hyponatremia.11 For instance, although hyponatremia is usually defined as serum sodium levels of less
than 135mEq/L, it is not generally considered clinically
significant until the level falls to less than 125mEq/L;
serious complications are generally restricted to levels
of less than 120mEq/L. In addition, acute hyponatremia can result in brain swelling and various complications ranging from headaches and seizures to brain herniation and death.12–14 In contrast, when chronic
hyponatremia is symptomatic, it is associated with
more subtle symptoms, such as anorexia, nausea,
cramps, personality changes, and, in rare cases, seizures.11 Once hyponatremia is detected, it is useful to
determine whether the concomitant serum osmolality
is elevated, normal, or decreased.12,15,16 When hyponatremia is associated with a normal (normotonic hyponatremia or pseudohyponatremia) or increased serum osmolality (hypertonic hyponatremia), it is not in
From the 1University of Medicine and Dentistry of New Jersey,
New Brunswick, NJ; 2University of Pennsylvania Medical Center,
Philadelphia, PA; and 3Novartis Pharmaceuticals, East Hanover, NJ.
Address correspondence to Dr Sachdeo, New Jersey Comprehensive
Epilepsy Center, University of Medicine and Dentistry of New Jersey, 97 Paterson Street, New Brunswick, NJ 08901. E-mail:
[email protected]
Received Sep 4, 2001, and in revised form Jan 8, 2002. Accepted
for publication Jan 19, 2002.
Published online Apr 23, 2002 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10190
© 2002 Wiley-Liss, Inc.
613
itself harmful and is usually the result of a rise in an
osmolar solute, such as lipids, proteins, or glucose.11
When combined with a reduction in serum osmolality,
it causes water to shift from extracellular compartments
to intracellular compartments. This hypotonic hyponatremia is caused by an inability of the renal tubules to
excrete sufficiently dilute urine,17 resulting from increased levels of antidiuretic hormone (ADH) or from
some impairment in the diluting capability of the renal
tubules. Either process can be aggravated by excessive
water load or by medications, such as diuretics, which
impair renal salt and water regulation.
Although early reports suggested that CBZ could induce the excessive release of ADH18,19 and lead to the
syndrome of inappropriate secretion of ADH, more recent studies have not found such an increase. Indeed,
most studies documented a reduction of circulating
levels of arginine vasopressin (AVP) during CBZ administration20,21 that was associated with impaired water excretion after a water load.20 Although the mechanisms of CBZ-induced antidiuresis have not been
elucidated, a variety of explanations, including an increased sensitivity of renal tubules to circulating levels
of ADH caused by a dysregulation of osmoreceptor receptivity6 or a direct action of CBZ on the renal tubules,20 –22 have been proposed. The mechanisms of
OXC-induced hyponatremia have not yet been formally evaluated.
The aim of this study was to evaluate whether abnormalities in water handling occur in healthy volunteers and patients with epilepsy after an intake of OXC
and to correlate any changes in water handling with
plasma AVP concentrations.
Patients and Methods
Subjects
Two groups of subjects, one consisting of normal healthy
volunteers and the other of patients with epilepsy, were enrolled in the study. Eligible participants were men and
women, aged 16 to 65 years and weighing 45kg or more,
with a pretreatment sodium level of greater than 130mEq/L,
who were free of major medical and psychiatric disorders.
Subjects who at screening had abnormal thyroid function
tests or an abnormal response to the adrenocorticotropic hormone stimulation test were excluded. Also excluded were
subjects taking dihydropyridine calcium-channel blockers, diuretics, or monoamine oxidase inhibitors or those who had
recently used an experimental drug. Women had to be postmenopausal or incapable of bearing children or had to be
using an acceptable method of contraception for a period of
30 days or more before enrollment in the study.
Additional inclusion criteria for the group of patients with
epilepsy were a diagnosis of partial-onset seizures and maintenance on a constant dose of an antiepileptic drug (AED) as
monotherapy for at least 21 days before the treatment phase
was entered. Patients previously exposed to OXC or who had
undergone recent treatment with felbamate or barbiturates at
dosages of greater than 15mg/day were excluded.
This study was conducted in accordance with the provisions of the Declaration of Helsinki and was reviewed and
approved by the Institutional Review Board. All participants
in this study were informed about the potential risks and
were required to sign a consent form.
Study Phases
The study consisted of three phases (Table 1). The first was
a 21-day baseline phase, during which patients with epilepsy
remained on constant doses of their prestudy AED. No patient in either group received OXC during this period.
The second phase was a 21-day open-label treatment
phase that included a 14-day titration period followed by a
Table 1. Study Design
Treatment Phase
Phase
Titration Period
Baseline Phase
Visit
Day
Test
Treatment
1
⫺7
2
0
Water-load test
Maximum of one
AED at stable dose for
patients with epilepsy
3 (day 14)
1–14
OXC
Days 1–4: 600mg/day; days 5–7:
900mg/day; days 8–10: 1,200mg/day;
days 11–13: 1,800mg/day; day 14:
2,400mg/day
Baseline AED decreased by 25% on
days 1, 5, and 8 then discontinued
on day 11 for patients with epilepsy
a
Maintenance Period
15–20
4
21
Water-load test
Longterm
Extension
5a
ⱖ21
OXC
2,400mg/day or maximum tolerated dose
Healthy volunteers were tapered off OXC therapy (OXC dose reduced by 600mg every 2 days for 1 week). Patients with epilepsy could
continue into the extension phase on OXC or could be tapered off the drug with the same schedule used for healthy volunteers and converted
to their baseline AED or to another AED initiated at the investigator’s discretion.
AED ⫽ antiepileptic drug; OXC ⫽ oxcarbazepine.
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Annals of Neurology
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May 2002
7-day maintenance period. During the titration period, OXC
was titrated to less than 2,400mg/day or to the highest tolerated dose (see Table 1). If a subject could not tolerate the
scheduled OXC titration, the dose could be reduced by
300mg increments to the maximum tolerated dose. During
this period, patients with epilepsy were gradually tapered off
their baseline AED over a period of 11 days (see Table 1).
During the third phase (the extension phase), the normal
volunteers were tapered off OXC by 600mg every 2 days.
The same taper schedule was used for patients with epilepsy
who elected not to continue treatment with OXC. Those
patients were converted back to their baseline AED or to
another AED initiated at the investigator’s discretion.
Study Visits
Participants were seen for a minimum of four visits (see Table 1): (1) a screening visit during the baseline phase 7 days
before enrollment in the treatment phase (day ⫺7), (2) a
visit immediately before entry into the treatment phase (day
0), (3) a visit at the end of the titration period of the treatment phase (day 14), and (4) a visit at the end of the maintenance period of the treatment phase (day 21). Subjects
were required to return all unused pills, and compliance was
monitored at each visit during the treatment phase.
Approximately 1 week before entering
the treatment phase, prospective subjects signed a written informed consent and were screened for significant medical
conditions. This included a complete review of the medical
history, physical and neurological examinations, the recording of all current medications, and an electrocardiogram.
Subjects meeting study criteria were administered an adrenocorticotropic hormone stimulation test, and blood was drawn
for routine laboratory analysis, including thyroid function
tests, drug screening, and a serum pregnancy test. The adrenocorticotropic hormone test was done by the administration
of 250␮gm of cosyntropin intravenously and by the checking of serum cortisol levels drawn 0, 30, and 60 minutes
after the injection. At the conclusion of the screening visit,
subjects were provided with a container with instructions to
collect all urine 24 hours before their next visit. In addition,
they were instructed to abstain from fluids, food, alcohol,
medications, and smoking for 9 hours before their next visit,
with the exception that patients with epilepsy could take
their AED approximately 1 hour before that visit.
SCREENING VISIT.
On this visit, eligible subjects were instructed
to arrive at the testing facility at 9:00 AM with their 24-hour
urine collection. Patients were instructed to be fasting, with
no fluid or food intake for at least the previous 9 hours. All
subjects underwent a 20ml/kg water-load test and were asked
to ingest the fluid within a period of 30 minutes. The percentage of water load excreted, plasma AVP concentration,
plasma and urine osmolality, and serum and urine sodium
were measured before and at 1, 2, 3, and 4 hours after the
water-load test.
DAY 0 VISIT.
DAY 14 VISIT. On this visit, subjects were receiving either a
daily OXC dose of 2,400mg or their maximally tolerated
daily dose. An interim physical examination was performed,
and blood was collected for serum sodium. Subjects were
provided with a container for 24-hour urine collection with
instructions similar to those given during the screening visit.
DAY 21 VISIT. On this visit, the subjects underwent an adrenocorticotropic hormone stimulation test, a thyroid function test, drug screening, and a serum pregnancy test. In addition, procedures similar to those performed during the day
0 visit, including the water-loading test, were performed.
Monitoring of Seizures and Adverse Events
Seizure frequency for the baseline phase was determined at
day 0 (visit 2). During the treatment phase, the type and
frequency of seizures were recorded in a seizure diary.
Patients and normal volunteers were queried about adverse
events on days 14 and 21 of the treatment phase. All adverse
events that were not present at the visit on day 0 were recorded. In addition, worsening of a medical condition
present on day 0 was considered an adverse event.
Monitoring of Drug Levels
Blood levels of MHD, the active metabolite of OXC, were
obtained on day 21 of the study. These levels were assayed in
plasma samples by an established high-performance liquid
chromatography methodology.23,24
Sample Size and Statistical Analysis
A previous study20 showed a mean decrease in plasma AVP
concentrations of 0.74 ⫾ 0.13pmol/L after 1 week of CBZ
intake in 10 healthy volunteers ( p ⬍ 0.0005). If the mechanism for OXC is similar to that of CBZ, a requirement of
10 completed healthy volunteers and 10 completed patients
with epilepsy was determined to be adequate to assess the
influence of OXC on plasma AVP concentration and waterload test parameters.
The influence of OXC on the various serum and urine
parameters were assessed with paired t tests to compare the
values obtained at day 0 (pre-OXC exposure) and day 21
(post-OXC exposure). For each analysis, the data were summarized by subject group: patients with epilepsy and healthy
volunteers.
Results
Subjects
Eleven patients with epilepsy (4 men and 7 women) participated in the trial.
The mean age was 29.5 years (range, 16 –50 years),
and the mean body weight was 70.4kg (range, 52.3–
105.5kg). Of the 11 patients with epilepsy, 9 were
treated with an AED at baseline: 6 of these patients
were receiving CBZ, with 1 each receiving phenytoin,
lamotrigine, and valproate. In addition, 2 patients were
treated with sertraline and 1 with fluoxetine. During
the treatment phase, 8 patients were titrated to daily
OXC dosages exceeding 1,800mg, 2 received dosages
of 1,200 to 1,800mg, and 1 was titrated to less than
600mg.
PATIENTS WITH EPILEPSY.
Sachdeo et al: Effects of Oxcarbazepine on Sodium Concentration
615
NORMAL VOLUNTEERS. Ten healthy volunteers (7 men
and 3 women) with a mean age of 34.1 years (range,
24 – 44 years) and a mean weight of 69.6kg (range,
57.2– 89.7kg) were enrolled in the trial. One was titrated to daily OXC dosage exceeding 1,800mg, and 9
received dosages of 600 to 1,200mg.
Overnight Water Deprivation
The results of blood and urine studies collected from
the groups of healthy volunteers and patients with epilepsy after overnight water deprivation before and after
exposure to OXC are summarized in Table 2. No significant differences were found in the means of plasma
AVP, urine osmolality, plasma osmolality, serum sodium, or urine sodium between the baseline and treatment phases for either group.
The baseline AVP concentrations were not significantly different between the six patients with epilepsy on
CBZ and the healthy volunteers (t ⫽ 1.10, p ⫽ 0.30).
The average AVP concentrations were 3.41pg/ml for the
six patients on CBZ and 1.24pg/ml for the healthy volunteers. Similarly, there was no significant difference in
the AVP concentrations between the two groups after
the water-load tests (t ⫽ ⫺1.11, p ⫽ 0.28) with an average AVP concentration of 0.97pg/ml for the group of
patients receiving CBZ and 0.74pg/ml for the group of
healthy volunteers.
Water-Load Test
The results obtained after the water-load test before
and after intake of OXC are summarized in Table 3.
Before OXC exposure, the percentage of water load ex-
creted during the 4 hours after water loading was normal, as both groups excreted more than 80% of the
administered water load. In both groups, after OXC
intake, there were statistically significant reductions in
the percentage of water load excreted, free water clearance, serum sodium concentration, and plasma osmolality. After OXC intake, all but two subjects failed to
excrete 80% or more of the water load, suggesting that
this effect of OXC is physiological, rather than idiosyncratic. In addition, the urine osmolality was significantly increased in the group of healthy subjects, with
a strong statistical trend for the group of patients with
epilepsy. The changes in plasma AVP or urine sodium
concentrations were not significant for either group.
The time course over the 4 hours after the waterload test, for the means of the percentage of water load
excreted, plasma osmolality, serum sodium concentration, urine osmolality, and serum AVP concentration,
is shown in Figures 1 to 5, respectively.
At the conclusion of the water-load test, the mean
plasma osmolality dropped from 280.2 to 272.4mOsm/L in the group of patients with epilepsy and from
282.3 to 269.7mOsm/L in the group of healthy volunteers.
There was a statistically significant negative correlation between the MHD trough plasma concentration
and the percentage of water load excreted at 1 hour
(r ⫽ ⫺0.56, p ⫽ 0.01), as shown in Figure 6. A similar correlation between the MHD trough plasma concentration and the percentage of water load excreted at
4 hours was present, but it did not reach statistical significance (r ⫽ ⫺0.42, p ⫽ 0.08).
Table 2. Results of Blood and Urine Analyses after Overnight Fasting and Water Deprivation (Mean Values)
Pre-OXC
Exposure
Post OXC
Exposure
Change
p
Patients with epilepsy
Plasma AVP (pg/ml)
Urine osmolality (mOsm/L)
Plasma osmolality (mOsm/L)
Serum sodium (mEq/L)
Range (mEq/L)
Urine sodium (mEq/L)
1.14
615.00
283.20
138.70
135–142
115.30
0.92
712.00
278.90
136.10
121–142
134.60
⫺0.22
97.00
⫺4.30
⫺2.60
—
19.30
0.3
0.5
0.2
0.2
—
0.4
Healthy subjects
Plasma AVP (pg/ml)
Urine osmolality (mOsm/L)
Plasma osmolality (mOsm/L)
Serum sodium (mEq/L)
Range (mEq/L)
Urine sodium (mEq/L)
3.41
633.33
283.78
139.38
136–141
127.00
0.89
580.56
279.44
137.00
128–142
161.11
⫺2.53
⫺52.78
⫺4.33
⫺2.38
—
34.11
0.1
0.6
0.1
0.1
—
0.3
Values obtained from blood drawn at 9
of the treatment phase.
AM
and 24-hour urine collection brought in on days of water-load tests performed on days 0 and 21
AVP ⫽ arginine vasopressin; OXC ⫽ oxcarbazepine.
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Annals of Neurology
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May 2002
Table 3. Results of Blood and Urine Analyses after Water Load (Mean Values)
Pre-OXC
Exposure
Post OXC
Exposure
Change
p
Patients with epilepsy
% Water load excreted1
Plasma AVP (pg/mL)2
Urine osmolality (mOsm/L)2
Plasma osmolality (mOsm/L)2
Serum sodium (mEq/L)2
Range (mEq/L)
Urine sodium (mEq/L)2
% Free water clearance3
86.59
0.91
312.89
280.22
138.00
134–141
73.00
247.44
31.76
0.76
583.00
272.44
133.00
127–138
123.11
⫺10.24
⫺54.83
⫺0.15
⫺270.11
⫺7.78
⫺5.00
—
50.11
⫺257.68
0.0018
0.1689
0.0525
0.0052
0.0191
—
0.1524
0.0038
Healthy subjects
% Water load excreted1
Plasma AVP (pg/ml)2
Urine osmolality (mOsm/L)2
Plasma osmolality (mOsm/L)2
Serum sodium (mEq/L)2
Range (mEq/L)
Urine sodium (mEq/L)2
% Free water clearance3
112.19
0.74
222.38
282.33
138.89
133–141
64.25
345.30
54.07
1.06
384.00
269.67
132.67
120–139
118.00
17.43
⫺58.1
0.32
⫺161.62
⫺12.66
⫺6.22
—
53.75
⫺327.87
0.0002
0.1
0.0462
0.0025
0.0047
—
0.0702
0.0007
1
% water load excreted over 4 hours.
At 4 hours after water loading.
3
At 3 hours after water loading.
2
Adrenocorticotropic Hormone Test
No demonstrated significant change in adrenal function was demonstrated, as assessed by serum cortisol
levels after exposure to OXC.
Serum Monohydroxy Derivative Levels
The trough serum MHD levels averaged 95.4␮mol/L
(range, 2.4 –140.4␮mol/L) and 82.1␮mol/L (range,
31.2–100.8␮mol/L) in the groups of patients with epilepsy and healthy volunteers, respectively.
Seizures
The mean reported seizure frequency in the group of
patients with epilepsy decreased from 21.8 per 28 days
during the baseline phase (range, 0 –211) to 2.6 per 28
days (range, 0 –27) during the treatment phase.
Adverse Events
Somnolence and dizziness were the most common adverse events in the group of healthy volunteers, whereas
dizziness and insomnia were most common in the
group of patients with epilepsy. Most adverse events
were transient and were rated as mild to moderate in
severity. The adverse events experienced by three or
more subjects at the end of the titration period (visit 3
on day 14) and at the end of the maintenance period
(visit 4 on day 21) were tabulated separately to evaluate
whether specific adverse events were related to hyponatremia (Table 4). Except for a slightly higher frequency
of dizziness, most adverse events were experienced during the titration period. Two subjects, one from each
group, discontinued the trial because of a rash, which
in both incidences was considered by the primary investigator to be related to OXC. No serious adverse
experiences or deaths were reported during this study.
In addition, no clinically significant electrocardiographic changes were noted.
Discussion
This study indicates that OXC intake results in significant reductions in serum osmolality and serum sodium
concentration after a water-load test in both healthy volunteers and patients with epilepsy. This hypotonic hyponatremia, which is not associated with a significant
change in serum AVP, is the result of both a relative
inability to dilute the urine and a reduction in the percentage of water excreted after the water-load test.
As expected, before OXC exposure, the serum sodium concentration and plasma osmolality values at
baseline were within the normal range in both groups
after overnight fasting and water deprivation. In addition, despite some interindividual variability, the baseline water-load test resulted in the expected alteration
in urine osmolality with normal free water clearance in
both groups of subjects.
After exposure to OXC for 3 weeks, the overnight
water deprivation resulted in nonsignificant reductions
in serum sodium concentration, plasma osmolality, and
plasma AVP levels in both groups. However, there was
a significant inability to excrete the administered water
load, with the amount excreted during the 4-hour test
falling to less than 50% of the amount excreted at
Sachdeo et al: Effects of Oxcarbazepine on Sodium Concentration
617
Fig 1. Time course of the mean percentage
of water load excreted after the oral
water-load test before and after exposure to
oxcarbazepine in the group of healthy volunteers and the group of patients with
epilepsy. Scale bars ⫽ ⫾1 SD.
Fig 2. Time course of the mean plasma
osmolality after the oral water-load test
before and after exposure to oxcarbazepine
in the group of healthy volunteers and the
group of patients with epilepsy. Scale
bars ⫽ ⫾1 SD.
Fig 3. Time course of the mean serum
sodium concentration after the oral waterload test before and after exposure to oxcarbazepine in the group of healthy volunteers and the group of patients with
epilepsy. Scale bars ⫽ ⫾1 SD.
Fig 4. Time course of the mean urine
osmolality after the oral water-load test
before and after exposure to oxcarbazepine
in the group of healthy volunteers and the
group of patients with epilepsy. Scale
bars ⫽ ⫾1 SD.
baseline in both groups. This was associated with an
acute, significant fall in plasma osmolality and serum
sodium concentration. The mean serum sodium fell
into the hyponatremic range (⬍135mEq/ml) in both
groups, indicating that a mild hypotonic hyponatremia
was induced by the water-load procedure after exposure
618
Annals of Neurology
Vol 51
No 5
May 2002
to OXC. The reduction in free water clearance was associated with the excretion of a more hypertonic urine
associated with a nonsignificantly increased urine sodium level, suggesting an increase in the excretion of
solutes other than sodium during the water-load test.
The fact that the lowered osmolality and lowered se-
Fig 5. Time course of the mean plasma
arginine vasopressin concentration after the
oral water-load test before and after exposure to oxcarbazepine in the group of
healthy volunteers and the group of patients with epilepsy. Scale bars ⫽ ⫾1 SD.
rum sodium were not associated with significant alterations in the plasma AVP levels in either group indicates that OXC did not induce its hyponatremic effect
by means of inappropriate secretion of ADH. Alternative explanations include an enhanced renal tubular response to the circulating levels of ADH in the presence
of OXC or OXC acting by itself to increase renal tubular resorption of water and to reduce water clearance. Our study was not designed to answer those possibilities, and the precise mechanism involved will need
to be clarified by further studies. Our results, however,
suggest that the rare reported case of suspected inappropriate secretion of ADH25 after exposure to OXC is
an idiosyncratic effect.
During the short period of this study, it is notable
that only a very modest, most likely clinically insignificant reduction in serum sodium concentration resulted
from exposure to OXC while the subjects were freely
active in their normal environment. However, a significant reduction in serum sodium concentration occurred
when an imposed water load was added to their normal
activity. This finding suggests that other systems are usu-
ally able to compensate for the defective water regulation
induced by OXC, possibly by decreasing thirst and
thereby reducing water intake. However, patients receiving OXC may be at special risk for the development of
hyponatremia when subjected to increased fluid intake,
as commonly occurs in postsurgical patients, or even
perhaps in hot weather. In a recent study of 10 male
patients with epilepsy who underwent an overnight
switch from CBZ to OXC, the serum sodium levels assessed at 2 and 6 months after the switch remained unchanged in 6 patients and were reduced in 4 patients.26
Serum aldosterone levels were increased in the 6 patients
with stable sodium levels and remained stable in the 4
patients in whom the sodium levels had dropped, suggesting that an increase in aldosterone levels could involve a compensatory mechanism to prevent hyponatremia in these patients.26
OXC was overall well tolerated in this trial. One subject from each group discontinued treatment because of
a rash believed to be related to OXC therapy. The difference in the adverse event profile between the group of
healthy volunteers and the patients with epilepsy is
Fig 6. Correlation between the monohydroxy derivative (MHD) plasma concentration and the percentage of water-load
test excreted at 1 hour.
Sachdeo et al: Effects of Oxcarbazepine on Sodium Concentration
619
Table 4. Frequency of Adverse Events, Whether Trial-Drug
Related, Reported by 3 or More Subjects at the End of the
Titration and Maintenance Periods
Visit 4
(day 21)
(n ⫽ 19)
Visit 3
(day 14)
(n ⫽ 21)
Adverse Event
n
%
n
%
Somnolence
Dizziness
Headache
Abnormal vision
Insomnia
Ataxia
8
5
4
3
3
3
38
24
19
14
14
14
6
8
0
2
1
0
32
42
0
11
5
0
probably related to the fact that most patients with epilepsy were already on a baseline AED and were, therefore, exposed to the typical central nervous system adverse events associated with these medications.
The findings from this water-load study indicate that
OXC-induced hyponatremia is not attributable to inappropriate secretion of ADH. Possible mechanisms
include a direct effect of OXC on the renal collecting
tubules or an enhancement of their responsiveness to
circulating ADH.
This work was supported by Novartis Pharmaceuticals (to R.C.S.).
We thank Dr S. Sachdeo for assistance with the medical assessment
of subjects in this study and Dr J. Verbalis, at Georgetown University, Washington, DC, for the analysis of AVP levels.
References
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