Carbamazepine-Induced Hyponatremia: Assessment of Risk Factors

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Carbamazepine-Induced Hyponatremia: Assessment of Risk Factors Glenn M Kuz and Alina Manssourian

OBJECTIVE: To report a case of carbamazepine-induced acute hyponatremia resulting in seizures. CASE SUMMARY: A 44-year-old white woman developed acute hyponatremia and 2 subsequent tonic–clonic seizures after ingesting twice her evening dose of carbamazepine (usual evening dose 600 mg). On admission, her serum sodium level was 122 mEq/L. An infusion of NaCl 0.9% was begun and, within 24 hours, the serum sodium level had returned to her previous level of 136 mEq/L. The woman’s preadmission carbamazepine concentration was 8.6 µg/mL, and it was 11.3 µg/mL on admission. Carbamazepine was withheld and, the following day, the concentration was 5.6 µg/mL. The woman had experienced a similar event 6 months earlier when she also took a large dose of carbamazepine. DISCUSSION:

We attributed the acute hyponatremia and seizures to the large increase in dose of carbamazepine in the presence of other risk factors for hyponatremia. Hyponatremia associated with carbamazepine has been well described. The incidence ranges from 1.8% to 40% depending on the patient population studied. Severe hyponatremia in patients treated with monotherapy is uncommon. Several risk factors have been reported to increase the risk of hyponatremia including age >40 years, concomitant use of medications associated with hyponatremia, menstruation, psychiatric condition, surgery, psychogenic polydipsia, and female gender. Treatment is focused on removal of the precipitating factors or discontinuation of carbamazepine therapy. Use of the Naranjo probability scale indicated a highly probable relationship between acute hyponatremia and carbamazepine in our patient.

CONCLUSIONS: Hyponatremia with carbamazepine is well known. The factors associated with increased risk are less understood. An

increased awareness of these risks, careful monitoring, and patient education are important in the prevention of neurologic complications. KEY WORDS: carbamazepine, hyponatremia.

Ann Pharmacother 2005;39:1943-6. Published Online, 27 Sept 2005, www.theannals.com, DOI 10.1345/aph.1G209

arbamazepine is indicated for the treatment of various C forms of epilepsy and neuropathic pain. It is also used successfully in the treatment of certain bipolar disorders and mania. Carbamazepine is known to cause clinically meaningful drug interactions mainly via inhibition or induction of the cytochrome P450 enzyme system, specifically CYP3A4.1 There are few reports, however, of the potential for a pharmacodynamic interaction that results in an augmented effect of the commonly known adverse effect of hyponatremia. We describe a patient who exhibited severe hyponatremia resulting in seizures, most likely due to an additive pharmacodynamic effect in the presence of paroxetine and other risk factors for hyponatremia.

Author information provided at the end of the text.

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Case Report A 44-year-old white woman presented to the emergency department after experiencing 2 new-onset, tonic–clonic seizures. Her past medical history included bipolar disorder, post-traumatic stress disorder, schizoaffective disorder, hyperlipidemia, amenorrhea, galactorrhea, and an episode of syncope 6 months earlier. She denied the use of nicotine or illicit drugs and reported only occasional use of alcohol. The patient did not report being allergic to any medications. On admission, the patient’s vital signs were stable. Physical examination was notable only for 3 beats of nystagmus on left lateral gaze. Motor examination was normal, and there was no apparent ataxia. There was no history of surgery. Her medication regimen included carbamazepine 400 mg twice daily (morning and noon) and 600 mg at bedtime, paroxetine 40 mg in the morning and 20 mg in the evening, risperidone 4 mg twice daily, buspirone 20 mg 3 times daily, nadolol 10 mg in the morning and 40 mg at bedtime, and hydroxyzine 50 mg twice daily. Three days prior to admission, the patient had failed to refill hydroxyzine and nadolol and so had no doses available. She compensated for this by taking carbamazepine 1200 mg the night prior to admission to

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help her sleep. The following morning, she took one more dose of 200 mg. That same day, during her attendance at a grief and loss workshop, she reported feeling “faint, dizzy, lightheaded, and the sensation of blood rushing to her head.” She also stated that her vision “began narrowing,” at which point she lost consciousness and began experiencing what was observed to be tonic–clonic seizures. After she regained consciousness, she was escorted into the hall, where she experienced a second seizure. Bystanders reported that all 4 extremities were shaking after she lost consciousness and that she was confused after the episode. After the second seizure episode, the woman was transported to the local emergency department. Review of her medical record indicated that she had experienced a similar event 6 months earlier when she also took a large dose of carbamazepine. Laboratory testing on admission showed serum sodium 122 mEq/L (reference range 135–145) and chloride 85 mEq/L (98–108). Serum osmolality was 259 mOsm/kg (280 –300), and urine osmolality was 202 mOsm/kg (150–800). A random urine sodium level was 32 mEq/L (24h collection reference range 40 –200). The serum carbamazepine concentration was 11.3 µg/mL (4–12). A urine toxicology panel was negative. Thyroid-stimulating hormone was not measured, but had previously been within normal limits. The patient was not hypovolemic. A complete blood cell count and computed tomography scan of the head were normal. Cardiovascular examination noted regular rate and rhythm; an electrocardiogram was not performed. Psychiatric evaluation indicated she was at her baseline level and that this was not a suicide attempt. In the emergency department, the patient was given a 1-L bolus of NaCl 0.9% followed by another liter at a rate of 125 mL/h. She was then admitted, and carbamazepine was withheld. Serial monitoring of her sodium levels indicated an appropriate response to the intravenous fluids and, by the following day, the serum sodium level had increased to the baseline of 136 mEq/L. The carbamazepine concentration decreased to 5.6 µg/mL (baseline concentration from a previous admission was 8.6 µg/mL). The home medication regimen was restarted, and the woman was discharged with extensive counseling regarding the potential for large doses of carbamazepine to cause alterations in her sodium level that could progress to seizures.

Discussion The definition of hyponatremia is a serum sodium level <136 mEq/L resulting in excess total body water relative to total solute.2,3 Hyponatremia is considered mild when sodium levels are 125–135 mEq/L, significant at 115–125 mEq/L, and severe when <115 mEq/L. Acute hyponatremia (developing within 48 h) is generally more serious and more likely to be symptomatic than the chronic form (>48 h).2,4 Acute severe hyponatremia is associated with neurologic symptoms, such as seizures or coma, and should be treated urgently to prevent complications such as cerebral edema and encephalopathy.3,4 The hyponatremia commonly described with carbamazepine (and its keto-analog oxcarbazepine) is usually chronic and occurs most often within the first 3 months of therapy.5 The hyponatremia progressing to seizures in our patient was apparently dose related. Hyponatremia as a result of carbamazepine therapy has been well described. The antidiuretic effect of carbamazepine was initially reported in 1966 when it was found to be beneficial in patients with diabetes insipidus.6 However, the mechanisms whereby carbamazepine causes hyponatremia are not completely understood. Evidence has suggested that carbamazepine may increase the secretion of antidiuretic hormone (ADH) from the posterior pituitary. A more reliable explanation may be that carbamazepine may increase the sensitivity of osmoreceptors to ADH in the distal convoluted tubules and collecting ducts, 1944



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thus leading to water retention, or may exert a direct effect on receptors in the distal convoluted tubules.2,5 Typically, patients present with a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, most evidence suggests a peripheral mechanism since many of the studies have failed to consistently detect elevated levels of ADH.2,7 The incidence of hyponatremia from carbamazepine ranges from 1.8% to 40%, depending on the patient population studied.2 Most of the hyponatremia described in the literature is asymptomatic or mild. Water intoxication may be asymptomatic hyponatremia (<135 mEq/L) or may produce symptoms including drowsiness, confusion, mental slowing, and fatigue.2,8 There are few reports describing seizures. Review of the literature indicates that severe hyponatremia in patients treated with carbamazepine monotherapy is rare.8 There are, however, confounding variables that seem to increase the risk of hyponatremia. Specific risk factors for hyponatremia associated with carbamazepine include age >40 years, concomitant use of medications associated with hyponatremia, menstruation, psychiatric condition, surgery, psychogenic polydipsia, and female gender.5,8 Medications commonly known to cause hyponatremia include desmopressin, oxytocin, prostaglandin-synthesis inhibitors, nicotine, phenothiazines, tricyclic antidepressants, selective serotonin-reuptake inhibitors (SSRIs), opiates, chlorpropamide, clofibrate, cyclophosphamide, and vincristine.3 Gender-specific differences in sodium metabolism have been described that put females at greater risk of this adverse effect.9 As monotherapy, carbamazepine is unlikely to cause clinically significant hyponatremia. However, when used in broad clinical aspects, from neurology to psychiatry, where polypharmacy is not uncommon, clinicians need to be aware of the potential for the development of serious, clinically significant hyponatremia. The established risks, such as increasing dose, age, surgery, and drug interactions, need to be discussed with patients so they fully understand the risks associated with this therapy. In our patient, several features point to carbamazepine as the cause of acute hyponatremic seizures. First, there was a temporal relationship between the drug administration and the observed effect. Second, there is strong evidence indicating that hyponatremia is commonly associated with carbamazepine and there did not appear to be alternative causes for the hyponatremia. Third, the reaction appeared after ingestion of a large dose, and the serum carbamazepine concentration obtained several hours after the event was at the upper end of the therapeutic range. It was likely that the patient’s concentration was above the therapeutic range at the time of the event. Finally, she reported experiencing a similar episode of syncope 6 months earlier, again after ingesting a large dose of carbamazepine. Her serum carbamazepine concentration at the prior incident was slightly above the therapeutic range (12.8 µg/mL). Use of the Naranjo probability scale indicated a highly probable relationship between acute hyponatremia and carbamazepine.10 One confounding variable that may have in-

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Carbamazepine-Induced Hyponatremia

fluenced the outcome in this case is the concomitant use of paroxetine, an SSRI that is also a common cause of druginduced SIADH. However, the patient had been previously stable on the combination of carbamazepine and paroxetine, and it was not until the excessive dose was ingested that the event occurred. This may be evidence for a pharmacodynamic effect between the 2 medications that may have resulted in increased sensitivity to the effects of carbamazepine. A final confounding variable is that the patient was also on risperidone, which may lower seizure threshold.11 She reported that she had been taking the risperidone as prescribed and had been stable for 6 months prior to this event. Considering all possibilities, a pharmacodynamic interaction with these medications cannot be excluded. A case report from Spain illustrates a similar interaction between carbamazepine and paroxetine.12 A 79-year-old male was being treated with carbamazepine 400 mg/day for trigeminal neuralgia secondary to herpes zoster. Paroxetine 20 mg/day was added to the regimen 4 weeks later for treatment of depression. Approximately 2 weeks after the addition of the paroxetine, the patient was admitted to the hospital after experiencing intense vertigo, syncope, and a 2-minute loss of consciousness. Serum sodium values were 120 mEq/L. Carbamazepine was discontinued and, over the next 5 days, the serum sodium level increased to 127 mEq/L. On day 25, it increased to 133 mEq/L and, by day 45, was 135 mEq/L. Carbamazepine concentrations were not reported. The authors concluded that a probable interaction between carbamazepine and paroxetine occurred, likely due to an additive effect of SIADH from both medications. Conclusions It is very likely that our patient was predisposed to carbamazepine-associated seizures due to her age, gender, and concurrent use of paroxetine and risperidone. We believe these factors increased her sensitivity to an acute alteration in the dose of carbamazepine. It is imperative that patients understand the signs and symptoms of hyponatremia, especially during episodes of dose adjustment or addition of new medications. This was the second time that this patient experienced this type of episode after taking a large dose of carbamazepine. It was not recognized the first time it occurred, demonstrating the need for increased awareness by providers and patients. Careful monitoring is needed during initiation and dosage changes of carbamazepine, as well as careful assessment of risks and concomitant use of drugs that may interact with carbamazepine.

References 1. Micromedex healthcare series, Greenwood Village, CO: Thomson Micromedex. www.thomsonhc.com.offcampus.lib.washington.edu (accessed 2005 June 6). 2. Van Amelsvoort T, Bakshi R, Devaux B, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994;35:181-8. 3. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:15819. 4. Goh KP. Management of hyponatremia. Am Fam Physician 2004;69: 2387-94. 5. Asconapé JJ. Some common issues in the use of antiepileptic drugs. Semin Neurol 2002;22:27-39. 6. Braunhofer J, Zicha L. [Does tegretal offer new possibilities of therapy in several neurologic and endocrine diseases? A clinical electroencephalographic and thin-layer chromatographic study] German. Med Welt 1966; 3:1875-80. 7. Gandelman MS. Review of carbamazepine-induced hyponatremia. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:221-33. 8. Kalff R, Houtkooper MA, Meyer JW, Goedhart DM, Augusteijn R, Meinardi H. Carbamazepine and serum sodium levels. Epilepsia 1984;25:390-7. 9. Grikiniené J, Volbekas V, Stakiˇsaitis D. Gender differences of sodium metabolism and hyponatremia as an adverse drug effect. Medicina 2004;40:935-42. 10. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. 11. Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug Saf 2002;25:91-110. 12. Sempere i Verdu E, Bel Reverter M, Palop Larrea V, Hidalgo Mora JJ. [Hyponatremia due to carbamazepine and paroxetine] Spanish. Aten Primaria 2004;33:473-4.

EXTRACTO OBJETIVO: Describir un caso de hiponatremia aguda que causó ataques epilépticos asociado al uso de carbamazepina. RESUMEN DEL CASO: Una mujer caucásica de 44 años desarrolló hiponatremia aguda y, posteriormente, ataques epilépticos tras ingerir el doble de la dosis usual de carbamazepina en una tarde. DISCUSIÓN: Se atribuyó una hiponatremia aguda y ataques epilépticos a un gran aumento en dosis de carbamazepina en presencia de otros factores de riesgo para hiponatremia. La hiponatremia como resultado del uso de carbamazepina está bien descrita. La incidencia fluctúa entre el 1.8 y el 40%, dependiendo de la población estudiada. La hiponatremia severa en pacientes tratados con monoterapia es poco común. Los factores de riesgo incluyen edad mayor de 40 años, uso concomitante de medicamentos asociados a hiponatremia, mujeres en menstruación, alteraciones psiquiátricas, cirugía, polidipsia psicogénica, y género femenino. El tratamiento está enfocado a eliminar los factores precipitantes o abandonar por completo la terapia de carbamazepina. De acuerdo con el algoritmo de Naranjo, la relación se causalidad entre hiponatremia y carbamazepina es probable. CONCLUSIONES: La hiponatremia por carbamazepina es bien conocida. No se comprenden demasiado bien los factores de riesgo asociados a un aumento del riesgo. Un aumento de la concienciación de los riesgos, seguimiento estrecho y educación a pacientes, son importantes en el proceso de prevención de complicaciones neurológicas.

Wilma M Guzmán-Santos

Glenn M Kuz BSPharm, Clinical Pharmacist, Internal Medicine, Department of Pharmacy Services, University of Washington Medical Center, Seattle, WA Alina Manssourian, PharmD Student, School of Pharmacy, University of Washington Reprints: Mr. Kuz, Department of Pharmacy Services, University of Washington Medical Center, 1959 NE Pacific St., Box 356015, Seattle, WA 98195-6015, fax 206/598-0196, [email protected]

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RÉSUMÉ

Décrire un cas d’hyponatrémie aiguë induite par la carbamazépine, accompagnée de convulsions. SOMMAIRE DU CAS: Une femme caucasienne de 44 ans ayant comme antécédents des troubles bipolaires, un syndrome de stress posttraumatique, une maladie schizo-affective, une l’hyperlipidémie ainsi OBJECTIF:

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que de l’aménorrhée, de la galactorrée, et un épisode significatif de syncope survenu il y a 6 mois consécutif à la prise d’une dose élevée de carbamazépine, a présenté une hyponatrémie aiguë et des convulsions après avoir ingéré le double de la dose habituelle de fin de journée de carbamazépine. Cette personne a nié avoir fait usage de nicotine ou de drogues de rue. Elle recevait de la carbamazépine à raison de 400 mg le matin et le midi et de 600 mg au coucher, en plus de la paroxétine, 40 mg le matin et 20 mg en après-midi, de la rispéridone 4 mg 2 fois par jour, de la buspirone 20 mg 3 fois par jour, du nadolol 10 mg le matin et 40 mg au coucher, et finalement de l’hydroxyzine 50 mg 2 fois par jour. Trois jours avant son admission pour son épisode d’hyponatrémie, elle n’avait plus d’hydroxyzine et de nadolol et a compensé en prenant 1200 mg de carbamazépine pour l’aider à dormir. DISCUSSION: Les auteurs attribuent l’épisode d’hyponatrémie aiguë observée chez cette personne, ainsi que les convulsions, à l’augmentation importante de la dose de carbamazépine en présence d’autres facteurs de risque d’hyponatrémie. Des cas d’hyponatrémie induite par la carbamazépine sont bien décrits; leur incidence varie de 1.8% à 40% selon les populations de patients étudiées. L’hyponatrémie grave est cependant rare chez les patients recevant la carbamazépine en monothérapie. Plusieurs facteurs de risque contribuant à augmenter l’incidence de cet effet indésirable ont été identifiés. Ces facteurs sont

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l’âge (supérieur à 40 ans), l’utilisation concomitante de médicaments causant eux aussi de l’hyponatrémie, les menstruations, la condition psychiatrique de la personne, la chirurgie, la polydypsie psychogénique, et le sexe féminin. Le traitement est centré sur le retrait des facteurs précipitants ou sur l’arrêt complet du traitement par la carbamazépine. La carbamazépine cause de nombreuses interactions médicamenteuses cliniquement significatives, par inhibition ou induction du système enzymatique du cytochrome P450; un effet pharmacodynamique additif en présence de paroxétine, jumelé à d’autres facteurs, semble responsable de cette réaction chez cette personne. L’application de l’échelle de probabilité de Naranjo a montré une relation hautement probable entre l’hyponatrémie et la carbamazépine. CONCLUSIONS: Les cas d’hyponatrémie secondaires à la carbamazépine sont bien connus. Cependant, les facteurs de risque associés à une élévation de cet effet indésirable le sont moins bien. Une meilleure surveillance de ces risques, un suivi plus étroit, et l’éducation des patients sont importants afin de prévenir les complications neurologiques associées.

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Denyse Demers

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Carbamazepine-Induced Hyponatremia: Assessment of Risk Factors

Carbamazepine-Induced Hyponatremia: Assessment of Risk Factors Glenn M Kuz and Alina Manssourian OBJECTIVE: To report a case of carbamazepine-induced...

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