A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Berghuis, Bianca; Stapleton, Caragh; Sonsma, Anja C. M.; Hulst, J. van der; Haan, Gerrit-Jan de; Lindhout, Dick; Demurtas, Rita; Krause, Roland; Depondt, Chantal; Kunz, Wolfram S.; Zara, Federico; Striano, Pasquale; Craig, John; Auce, Pauls; Marson, Anthony G; Stefánsson, Hreinn; O’Brien, Terence J.; Johnson, Michael R.; Sills, Graeme J.; Wolking, Stefan; Lerche, Holger; Sisodiya, Sanjay M.; Sander, Josemir W.; Cavalleri, Gianpiero L.; Koeleman, Bobby P. C.; McCormack, Mark

doi:10.1002/epi4.12297

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…High serum levels of CBZ or OXC, concomitant use of other ASMs, and being female are risk factors for COIH, as well as age >40 years 5 . A genetic predictor for COIH has not yet been identified 6 …”

Section: Introductionmentioning

confidence: 99%

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Symptomatology of carbamazepine‐ and oxcarbazepine‐induced hyponatremia in people with epilepsy

et al. 2021

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Objective To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine‐ or oxcarbazepine‐induced hyponatremia (COIH). Methods We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. Results A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti‐seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. Significance People with COIH had a 7‐fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.

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Section: Introductionmentioning

confidence: 99%

“…5 A genetic predictor for COIH has not yet been identified. 6 COIH is often assumed to be asymptomatic, but it can lead to symptoms ranging from unsteadiness and mild confusion to acute symptomatic seizures and coma. We found previously that almost half of people with COIH were symptomatic, and in 3% this led to hospital admissions.…”

Section: Introductionmentioning

confidence: 99%

Symptomatology of carbamazepine‐ and oxcarbazepine‐induced hyponatremia in people with epilepsy

et al. 2021

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“…Use of other AEDs (dibenzazepine carboxamide AEDs in particular) has also been associated with the occurrence of hyponatremia. For example, a retrospective study of data from 1252 patients treated at tertiary epilepsy referral clinics found that hyponatremia ([Na+] <135 mEq/L) occurred in 57% of patients taking OXC and 32% of patients taking CBZ . Another analysis of 560 adult inpatients at a single center found that hyponatremia occurred in 16% of patients taking CBZ, 43% of patients taking OXC, and 33% of patients taking ESL .…”

Section: Discussionmentioning

confidence: 99%

“…For example, a retrospective study of data from 1252 patients treated at tertiary epilepsy referral clinics found that hyponatremia ([Na+] <135 mEq/L) occurred in 57% of patients taking OXC and 32% of patients taking CBZ. 23 Another analysis of 560 adult inpatients at a single center found that hyponatremia occurred in 16% of patients taking CBZ, 43% of patients taking OXC, and 33% of patients taking ESL. 24 A separate analysis of 1782 patients attending a tertiary epilepsy center found that hyponatremia ([Na+] ≤134 mEq/L) occurred in 26% of patients taking CBZ and 46% of those taking OXC.…”

Section: Discussionmentioning

confidence: 99%

Serum sodium levels and related treatment‐emergent adverse events during eslicarbazepine acetate use in adults with epilepsy

et al. 2019

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Objective To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal‐ (partial‐) onset seizures. Methods This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400‐1200 mg once daily), two phase 3 trials of ESL monotherapy (1200‐1600 mg once daily), and their open‐label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+]), incidences of hyponatremia‐related treatment‐emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. Results The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open‐label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+] from baseline, <6% had a hyponatremia‐related TEAE, and <2% discontinued the controlled trials due to a hyponatremia‐related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator‐reported TEAE of “hyponatremia” or “blood sodium decreased” did not have a corresponding laboratory [Na+] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+] measurement ≤125 mEq/L. Significance Reductions in serum sodium concentrations and hyponatremia‐related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+] measurements.

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“…Lin et al reported that the use of OXC in patients with epilepsy is associated with a dose-dependent reduction in serum sodium levels [ 9 ]. A genetic predictor of OXC-induced hyponatremia has not yet been identified [ 10 ]. During our clinical practice, we have noticed that a longer duration of treatment with OXC could be associated with a higher risk of hyponatremia, therefore, in this study, we aim to evaluate the factors that may increase the risk of OXC-induced hyponatremia.…”

Section: Introductionmentioning

confidence: 99%

Oxcarbazepine and Hyponatremia

2022

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Background and Objectives: Hyponatremia is one of the most common adverse effects in patients treated with oxcarbazepine (OXC). Different risk factors for OXC-induced hyponatremia have been described as age, female gender, dosage, and combination with other drugs During our clinical practice, we noticed that a longer duration of treatment with OXC could be associated with a higher risk of hyponatremia, therefore, in this study, we aimed to evaluate factors that may increase the risk of OXC-induced hyponatremia. Materials and Methods: Data were retrospectively collected from our clinical database at the Department of Neurology of the Hospital of Lithuanian University of Health Sciences Kaunas Clinics. The sample was divided into three groups: OXC consumers (n = 31), other anti-seizure medications (ASMs) consumers (n = 43), and controls absent ASMs (n = 31). All groups were matched by age and gender. Hyponatremia was defined as <136 mmol/L. Results: The frequency of hyponatremia was significantly higher among OXC patients (61.3%) compared to other ASM patients (5.4%) and controls (3.2%). The mean serum sodium concentration in the OXC group was 133.1 ± 5.1 mmol/L. The frequency of severe hyponatremia among OXC-treated patients was 19.4%; this subgroup was older than patients with moderate hyponatremia and normonatremia and had a longer OXC treatment duration compared to a subgroup of normonatremia. The average duration of OXC therapy was 8.7 ± 5.5 years with a range from 1 to 21 years. Serum sodium concentration and duration of treatment with OXC demonstrated a significant negative correlation (r = −0,427, p = 0.017). Each year of therapy with OXC increased the risk of hyponatremia 1.3 times (OR = 1.326, 95% Cl 1.027–1.712, p = 0.031). Other factors (gender, age, polypharmacy, OXC dosage, and serum concentration) did not show a significant association with the development of hyponatremia. Conclusions: Longer duration of treatment with OXC is an important factor in the development and severity of hyponatremia.

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A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Cited by 9 publications

References 29 publications

Symptomatology of carbamazepine‐ and oxcarbazepine‐induced hyponatremia in people with epilepsy

Symptomatology of carbamazepine‐ and oxcarbazepine‐induced hyponatremia in people with epilepsy

Serum sodium levels and related treatment‐emergent adverse events during eslicarbazepine acetate use in adults with epilepsy

Oxcarbazepine and Hyponatremia

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