Oxcarbazepine - Treating Partial Seizures Materials

OXCARBAZEPINE AND THE TREATMENT OF PARTIAL SEIZURES

AMANDA MAYER, PharmD

Amanda Mayer is a graduate of the University of Montana, Skaggs School of Pharmacy. She has clinical experience as a pharmacist in the inpatient mental health setting, which is her passion. She has also done fill-in work at retail pharmacies throughout her career. Amanda appreciates the wide variety of professional opportunities available to pharmacists. Amanda loves spending time with her family and spends most of her free time exploring new restaurants, hiking in the summer, snowboarding, and cross-country skiing in the winter.

Topic Overview

Oxcarbazepine is an anticonvulsant (also known as an antiepileptic) that has a labeled use as monotherapy or as an adjunctive treatment for patients who have partial- onset seizures. Oxcarbazepine is available in extended-release, immediate-release oral tablets and an immediate-release oral solution. Hyponatremia, Stevens- Johnsons Syndrome, and toxic epidermal necrolysis are serious side effects of oxcarbazepine therapy. A multidisciplinary approach should be taken to identify, treat, and monitor patients who may benefit from oxcarbazepine therapy.

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Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-23-077-H01-P

Pharmacy Technician  0669-0000-23-078-H01-T

Credits: 2 hours of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $6.99

Estimated time to complete activity: 2 hours, including Course Test and course evaluation

Release Date: May 30, 2023 Expiration Date: May 30, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From May 30, 2023, through May 30, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Identify the appropriate indications for the use of oxcarbazepine

Describe the proposed mechanism of action of oxcarbazepine

List common side effects of oxcarbazepine

Discuss the increased risk of suicidal thoughts or behavior in patients who start or stop oxcarbazepine

Discuss the roles of different healthcare providers in oxcarbazepine therapy

Disclosures

The following individuals were involved in developing this activity: Amanda Mayer, PharmD, Jeff Goldberg, PharmD, BCPP, and Pamela Sardo, PharmD, BS. Pamela Sardo, PharmD, BS, was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Introduction

Oxcarbazepine is an anticonvulsant that has a labeled use as a monotherapy or as an adjunctive treatment for patients who have focal seizures, also known as partial seizures. Oxcarbazepine is used off-label to treat neuropathic pain and mania associated with bipolar disorder in adults and pediatric patients. Oxcarbazepine can cause adverse events in patients. The primary events discussed here are central nervous system events, hyponatremia, and serious dermatologic reactions. Patients’ serum sodium levels should be monitored, and multidisciplinary involvement in a patient’s treatment with oxcarbazepine provides the best approach for patient outcomes.

Overview of Focal Seizures

Seizures are classified as focal seizures, generalized seizures, or seizures of unknown onset.1 Focal seizures are also referred to as localized or partial seizures. Although the term partial seizure is still commonly used, the current and preferred term is focal seizure.1 The package inserts for oxcarbazepine currently have partial seizures listed as the indication, and this course will primarily reflect that language. Once a patient’s seizure type has been classified, a healthcare provider can classify the epilepsy type. They include generalized epilepsy, focal epilepsy, combined generalized and focal epilepsy, or unknown.1 Epilepsy classification is key in evaluating a patient’s seizures, and it guides the selection of antiepileptic therapies.1

A focal or partial seizure is unlike a generalized seizure in that only part of the cerebral cortex is involved. Focal seizures are typically divided into two types: 1) focal seizure with retained awareness and 2) focal seizure with impaired awareness.2,3

A focal seizure with retained awareness is characterized by full awareness during the seizure, but the patient experiences a wide variety of signs and symptoms that can be autonomic, motor, physical, or sensory; for example, a rapid heartbeat, abnormal involuntary and repetitive movement

of a body part, incontinence, memory loss, or spatial perception distortion.2,3 Tonic-clonic movements (convulsions) do not happen during a focal seizure.2,3 When a patient has a focal seizure with impaired awareness there is impaired consciousness and the patient is unaware of surroundings.2,3 The changes in consciousness or awareness are complex in presentation, and the patient may have autonomic, motor, physical, or sensory signs and symptoms.2,3

Focal seizures with retained awareness and impaired awareness may be preceded by an aura, which can be one of the autonomic, motor, physical, or sensory signs and symptoms of this type of seizure.2,3 Both types of focal seizures are often followed by a postictal period, during which the patient’s neurologic function has not returned to baseline.2,3

History of Oxcarbazepine

Oxcarbazepine is classified as an anticonvulsant, also known as an antiepileptic. The extended-release formulation known as Oxtellar XR® initially received FDA approval in 2000,4 and the immediate-release formulation known as Trileptal® was approved in 2003.5,6 Oxcarbazepine is an analog of carbamazepine that functions as a prodrug that is rapidly converted to 10- hydroxycarbazepine.7 Oxcarbazepine was developed in an attempt to avoid the common side effects of carbamazepine and help decrease the amount of potential drug-drug interactions.8 Oxcarbazepine appears to have the same therapeutic mechanism and effects as carbamazepine but presents with fewer side effects, making it advantageous in individuals who do not tolerate carbamazepine for partial seizures.7

Clinical Pharmacology

Mechanism of Action

Oxcarbazepine is a prodrug that is extensively metabolized by the liver to the pharmacologically active 10-monohydroxy derivative (MHD).4,6 The active derivative, MHD, is responsible for most antiepileptic activity seen with oxcarbazepine. The exact mechanism of action is unknown; however, in vitro

studies have shown that oxcarbazepine stabilizes neuronal membranes by blocking the movement of sodium through voltage-gated sodium channels, preventing rapid depolarization of neurons, and preventing transmission of action potentials. The drug also affects the movement of calcium and potassium through ion channels.4,6

Pharmacokinetics

Oxcarbazepine taken orally is absorbed and extensively metabolized by the liver to MHD.4,6 Approximately 40% of MHD binds to the serum protein albumin and is then metabolized through conjugation to minor metabolites. Oxcarbazepine is a substrate of CYP2C19 and CYP3A4. Approximately 95% of the oxcarbazepine dose is renally excreted, with almost half of the dose being eliminated as metabolites of MHD. The remaining amount of oxcarbazepine is excreted in the feces. The immediate-release formulation of oxcarbazepine has a half-life of about 2 hours, with the half-life of MHD being about 9 hours.4,6 The extended-release oxcarbazepine formulation was 7 to 11 hours, and the half-life of MHD was about 9 to 11 hours.4

Labeled Uses

Immediate-release Oxcarbazepine6

Monotherapy or adjunctive therapy in the treatment of partial seizures in adults

Monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy

Adjunctive therapy in children aged 2 years and above with epilepsy Extended-release oxcarbazepine4

Adjunctive treatment for adults and patients six years to 17 years old who have partial seizures.

Off-Label Uses

Off-label uses of oxcarbazepine include the treatment of neuropathic pain, such as trigeminal neuralgia, and the treatment of mania associated with bipolar disorder in adults and pediatric patients.9-11 Oxcarbazepine shows some positive evidence of acute antimanic effects in mild-to-moderate manic patients; however, its efficacy in severely ill patients is lacking.12 Carbamazepine shows much better evidence than oxcarbazepine in patients with bipolar disorder; however, oxcarbazepine is still commonly used in patients who responded well to carbamazepine but may have had tolerability or drug interactions with treatment. There is a lack of convincing data for using oxcarbazepine for the treatment of depression or prevention of depressive relapses in patients with bipolar disorder.12

Available Forms

Dosing

Dosing oxcarbazepine for epilepsy should be individualized, and protocols for rapid conversion from carbamazepine to oxcarbazepine may vary.13 In general, the usual daily maintenance dose of oxcarbazepine is approximately 1.5 times that of carbamazepine in adults up to 65 years old and approximately 1.2 times that of carbamazepine in patients 65 and up. Lower dose conversions of carbamazepine to oxcarbazepine of 1 to 1.25 may be better tolerated by all individuals.13

Hepatic Impairment Dosing Adjustments

Use of oxcarbazepine is not recommended in patients with severe hepatic impairment.4,6

Renal Impairment Dosing Adjustments

If the patient’s creatinine clearance (CrCl) is < 30 mL/minute, the starting dose of immediate-release oxcarbazepine should be one-half the normal starting dose and increased slowly to desired clinical response.4 Extended-release oxcarbazepine should be initiated at one-half the usual starting dose for CrCl <30 mL/minute, and subsequent dose increases can be made weekly at increments of 300 to 450 mg/day.6

Immediate-release oxcarbazepine formulations are recommended in patients with end-stage renal disease on dialysis instead of extended-release tablets.4,6

Geriatric Patient Dosing Adjustments

The starting dose for geriatric patients should be 300 mg – 450 mg a day, with dose increases being made weekly in increments of 300 mg to 450 mg/day, to achieve the desired clinical response.4,6

Administration

Immediate-release:6

It may be taken with or without food

When using oral suspension: Shake the bottle well and prepare the dose immediately afterward. Oral syringes provided by the manufacturer in the box should be used. Oxcarbazepine can be mixed in a small glass of water just before administration OR swallowed directly from the syringe. Discard any unused medication after 7 weeks of first opening the bottle.

Extended-release:4

It should be taken as a single daily dose

Take on an empty stomach or at least 1 hour before or at least 2 hours after meals. Administration of food can cause increased peak levels leading to an increased risk of adverse reactions.

Swallow tablets whole - do not crush, cut, or chew.

Contraindications

Oxcarbazepine is contraindicated if the patient has a hypersensitivity to the drug or any component of the product.4,6

Warnings and Precautions Central Nervous System (CNS)

Oxcarbazepine can cause cognitive impairment and may include coordination difficulties, problems with concentration, somnolence, and speech and language difficulties.4,6 Oxcarbazepine has been reported to cause or exacerbate primary generalized seizures, especially in children.4,6

Hyponatremia

Clinically significant hyponatremia, with a sodium level of <125 mmol/L, has been associated with the use of oxcarbazepine.4,6 Hyponatremia is a common adverse effect of oxcarbazepine with a reported incidence of 23%- 73%.14 In the 14 clinical trials of oxcarbazepine for epilepsy, 2.5% of all patients developed a serum sodium level < 125 mEq/L at some point during therapy, while no patients on placebo or active control developed hyponatremia. Clinically significant hyponatremia usually happened within the first three months of therapy, but there were reports of an onset of hyponatremia one year or more after the patient began taking the drug. Normalization of serum sodium was typically achieved within a few days of discontinuing oxcarbazepine without additional treatment.6

A recent (2017) large tertiary hospital study that included 358 patients taking oxcarbazepine and 1424 taking carbamazepine found that 46% of the patients taking oxcarbazepine developed hyponatremia (serum sodium < 134 mEq/L), 48% of all patients symptomatic hyponatremia, 22% developed severe hyponatremia (serum sodium < 128 mEq/L), and 3% of the patients required hospitalization.14 Factors identified as increasing the risk for developing hyponatremia were age > 40, female gender, and high serum oxcarbazepine levels.14 The authors noted that a decreased thirst sensation, impaired renal function, and changes in the hormonal mechanisms that control sodium and water balance, which are all age-related, may explain why the risk of hyponatremia was doubled in patients > age 40 years.14

Monitor serum sodium closely during the first few months of therapy with the drug, particularly if the patient is receiving other medications known to decrease serum sodium levels.6 Hyponatremia can be particularly harmful to elderly patients.6

The signs and symptoms of hyponatremia depend on the serum sodium level and how quickly it decreases.14 Patients with a mild level of hyponatremia will present with non-specific signs and symptoms like dizziness, fatigue, nausea, and vomiting; if the decrease in serum sodium is severe and sudden, coma, seizures, and death are possible.4,6 Oxcarbazepine-induced hyponatremia is thought to be caused by a drug effect on the activity of the antidiuretic hormone.15

Dermatologic Reactions

Serious dermatologic reactions to oxcarbazepine have been reported, including the potentially life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).4,6 The reporting rate of Stevens-Johnson Syndrome and TEN associated with the use of oxcarbazepine has been estimated to be 3 to 10-fold the background incidence of these pathologies in the public. Stevens-Johnson syndrome and TEN are essentially the same, and they are distinguished only by the extent of dermal involvement, with SJS being less severe than TEN.16 If the dermal involvement is < 10%, this indicates SJS, > 30% indicates TEN, and a 10%-30% involvement is SJS-TEN overlap.17,18 Oxcarbazepine should be discontinued if a patient develops a skin reaction, and another antiepileptic medication should be considered.6

The onset of SJS and TEN typically begins with a prodromal period of several days to a week and after a median time of 19 days after therapy with oxcarbazepine was begun.4 The prodromal period is characterized by nonspecific signs and symptoms such as conjunctival irritation, cough, fever, and malaise. These symptoms precede dermal involvement for several days or a week and are followed by the development of mucocutaneous lesions. The mucocutaneous lesions are typically on the mucosa of the eyes, genitals, and mouth, and on the face, palms, soles, and trunk.16,19 As the disease

progresses, the lesions worsen, epidermal necrosis and sloughing start to happen, and in some cases, the lungs, other areas of the respiratory tract, the liver, and the kidneys may be affected.20 The mortality rate for SJS has been estimated to be between 3% - 10% and for TEN, 20% - 40%.21

Patients with the HLA-B*1502 allele of the HLA-B gene may have an increased risk of developing Stevens-Johnson syndrome or TEN if they take oxcarbazepine.4 The HLA-B*-1502 allele occurs more often in certain Asian populations, including Han Chinese, Thai, Philippines, Malaysian, and Korean. The presence of the HLA-B*1502 is negligible in people of European descent, Native Americans, Hispanics, Japanese, and certain African populations.4 Clinicians should consider genetic testing for susceptible patients before starting therapy with oxcarbazepine.

Hypersensitivity Reactions

Anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported after the first or subsequent doses of oxcarbazepine; however, they are rare but should still be monitored for as angioedema may be fatal.6 Approximately 25-30% of patients who are hypersensitive to carbamazepine may be hypersensitive to oxcarbazepine.6

The drug reaction with eosinophilia and systemic symptoms, DRESS, has been reported as a possible adverse effect of oxcarbazepine.4,6 DRESS is a rare, immune-system mediated hypersensitivity reaction that can be caused by many medications and involves multiple complicated tissue and organ damage patterns. The characteristic signs of DRESS are fever, rashes, eosinophilia, lymphadenopathy, and hepatic damage.22,23 The kidneys, lungs, and other organs can also be affected.22,23 For oxcarbazepine, the median time to detection of DRESS was 13 days with a range of three to 40.4 The rash does not involve the mucous membranes, which helps distinguish DRESS from SJS and TEN.22

Hematologic abnormalities associated with DRESS are common and can include agranulocytosis, leukopenia, thrombocytopenia, and other blood dyscrasias.22,23 Generalized and local lymphadenopathy will be seen; liver damage is also common. Hepatitis with jaundice is the most common cause of death from DRESS, with a fatality rate >10%.22 The DRESS syndrome caused by oxcarbazepine is rare; three cases were found in a literature search.24

Suicidal Behavior and Ideation

Studies of antiepileptics have shown that there is an increased risk of suicidal thoughts or behavior in patients who are taking these drugs.6 The increase can begin 1 week after starting therapy with the drug. All antiepileptic patients should be closely monitored for signs and symptoms of depression and suicidal behavior and thoughts. When starting an antiepileptic drug, discontinuing a drug (e.g., oxcarbazepine), or switching from one to another, the patient should be carefully monitored for suicidal behavior and thoughts or mood changes.6,25 Patients should be instructed to inform the treating physician if they have any of these signs or symptoms.6

Kanner (2022) distinguishes the suicide risk in patients with epilepsy, depending on the antiepileptic drug type.25 A determination of whether suicidal ideation or behavior was caused by introducing or discontinuing an antiepileptic drug must be ruled-out: if suicidal ideation or behavior is followed by “the introduction of an [antiseizure drug] with negative psychotropic properties (e.g., levetiracetam, topiramate, zonisamide, brivaracetam, and perampanel) or the discontinuation of an [antiseizure drug] with positive psychotropic properties (e.g., carbamazepine, oxcarbazepine, valproic acid, and lamotrigine) that was keeping the patient’s psychiatric disorder in remission … In the former case, a rapid switch-over to another [antiseizure drug], or the discontinuation of the offending drug should be conducted in an inpatient setting (if possible, with EEG monitoring) to minimize the risk of seizures resulting from its discontinuation. In the latter, the [antiseizure drug] that was discontinued should be restarted or replaced by another with similar psychotropic properties.”25

Withdrawal

Abrupt discontinuation of an antiepileptic may cause seizures, and if therapy with the drug is to be stopped, the dose should be tapered, not abruptly discontinued, as this may increase the risk for seizures.26 Abrupt discontinuation may also cause suicidal ideation or behavior,25 as discussed above.

Tapering doses of anticonvulsants and avoiding abrupt discontinuation of these drugs are standard recommendations, but there is very little information about tapering antiepileptics, and there are no standard guidelines for doing so.26

Adverse Effects

Adverse effects of oxcarbazepine with an incidence of > 5% include dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, and abnormal gait.6

Laboratory Tests and Monitoring

Used in the treatment of focal seizures

Do not cut, crush, or chew extended-release formulation

Renal dosing adjustments may be required if CrCl <30 mL/min

Hyponatremia is a common adverse effect, with age greater than 40, female gender, and high serum oxcarbazepine levels increasing the risk

Oxcarbazepine Clinical Pearls

Serum sodium levels may be monitored, especially at the onset of therapy if a patient is taking other medications that can cause hyponatremia.6 If a patient experiences hyponatremia with serum sodium levels below 125 mmol/L, reducing or discontinuing the dose will help levels return to normal. Other laboratory data from clinical trials suggest that oxcarbazepine. use was associated with decreased T4 levels without changes in T3 or TSH.6

Avoid abrupt discontinuation as it may increase the risk for seizures

Concurrent use of oxcarbazepine and oral contraceptives containing ethinyl estradiol and levonorgestrel may decrease the efficacy of the oral contraceptives

Drug Interactions

Oxcarbazepine is a dose-dependent inhibitor of CYP2C19 which can cause a significant interaction if using high doses of oxcarbazepine with an additional CYP2C19 substrate (e.g., phenytoin).6 Oxcarbazepine can also cause clinically relevant interactions with medications through the induction of CYP3A4; however, this seems to be less than the interactions caused by carbamazepine as oxcarbazepine and MHD are less potent inducers.6

Concurrent use of oxcarbazepine and phenytoin can increase serum phenytoin levels.6 In patients taking 1200 mg – 2400 mg a day of oxcarbazepine, the serum phenytoin levels increased by as much as 40%.6 If a patient is using phenytoin adjunctive treatment, a lower phenytoin dose may be required.6

Concurrent use of oxcarbazepine and strong inducers of CYP450 enzymes, such as carbamazepine, phenytoin, or phenobarbital, decreased the plasma level of MHD by 40%, 30%, and 25%, respectively.4,6 The mechanism of action of this effect is not known.

Concurrent use of oxcarbazepine and oral hormonal contraceptives may decrease the effectiveness of the contraceptive.4,6 The two hormonal components affected by the coadministration of oxcarbazepine and hormonal contraceptives are ethinylestradiol (EE) and levonorgestrel (LNG).4,6

The calcium antagonist felodipine had a lowered area under the curve of 28% when repeatedly coadministered with oxcarbazepine.4,6 The drug verapamil caused a 20% decrease in plasma levels of MHD upon coadministration with oxcarbazepine.4,6

Specific Populations Pregnancy and Breastfeeding

Oxcarbazepine was previously classified as a pregnancy risk category C drug; this means that there are no well-controlled studies of its use during pregnancy, teratogenic effects have occurred in animal studies, and the benefits of using oxcarbazepine during pregnancy may outweigh the risks.4,6 Limited data from pregnancy registries suggest that oxcarbazepine monotherapy may be associated with oral clefts and ventricular defects. Pregnancy may alter concentrations of MHD, causing an increase in seizure frequency; therefore, patients should be carefully monitored during pregnancy and in the postpartum period.4,6

Oxcarbazepine is structurally similar to carbamazepine, a known teratogen drug, and there is some evidence that oxcarbazepine may cause congenital malformations. The potential of a drug to cause fetal harm has been categorized by a system developed by the Food and Drug Administration (FDA). The system used five categories, A, B, C, D, and X; a drug would be considered category C if data from animal studies had shown adverse fetal effects, no well-controlled studies in humans existed, and the potential benefits of the drug may outweigh the risk of its use during pregnancy.

The A-X system is still widely used, albeit informally. However, the FDA has required manufacturers to no longer use the A-X system in the prescribing information and to change package inserts to comply with the FDA Pregnancy and Lactation Labeling Rule (PLLR). Using the PLLR rule, the prescribing information must provide data about a pregnancy registry for the drug (if one exists), a risk summary, clinical considerations, and a summary if available. The Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products — Content and Format Guidance for Industry (Small Entity Compliance Guide) may be downloaded from the FDA website.27

Clinicians are advised to encourage pregnant patients taking oxcarbazepine to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The NAAED collects information about the in utero effects of antiepileptics. Patients may reach the NAAED at 1-888-233-2334 or through their website at http://www.aedpregnancyregistry.org/.

Oxcarbazepine and MHD are excreted in breast milk.4,6 The risks to a nursing infant and the mother's need for the drug must be considered if oxcarbazepine will be used while breastfeeding.

Pediatric Use

Oxcarbazepine is indicated for use in patients ages 2-16 as an adjunctive therapy for partial seizures and for patients ages 4-16 as monotherapy for partial seizures. This population's dosing should always be done with reference to the package insert, as the dose is weight-based. Oxcarbazepine is also available as a liquid solution for ease of administration in patients who cannot swallow whole tablets.

Geriatric Use

When oxcarbazepine was given to patients 60 – 82 years of age, the area under the curve (AUC) and the maximum plasma concentrations of the active metabolite of oxcarbazepine (MHD) were 30% - 60% higher than these values in patients 18 – 32 years of age.4,6 This difference was likely due to the difference in CrCl between the two groups, with the older patients having a lower CrCl.4,6 Renal function decreases with age, so measurement of an elderly patient’s renal function before starting therapy with oxcarbazepine is prudent.

Oxcarbazepine can cause hyponatremia, an adverse effect that can be particularly harmful in older or other physically compromised patients. Symptoms to be aware of that can be especially dangerous in older adults include nausea, malaise, headache, lethargy, confusion, obtundation, or an increase in seizure frequency or severity.4,6

Dosing Adjustment: Hepatic Impairment

No specific dosing adjustments exist for patients with mild to moderate hepatic impairment. Oxcarbazepine should be used cautiously in patients who have severe hepatic impairment.4,6 During clinical trials, mild to moderate hepatic impairment did not affect the metabolism or the pharmacokinetics of oxcarbazepine.4,6

Dosing Adjustment: Renal Impairment

Oxcarbazepine is excreted by the kidneys, and there is a linear correlation between creatinine clearance (CrCL) and the renal clearance of MHD.4,6 If the patient’s CrCl is < 30 mL/minute, the AUC has a two-fold increase, and the renal clearance of MHD will be significantly prolonged with the elimination half-life of MHD increasing to 19 hours. Dosing adjustments are discussed above for a CrCl <30 mL/minute.4,6

Creatinine Clearance and Glomerular Filtration Rate

Creatinine clearance is a test that estimates glomerular filtration rate (GFR). The GFR is a highly accurate reflection of kidney function but directly measuring GFR is complex and invasive, and using the CrCl is an acceptable and widely used substitute method of estimating GFR. The creatinine clearance is determined by measuring serum creatinine and measuring the amount of creatinine in a 24-hour urine collection. The patient’s age and body weight and the results of the tests are used with standard formulas like the Cockcroft-Gault equation or the Modification of Diet in Renal Disease equation to establish a CrCl value. A normal CrCl is > 90 mL/minute and a CrCl of < 30 mL/minute is very low and indicates the presence of severely impaired renal function.

Misuse, Dependence, and Overdose

No human studies have evaluated the misuse potential of oxcarbazepine, and no signs of physical dependence as measured by the

desire to self-administer oxcarbazepine have been observed.4,6 Isolated cases of oxcarbazepine overdose have been reported, with the maximum dose taken amounting to approximately 24,000 mg.4,6 Signs and symptoms of oxcarbazepine overdose may include ataxia, coma, drowsiness, seizures, bradycardia, hypotension, tachycardia, hyponatremia, abdominal pain, nausea, and vomiting.28,29 There is no antidote for oxcarbazepine poisoning. The patient should be treated with symptomatic or supportive care.28 Upon overdose, removal by gastric lavage and/or inactivation by activated charcoal may be considered.4,6

Clinical Study

The efficacy and tolerability of oxcarbazepine as monotherapy in patients with partial seizures who were switched from their current AED monotherapy were evaluated in a prospective, open-label, multicenter study published in 2006.30 While this study done in the United States is slightly dated, the results are still relevant to today's practice. These patients were involved in the study because of a lack of efficacy or poor tolerability associated with their current AED.30 A total of 241 out of the 283 patients screened to participate in the study were able to be treated. Of these 241 patients, 135 patients were changing therapy to oxcarbazepine due to lack of efficacy, and 103 patients were changing due to poor tolerability.30 During the trial, 66 patients withdrew. Of the group that withdrew from the study, 42 of those patients were due to adverse events, and the rest due to other factors.30

The most common, as well as a median, daily dose of oxcarbazepine at the endpoint was 1200 mg/day.30 A total of 101 patients were able to provide tolerability data, and 66% of those patients reported substantial improvement in the tolerability profile compared to their previous therapy.30 More than 50% of individuals in the lack of tolerability to other AED therapy group experienced an improvement in seizure frequency; however, it should be noted that 21% experienced a worsening in seizure frequency.30 There were a total of 135 individuals classified as switching therapy due to lack of efficacy. In the lack of efficacy group, 50% reported improvement in seizure frequency, with only 15% having worsened seizure frequency.30

Hyponatremia was monitored in this study.30 Of the 203 participants who had normal serum sodium levels at baseline, low serum sodium values (<135 mEq/L) were observed in 31 patients (15%).30 This study reinforces that oxcarbazepine is an efficacious and well-tolerated monotherapy for patients who have failed treatment or not tolerated another AED.30 This study also addressed differences in patient tolerability when it comes to oxcarbazepine versus carbamazepine.30 There was a subgroup that switched due to tolerability issues with carbamazepine, and in that subgroup, 65% of those patients improved their tolerability profiles, and 18% said they experienced worse side effects.30

Look-alike Sound-alike Concerns

Oxcarbazepine may be confused with oxaprozin and carbamazepine. The TALL man letter formation of this medication to help decrease confusion is OXcarbazepine.31

Storage and Handling

Oxcarbazepine is listed as a hazardous drug, and healthcare professionals should use gloves to handle this medication. Oral liquid formulations require double chemotherapy gloves and a protective gown. Cutting, crushing, or otherwise manipulating tablets and capsules increases the exposure and requires additional protective equipment.32,33

Oxcarbazepine should be stored at room temperature of 22℃ or 77℉. Excursions of 15-30℃ (59-86℉) are permitted. Oral suspension oxcarbazepine should be stored in the original container.4,6

Multidisciplinary Approach

All healthcare providers should be aware of the indications and adverse effects associated with oxcarbazepine. For example, team members should discuss the patient’s creatinine clearance and kidney function with each other to improve patient outcomes. In this regard, providers should do a full

evaluation of the patient in order to screen for increased risk of hyponatremia or other adverse reactions that may occur, as well as evaluate if oxcarbazepine is an appropriate medication for the patient.

Pharmacists should screen for drug interactions when dispensing oxcarbazepine and provide detailed counseling points for the patient. Pharmacy technicians play an important role in stocking and preparing the medication for dispensing. Technicians should be aware of the indications for oxcarbazepine but be sure to refer to a pharmacist if a patient has any questions regarding the medication.

Nurses play an important role in monitoring therapy as they often do the initial evaluation of the patient’s physical symptoms. They collect background information and screen the patient. Nurses may also coordinate laboratory monitoring and have frequent contact with the patient, which can lead to the discovery of adverse effects. All healthcare providers should be aware of the hazardous drug indication - specifically pharmacy staff and nurses- as they may be exposed to the medication while dispensing and administering oxcarbazepine.

Summary

Oxcarbazepine is used as monotherapy and adjunctive therapy to treat focal seizures. The drug should only be used as an adjunctive therapy in its extended-release form. The medical literature indicates that oxcarbazepine has a more favorable pharmacological profile than carbamazepine.

Clinicians should use oxcarbazepine cautiously in patients with renal impairment, severe hepatic impairment, and hyponatremia. Adverse effects of oxcarbazepine have been reviewed, and hyponatremia is a common adverse effect of oxcarbazepine and occurs more frequently in women, people over age 40, and patients with high serum oxcarbazepine levels. Hyponatremia usually occurs within the first several months after starting therapy with oxcarbazepine.

Serious dermatologic reactions to oxcarbazepine have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients taking any epileptic drug should be closely monitored for physical and mental health complications, including depression and suicidal behavior and thoughts. All interdisciplinary healthcare team members are important in identifying and monitoring patients on oxcarbazepine.

Course Test

Oxcarbazepine is               that has a labeled use as a monotherapy or as an adjunctive treatment for patients who have focal seizures.

a hallucinogen

an anticonvulsant

a mood stabilizer

an antidepressant

Extended-release oxcarbazepine has a labeled use as an adjunctive treatment for adult patients and patients six years to 17 years old with

neuropathic pain.

bipolar disorder.

generalized seizures.

partial seizures.

The current and preferred term for a partial seizure is

a full awareness seizure.

a focal seizure.

a generalized seizure.

an epileptic seizure.

The oxcarbazepine starting dose for geriatric patients should be

600 mg a day.

< 300 mg a day.

300 mg – 450 mg a day.

150 mg - 300 mg a day.

Which of the following might be a multidisciplinary discussion opportunity involving oxcarbazepine and hyponatremia?

Informing the patient to store the drug at room temperature

Reading the Orange Book about therapeutic equivalence

Discuss creatinine clearance and kidney function

Awareness of TALL man lettering during verification

If a patient’s CrCl is < 30 mL/minute, initiate with      the usual oxcarbazepine dose and increase the dose cautiously and slowly.

double

half

three times

no dose adjustment is needed

True or False: Normalization of serum sodium levels in oxcarbazepine-induced hyponatremia typically takes weeks of extensive treatment.

True

False

Concurrent use of oxcarbazepine and oral hormonal contraceptives

may decrease the effectiveness of the contraceptive.

is associated with moderate renal impairment.

lead to a decreased metabolism of the progestin oral contraceptive.

increases the concentrations of oxcarbazepine.

A patient taking oxcarbazepine to keep a psychiatric disorder in remission presents with suicidal ideation or behavior following the discontinuation of oxcarbazepine. What is the best response?

Avoid prescribing any psychotropic drug to the patient.

The patient should be monitored without restarting oxcarbazepine or replacing it.

First, determine if suicidality has a bidirectional relationship with the patient’s epilepsy.

Restart oxcarbazepine or replace it with another drug with similar psychotropic properties.

A mother who takes oxcarbazepine while breastfeeding should know that

oxcarbazepine is contraindicated for mothers who breastfeed.

children who were breastfed developed significant developmental delays.

oxcarbazepine is excreted in breast milk.

20% of children who were breastfed developed adverse effects.

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