A Comprehensive Monograph on Oxcarbazepine (DB00776)

1.0 Executive Summary

This report provides a comprehensive analysis of the anticonvulsant medication Oxcarbazepine (DrugBank ID: DB00776), a small molecule drug belonging to the dibenzazepine class. Developed as a second-generation analogue of carbamazepine, Oxcarbazepine was engineered to retain the therapeutic efficacy of its predecessor while offering a significantly improved safety and tolerability profile. Its primary mechanism of action involves the blockade of voltage-gated sodium channels, an effect mediated almost entirely by its active metabolite, the 10-monohydroxy derivative (MHD). This action stabilizes hyperexcited neuronal membranes, thereby reducing the frequency of epileptic seizures.

Clinically, Oxcarbazepine is established as a first- or second-line therapy for partial-onset seizures, with or without secondary generalization, in both adult and pediatric populations. Its pharmacokinetic profile is a key differentiator from carbamazepine; as a prodrug, it undergoes rapid reductive metabolism to MHD, largely bypassing the cytochrome P450 system. This metabolic pathway minimizes the potential for drug-drug interactions, eliminates the issue of autoinduction, and reduces the risk of certain severe adverse events associated with carbamazepine.

Despite its favorable profile, Oxcarbazepine is associated with notable risks, including clinically significant hyponatremia, which necessitates serum sodium monitoring, particularly during the initial phase of treatment. Severe, life-threatening dermatological reactions, such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), can occur, with a markedly increased risk in individuals of Asian descent carrying the HLA-B*1502 genetic allele.

First approved by the U.S. Food and Drug Administration (FDA) in 2000 under the brand name Trileptal, Oxcarbazepine has since achieved widespread global use. The expiration of its market exclusivity has led to the availability of numerous generic formulations, increasing its accessibility and cementing its role as a cornerstone in the management of epilepsy. This monograph details the drug's complete profile, from its chemical synthesis and physicochemical properties to its detailed pharmacology, clinical applications, safety considerations, and global regulatory status.

2.0 Introduction and Drug Identification

2.1 Developmental History and Rationale

Oxcarbazepine is a second-generation antiepileptic drug (AED) that emerged from a concerted effort in rational drug design to improve upon the therapeutic profile of its predecessor, carbamazepine.[1] Patented by Novartis in 1969 and introduced into medical use in 1990, the development of Oxcarbazepine was driven by the need to mitigate the tolerability issues and safety concerns associated with carbamazepine, particularly its complex metabolism, propensity for drug interactions, and risk of serious hematologic and hepatic side effects.[3]

The core innovation in Oxcarbazepine's design is a minor but critical structural modification: the addition of a keto group at the 10-position of the dibenzazepine ring.[3] This chemical change fundamentally alters the drug's metabolic fate, shunting it away from the oxidative pathways of the cytochrome P450 system that are responsible for many of carbamazepine's liabilities. The result is a compound with a more predictable pharmacokinetic profile and an improved safety record, representing a significant therapeutic advance in the dibenzazepine class of anticonvulsants.[3]

2.2 Nomenclature, Synonyms, and Global Brand Names

To ensure unambiguous identification in clinical, research, and regulatory contexts, Oxcarbazepine is cataloged under a comprehensive set of names and identifiers.

• Generic Name: Oxcarbazepine [5]
• Systematic (IUPAC) Names:
• 10,11-Dihydro-10-oxo-5H-dibenz(b,f)azepine-5-carboxamide [3]
• 5-oxo-6H-benzo[b]benzazepine-11-carboxamide [6]
• CAS Number: 28721-07-5 [3]
• Database Identifiers:
• DrugBank ID: DB00776 [5]
• PubChem CID: 34312 [3]
• UNII: VZI5B1W380 [3]
• ChEBI ID: CHEBI:7824 [6]
• ChEMBL ID: CHEMBL1068 [6]
• KEGG ID: D00533 [6]
• Common Synonyms & Codes: OCBZ, Oxcarbamazepine, GP 47680, KIN-493, SPN-804 [5]

Oxcarbazepine is marketed globally under numerous brand names, with Trileptal and the extended-release formulation Oxtellar XR being most prominent in the United States.[5] The extensive list of international brand names, detailed in Table 2.1, reflects the drug's widespread adoption and the robust generic market that has developed following the expiration of its original patents. The first generic versions received FDA approval in 2007, and a multitude of manufacturers now produce both tablet and oral suspension formulations.[11] This history of patent expiry, extensive generic competition, and a vast global brand portfolio signifies that Oxcarbazepine is a mature, high-volume, and commercially significant AED with an established role in clinical practice worldwide.

Table 2.1: Comprehensive List of International Brand Names

Country/Region	Brand Names
United States (US)	Oxtellar XR, Trileptal 9
Argentina (AR)	Atoxecar, Aurene, Oxcarba, Oxcarbazepina, Oxcarbazepina dosa, Rupox, Trileptal 9
Australia (AU)	Trileptal 9
Brazil (BR)	Auram, Oleptal, Oxcarb, Oxcarbazepina, Trileptal, Zyoxipina 9
Canada (CA)	Trileptal 12
China (CN)	Mo yi, Ren ao, Trileptal, Wan Yi 9
France (FR)	Oxcarbazepine Mylan, Oxcarbazepine Sandoz, Oxcarbazepine Teva, Trileptal 9
Germany (DE)	Apydan, Desidox extent, Oxcarbazepin, Timox, Trileptal, and multiple generic-branded versions (e.g., -1a pharma, -CT, -Hexal, -neuraxpharm, -Ratiopharm, -Stada, -Teva) 9
India (IN)	Auxigin, Carbanerve, Carbox, Eoptal, Epigold xr, Epizox od, Epocarb, Euresta, Fobigone ox, Lovax, Mezalog, Nictal, Olepsy, Oleptal, Ox-mazetol, Oxahet, Oxalepsy, Oxana, Oxapine, Oxcarb, Oxcazo, Oxcee, Oxene, Oxep, Oxepin, Oxepin sr, Oxeptal, Oxetol, Oxicar, Oxileptin, Oxmazetol 9
Italy (IT)	Oxcarbazepina MG, Oxcarbazepina Tecnigen, Tolep, Zigabal 9
Japan (JP)	N/A (Note: Carbamazepine is used)
Mexico (MX)	Actinium, Deprectal, Deprectal S, Kallion xr, Mhide, Obepanac, Oxcarbazepina, Oxetol, Sinfonil, Trileptal, Zetoxen 9
Spain (ES)	Trileptal (Note: Generic versions may be available)
United Kingdom (GB)	Trileptal 9
This table is a representative, non-exhaustive list compiled from available data.9

2.3 Chemical Class: Dibenzazepine Anticonvulsants

Oxcarbazepine is formally classified as a dibenzazepine anticonvulsant.[6] This classification places it in the same chemical family as its parent compound, carbamazepine, and its successor, eslicarbazepine acetate. This structural relationship provides immediate context regarding its core mechanism of action, which is centered on the modulation of voltage-gated sodium channels, and also alerts clinicians to the potential for immunological cross-reactivity between these agents.

3.0 Physicochemical Properties and Pharmaceutical Formulations

3.1 Chemical Structure, Formula, and Stereochemistry

The definitive molecular formula for Oxcarbazepine is C15​H12​N2​O2​.[4] It has a calculated molecular weight of 252.27 g/mol.[4] The structure is achiral and consists of a tricyclic dibenzazepine core with a keto group at the 10-position and a carboxamide group attached to the nitrogen atom at the 5-position. For computational chemistry and database cross-referencing, its structure is represented by the following identifiers:

• SMILES: C1C2=CC=CC=C2N(C3=CC=CC=C3C1=O)C(=O)N [6]
• InChIKey: CTRLABGOLIVAIY-UHFFFAOYSA-N [4]

3.2 Physicochemical Characteristics and Predicted ADMET Profile

Oxcarbazepine exists as a white, solid crystalline powder.[4] Its physicochemical properties are critical determinants of its pharmaceutical behavior and pharmacokinetic profile. It has limited solubility in water but is more soluble in organic solvents like DMSO.[4] A summary of its key properties and predicted ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) features is provided in Table 3.1. These predictions suggest a molecule with high intestinal absorption and excellent penetration of the blood-brain barrier, both essential characteristics for a centrally acting agent. Furthermore, the predictions indicate a low likelihood of being a substrate or inhibitor for most major CYP450 enzymes, which aligns with its known metabolic profile and reduced potential for drug-drug interactions.

Table 3.1: Summary of Key Physicochemical and Predicted ADMET Properties

Property	Value	Source
Physicochemical Properties
Molecular Formula	C15​H12​N2​O2​	6
Molecular Weight	252.27 g/mol	6
Physical State	Solid, white powder	4
Water Solubility	0.16 mg/mL	5
logP (Octanol-water partition coefficient)	1.76	5
pKa (strongest acidic)	13.18	5
Polar Surface Area	63.4 A˚2	5
Predicted ADMET Features
Human Intestinal Absorption	Positive (Probability: 0.9894)	5
Blood Brain Barrier Penetration	Positive (Probability: 0.9975)	5
P-glycoprotein Substrate	Non-substrate (Probability: 0.7157)	5
CYP450 3A4 Substrate	Non-substrate (Probability: 0.6022)	5
CYP450 2C9 Inhibitor	Non-inhibitor (Probability: 0.7371)	5
CYP450 2D6 Inhibitor	Non-inhibitor (Probability: 0.9329)	5
Ames Test (Mutagenicity)	Non-toxic (Probability: 0.5078)	5
Carcinogenicity	Non-carcinogenic (Probability: 0.9118)	5
ADMET properties are predicted using admetSAR and are for informational purposes.5

3.3 Available Formulations and Excipients

Oxcarbazepine is commercially available in several formulations designed to meet the needs of a diverse patient population, from young children to adults, and to improve treatment adherence.[10] The availability of these distinct formulations is not incidental; it reflects a deliberate, market-driven evolution of the product to address specific clinical challenges. The oral suspension is crucial for pediatric patients and those with dysphagia, while the extended-release tablet was developed as a life-cycle management strategy to offer the convenience of once-daily dosing, thereby enhancing patient compliance.

The available formulations include:

• Immediate-Release (IR) Film-Coated Tablets: Available in strengths of 150 mg, 300 mg, and 600 mg.[10]
• Extended-Release (XR) Tablets: Marketed as Oxtellar XR, available in strengths of 150 mg, 300 mg, and 600 mg. This formulation was developed by Supernus Pharmaceuticals using a proprietary monolithic matrix delivery technology (SPN-804O) to achieve a pharmacokinetic profile suitable for once-daily administration.[15]
• Oral Suspension: A formulation containing 300 mg of Oxcarbazepine per 5 mL of suspension (equivalent to 60 mg/mL), which is particularly useful for pediatric dosing and for patients unable to swallow tablets.[10]

4.0 Chemical Synthesis and Manufacturing

4.1 Analysis of Key Patented Synthetic Routes

The industrial production of Oxcarbazepine has evolved over time, with various synthetic routes developed to improve efficiency, safety, and cost-effectiveness. The progression of these methods reflects a broader trend in pharmaceutical chemistry toward process optimization and "green chemistry," moving from initial discovery syntheses to scalable manufacturing processes that are safer, more economical, and more environmentally sustainable.

• Route 1: via 10-methoxy-iminostilbene (MISB) This is a prominent industrial route where 10-methoxy-iminostilbene (MISB) serves as a key intermediate.17 Iminostilbene is first converted to MISB, which is then transformed into Oxcarbazepine, often through a reaction with sodium cyanate.17 A significant process improvement for the synthesis of MISB involves the use of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) on N-acetyliminostilbene. This method is noted for its efficiency, scalability, and the generation of recyclable, non-toxic byproducts, making it highly suitable for industrial production.17
• Route 2: via 5-cyano-10-nitro-5H-dibenz[b,f]azepine A patented one-pot synthesis method starts with 5-cyano-10-nitro-5H-dibenz[b,f]azepine.18 This process involves two main steps conducted in a single reactor:

1. Reduction: The starting material is reduced using hydrogen gas in the presence of a Raney nickel catalyst. This converts the nitro group to an amino group, forming the intermediate 5-cyano-10-amino-5-dibenz[b,f]azepine.[18]
2. Hydrolysis: The intermediate is then hydrolyzed with concentrated hydrochloric acid to yield the final Oxcarbazepine product.[18]

This route is promoted for its operational simplicity, high yield, and, critically, its avoidance of highly toxic reagents like cyanides or phosgene that were used in older methods, thus representing a significant improvement in process safety.18

• Route 3: via Diclofenac Sodium A less conventional, modified route has been described that uses the widely available and relatively inexpensive non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium as the starting material.2 This multi-step synthesis involves:

1. Dechlorination of diclofenac using a nickel-aluminum alloy.
2. Cyclization of the resulting 2-(2-phenylamino) benzene acetic acid using polyphosphoric acid (PPA).
3. Phosgenation to form a carbonyl chloride intermediate.
4. Amidation with ammonia to yield Oxcarbazepine. This approach aims to reduce production costs by leveraging a common and low-cost raw material.2

4.2 Industrial-Scale Production and Key Intermediates

Across multiple synthetic strategies, 10-methoxy-iminostilbene (MISB) stands out as a crucial advanced intermediate for the large-scale production of Oxcarbazepine.[17] The development of efficient and safe methods to produce MISB has been a key focus of process chemistry research. The evolution from early, hazardous processes to modern, optimized routes underscores the economic and regulatory pressures that shape pharmaceutical manufacturing, prioritizing worker safety, environmental impact, and production cost alongside product yield and purity.

4.3 Comparative Analysis of Synthesis Methods

Each synthetic route offers a different balance of advantages and disadvantages. The MISB route is well-established and has been optimized for industrial scale. The one-pot method starting from the nitro-cyano derivative offers significant safety and operational simplicity benefits. The diclofenac route presents a potentially cost-effective alternative, though it involves multiple discrete steps. The choice of method for commercial production depends on a manufacturer's specific capabilities and priorities regarding raw material costs, process safety infrastructure, and desired throughput.

5.0 Comprehensive Pharmacological Profile

5.1 Pharmacodynamics: Mechanism of Action

The anticonvulsant effects of Oxcarbazepine are primarily mediated through its influence on neuronal ion channels, leading to the stabilization of pathologically hyperexcitable neurons.

5.1.1 Primary Mechanism: Blockade of Voltage-Gated Sodium Channels

The principal mechanism of action for Oxcarbazepine and its active metabolite, MHD, is the blockade of voltage-gated sodium channels.[1] By binding to these channels, they limit the influx of sodium ions into neurons. This action leads to the stabilization of neuronal membranes, which in turn suppresses high-frequency, repetitive neuronal firing and diminishes the propagation of synaptic impulses—the neurophysiological hallmarks of seizure activity.[3] It is thought that the drug binds preferentially to the

inactive state of the sodium channel. This prolongs the channel's refractory period, meaning it remains unavailable for depolarization for a longer duration, thereby effectively dampening excessive neuronal excitability.[5]

5.1.2 The Role of the Active Metabolite: 10-Monohydroxy Derivative (MHD)

A fundamental aspect of Oxcarbazepine's pharmacology is that it functions as a prodrug.[3] Following oral administration, it is rapidly and extensively metabolized to its principal pharmacologically active metabolite, the 10-monohydroxy derivative (MHD), also known as licarbazepine.[1] MHD is responsible for the vast majority of the drug's therapeutic antiepileptic activity and circulates in the plasma at concentrations far exceeding those of the parent compound.[5] This conversion is so efficient that the clinical effects observed are almost entirely attributable to MHD.

5.1.3 Ancillary Mechanisms and Receptor Interactions

While sodium channel blockade is the primary mechanism, other actions may contribute to Oxcarbazepine's overall anticonvulsant profile. These include the enhancement of potassium conductance and the modulation of high-voltage-activated calcium channels.[3] An early hypothesis suggesting that inhibition of glutamatergic activity played a role could not be substantiated in subsequent in vivo studies and is no longer considered a significant mechanism.[5]

5.2 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Oxcarbazepine is a key feature that distinguishes it from carbamazepine and underpins its improved tolerability and reduced interaction potential.

5.2.1 Absorption and Bioavailability

Oxcarbazepine is completely and rapidly absorbed following oral administration, demonstrating high bioavailability.[3] After a single 600 mg oral dose, peak plasma concentrations (

Cmax​) of the active metabolite MHD are reached at a median time (Tmax​) of 4.5 hours.[5]

5.2.2 Distribution, Volume, and Plasma Protein Binding

The active metabolite MHD is moderately bound to plasma proteins, with approximately 40% bound, predominantly to albumin.[5] This relatively low level of protein binding minimizes the potential for displacement interactions with other highly protein-bound drugs. The apparent volume of distribution of MHD is approximately 49 L, indicating distribution into total body water.[5]

5.2.3 Metabolism: The Prodrug Pathway and Cytochrome P450 System Interactions

The metabolism of Oxcarbazepine is the cornerstone of its improved pharmacological profile. This is a classic example of successful second-generation drug development, where a specific structural modification directly leads to a more favorable clinical profile. The 10-keto group on Oxcarbazepine prevents the oxidative epoxidation that is characteristic of carbamazepine metabolism. Instead, Oxcarbazepine is rapidly and extensively reduced by cytosolic aldo-keto reductase enzymes in the liver to its active metabolite, MHD.[5] This reductive pathway has several critical consequences:

1. Avoidance of Problematic Metabolites: It prevents the formation of the carbamazepine-10,11-epoxide metabolite, which is reactive and has been implicated in some of carbamazepine's adverse effects.
2. No Autoinduction: Unlike carbamazepine, which induces its own metabolism over time (autoinduction), Oxcarbazepine does not, leading to more stable and predictable plasma concentrations.
3. Reduced Drug-Drug Interactions: Because its primary metabolism is not dependent on the cytochrome P450 (CYP) enzyme system, Oxcarbazepine has a significantly lower propensity for clinically significant drug-drug interactions compared to carbamazepine.[5]

However, its interaction profile is not completely inert. Oxcarbazepine is a weak inducer of the CYP3A4 enzyme, which can be clinically relevant as it may reduce the plasma concentrations and efficacy of certain co-administered drugs, most notably hormonal contraceptives.[1] It is also a weak inhibitor of CYP2C19 and can, at high doses, increase the concentrations of drugs metabolized by this enzyme, such as phenytoin.

The continued scientific and commercial interest in this pharmacological pathway is further evidenced by the development of Eslicarbazepine acetate (marketed as Zebinix). This third-generation agent is a prodrug designed to deliver only the (S)-enantiomer of MHD, which is the more pharmacologically active stereoisomer.[5] This progression from carbamazepine (Gen 1) to Oxcarbazepine (Gen 2) to Eslicarbazepine (Gen 3) illustrates a clear, multi-decade R&D strategy focused on first solving a major metabolic problem and then optimizing for potency by isolating the active enantiomer.

5.2.4 Elimination and Renal Clearance

Elimination of Oxcarbazepine and its metabolites is almost exclusively via the kidneys, with over 95% of an administered dose recovered in the urine.[3] The parent drug has a very short half-life of approximately 2 hours, while the active metabolite MHD has a much longer half-life of about 9 hours, which is the primary determinant of the twice-daily dosing regimen.[3] The urinary excretion products consist mainly of glucuronide conjugates of MHD (approximately 49%), unchanged MHD (approximately 27%), and only a negligible amount (<1%) of the unchanged parent drug, Oxcarbazepine.[5]

5.2.5 Pharmacokinetic Variability in Special Populations

The pharmacokinetics of Oxcarbazepine can vary in certain populations. Pediatric patients, particularly younger children, exhibit a higher clearance of MHD on a body-weight basis compared to adults. Consequently, children may require higher doses per kilogram of body weight to achieve therapeutic plasma concentrations similar to those in adults.[1] In patients with significant renal impairment (creatinine clearance

<30 mL/min), the elimination of MHD is impaired, necessitating a 50% reduction in the starting dose and a slower titration schedule.[14]

6.0 Clinical Efficacy and Therapeutic Applications

6.1 Approved Indications: Epilepsy

Oxcarbazepine is a well-established antiepileptic drug with specific, well-defined indications approved by regulatory agencies such as the U.S. FDA.

6.1.1 Monotherapy for Partial-Onset Seizures

Oxcarbazepine is indicated for use as monotherapy in the treatment of partial-onset seizures in adults and in pediatric patients aged 4 years and older.[5]

6.1.2 Adjunctive Therapy for Partial-Onset Seizures

It is also indicated for use as adjunctive (add-on) therapy in the treatment of partial-onset seizures in adults and in pediatric patients aged 2 years and older.[5]

6.1.3 Analysis of Pivotal Clinical Trial Efficacy Data

Clinical trials have demonstrated the robust efficacy of Oxcarbazepine in its approved indications. In head-to-head comparative studies, Oxcarbazepine was found to be as effective as older, first-generation antiepileptics, including carbamazepine, phenytoin, and valproic acid, for controlling partial-onset and secondarily generalized tonic-clonic seizures in both adult and pediatric populations.[15] Furthermore, placebo-controlled trials have confirmed its efficacy as an add-on therapy, showing a significant reduction in seizure frequency compared to placebo when added to a patient's existing regimen.[15]

6.2 Off-Label and Investigational Uses

The clinical application of Oxcarbazepine extends beyond its approved indications, with clinicians and researchers exploring its utility in other conditions. These off-label and investigational uses are not random; they are typically mechanistically driven extensions of its primary pharmacology, targeting disorders that are thought to share a common pathophysiology of neuronal hyperexcitability.

6.2.1 Bipolar Disorder and Mood Stabilization

Oxcarbazepine is frequently used off-label as a mood-stabilizing agent in the management of bipolar disorder, particularly for patients who have not responded to or cannot tolerate first-line treatments like lithium or valproate.[3] Its mechanism of stabilizing hyperexcited neurons provides a clear rationale for its use in managing the mood fluctuations characteristic of this disorder.

6.2.2 Neuropathic Pain Syndromes (incl. Trigeminal Neuralgia)

Another common off-label use is in the treatment of various neuropathic pain syndromes.[13] It is considered an effective option for trigeminal neuralgia, a condition characterized by severe, lancinating facial pain driven by ectopic firing of the trigeminal nerve.[4] Its ability to block sodium channels makes it well-suited to quell this type of neuronal hyperexcitability. A clinical trial has specifically investigated its use for symptomatic trigeminal neuralgia associated with multiple sclerosis.[21]

6.2.3 Review of Other Investigational Trials

The therapeutic potential of Oxcarbazepine has been explored in a range of other conditions. A completed Phase 4 clinical trial assessed its efficacy in treating impulsivity and aggressive behavior in adolescents with Oppositional Defiant Disorder, another condition linked to frontal lobe disinhibition and neuronal excitability.[22] In contrast, a more speculative Phase 1 trial investigating its use in combination with radionuclide therapy for metastatic prostate cancer was withdrawn, suggesting that its therapeutic utility is likely confined to the neurological and psychiatric disease cluster where channelopathy is a core feature.[23]

7.0 Safety, Tolerability, and Risk Management

While Oxcarbazepine offers an improved safety profile over carbamazepine, it is associated with a distinct set of risks that require careful management. The risk profile can be broadly divided into two categories: predictable, dose-related effects that can be managed with careful titration and monitoring, and rare, idiosyncratic reactions that can be life-threatening and may be linked to genetic predispositions.

7.1 Adverse Drug Reactions

The most frequently reported adverse reactions are related to the central nervous system (CNS). A structured overview of common and serious adverse reactions is presented in Table 7.1.

• Common Adverse Reactions: The most common side effects include dizziness, somnolence (drowsiness), headache, fatigue, ataxia (impaired coordination), nausea, vomiting, and diplopia (double vision).[10] These effects are often dose-dependent and can be minimized by initiating therapy at a low dose and titrating slowly.
• Serious Adverse Reactions: Although less common, Oxcarbazepine can cause severe and potentially fatal adverse reactions. These include:
• Dermatological Reactions: Life-threatening skin reactions such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported.[5]
• Hypersensitivity Reactions: Anaphylactic reactions, angioedema (swelling of the face, lips, and throat), and multi-organ hypersensitivity reactions (known as Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS) can occur.[5]
• Hematologic Abnormalities: Rare reports of blood dyscrasias, including agranulocytosis and aplastic anemia, have been associated with Oxcarbazepine use, warranting monitoring for signs of bone marrow suppression.[5]

Table 7.1: Adverse Reactions by System Organ Class

System Organ Class	Very Common (≥10%)	Common (1% to <10%)	Serious/Rare (<1%)
Nervous System	Dizziness, Somnolence, Headache, Diplopia	Ataxia, Tremor, Nystagmus, Abnormal Gait, Amnesia, Confusion	-
Gastrointestinal	Nausea, Vomiting	Abdominal Pain, Constipation, Diarrhea, Dyspepsia	Pancreatitis
General Disorders	Fatigue	Asthenia (Weakness)	-
Metabolism & Nutrition	-	Hyponatremia	Clinically significant hyponatremia (<125 mmol/L)
Psychiatric	-	Agitation, Depression, Apathy, Emotional Lability	Suicidal Ideation
Skin & Subcutaneous Tissue	-	Rash, Acne, Alopecia	Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Angioedema, Urticaria
Blood & Lymphatic System	-	-	Agranulocytosis, Aplastic Anemia, Pancytopenia, Leukopenia, Thrombocytopenia
Immune System	-	-	Anaphylaxis, Multi-organ hypersensitivity (DRESS)
Table compiled from data in.10 Frequencies are approximate and based on clinical trial data.

7.2 Contraindications, Warnings, and Precautions

Effective risk management requires awareness of specific contraindications and adherence to critical warnings.

• Contraindications: Oxcarbazepine is contraindicated in patients with a known hypersensitivity to the drug itself or to eslicarbazepine acetate.[10] Patients with a history of hypersensitivity to carbamazepine should be treated with caution, as there is an estimated 25-30% rate of cross-reactivity.

7.2.1 Hyponatremia

A key warning associated with Oxcarbazepine is the risk of developing clinically significant hyponatremia (serum sodium <125 mmol/L).[1] This risk is highest during the first three months of therapy. Symptoms can be non-specific and include nausea, malaise, headache, lethargy, confusion, or an increase in seizure frequency. Therefore, monitoring of serum sodium levels is recommended, especially upon initiation of therapy, during dose adjustments, and in patients with predisposing conditions or on concomitant medications (like SSRIs) that can also lower sodium levels.[1]

7.2.2 Pharmacogenomics: The HLA-B*1502 Allele

There is a strong association between the presence of the human leukocyte antigen (HLA) allele HLA−B∗1502 and an increased risk of developing SJS and TEN in response to treatment with carbamazepine and, by extension, Oxcarbazepine.[1] This allele is found almost exclusively in individuals of Asian ancestry. Therefore, genetic screening for the

HLA−B∗1502 allele should be considered for patients with Asian ancestry prior to initiating Oxcarbazepine therapy. If a patient tests positive, the drug should be avoided unless the potential benefit clearly outweighs the risk.[1]

7.2.3 Suicidality and CNS Effects

In line with a class-wide warning for all antiepileptic drugs, Oxcarbazepine may increase the risk of suicidal thoughts and behavior. Patients, their caregivers, and families should be counseled to be alert for the emergence or worsening of depression, any unusual changes in mood or behavior, or the emergence of suicidal ideation, and to report such symptoms immediately to a healthcare provider.[10] The CNS depressant effects, such as dizziness and somnolence, can impair judgment, thinking, and motor skills. Patients should be cautioned against driving or operating hazardous machinery until they are reasonably certain that Oxcarbazepine does not affect them adversely.[10]

7.3 Drug Interactions

While its potential for interactions is lower than that of carbamazepine, several clinically significant interactions exist.

Table 7.2: Clinically Significant Drug-Drug Interactions

Interacting Agent(s)	Mechanism of Interaction	Clinical Effect & Management
Hormonal Contraceptives (containing ethinylestradiol, levonorgestrel)	Induction of CYP3A4 by Oxcarbazepine	Decreased plasma levels of the contraceptive hormones, leading to potential contraceptive failure. Use of alternative or additional non-hormonal contraceptive methods is strongly recommended.14
Phenytoin, Phenobarbital	Induction of Oxcarbazepine metabolism; Inhibition of Phenytoin metabolism (at high doses)	Concomitant use with strong enzyme inducers can decrease MHD levels, potentially requiring an increased Oxcarbazepine dose. High-dose Oxcarbazepine can inhibit CYP2C19, increasing phenytoin levels; monitor phenytoin concentrations.
Alcohol, Benzodiazepines, and other CNS Depressants	Additive pharmacodynamic effects 5	Increased risk and severity of CNS depression (e.g., somnolence, dizziness, impaired coordination). Concomitant use should be avoided or undertaken with extreme caution.10
Valproic Acid	Decreased MHD levels	Co-administration with valproic acid can decrease MHD plasma levels by approximately 18%. Dose adjustments may be necessary.
Table compiled from data in.1

7.4 Use in Specific Populations (Pregnancy, Lactation, Renal Impairment)

• Pregnancy: Oxcarbazepine is classified as Pregnancy Category C in the United States, meaning that animal studies have shown an adverse effect on the fetus, but there are no adequate and well-controlled studies in humans.[3] While the drug carries a risk of causing congenital malformations, uncontrolled seizures during pregnancy also pose a significant risk to both the mother and the fetus. Therefore, its use during pregnancy requires a careful risk-benefit analysis. The risk of malformations with Oxcarbazepine appears to be lower than that associated with valproate.[1]
• Lactation: Oxcarbazepine and its active metabolite MHD are excreted into human milk. The European Medicines Agency (EMA) has noted that a causal relationship between Oxcarbazepine exposure via breastfeeding and neurodevelopmental disorders is possible but not clearly established, recommending revised wording on product labels.[26] A decision on whether to breastfeed should take into account the potential benefits and risks.
• Renal Impairment: In patients with severe renal impairment (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged. The starting dose of Oxcarbazepine should be reduced by 50% (e.g., 300 mg/day), and titration should proceed more slowly than usual.[14]

7.5 Overdose: Presentation and Management

Experience with Oxcarbazepine overdose is limited. Reported signs and symptoms include CNS and respiratory depression, ataxia, dyskinesia, nausea, vomiting, and hyponatremia.[5] There is no specific antidote. Management of an overdose should be supportive and symptomatic. This may include gastric lavage and/or the administration of activated charcoal to reduce absorption, particularly if the ingestion was recent.[5]

8.0 Regulatory Status and Dosing Guidelines

8.1 Global Regulatory History

Oxcarbazepine is a well-established medication with a long regulatory history, indicative of a mature drug lifecycle. The current focus of regulatory bodies is less on initial approval and more on post-marketing surveillance, management of generic competition, and optimization of use in specific populations.

• FDA (United States): The original New Drug Application (NDA 21-014) for the innovator product, Trileptal (tablets), submitted by Novartis, was approved by the FDA on January 14, 2000.[11] The oral suspension formulation was subsequently approved on May 25, 2001.[11] The first generic versions of Oxcarbazepine tablets were approved in 2007, opening the door to widespread generic competition.[11] The extended-release formulation, Oxtellar XR, was approved later, further expanding the therapeutic options.
• EMA (European Union): Oxcarbazepine is authorized for use throughout the European Union and is available by prescription only (Rx-only).[3] While much of the recent EMA documentation focuses on its successor, Eslicarbazepine (Zebinix), Oxcarbazepine remains an actively monitored and marketed product.[28] The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) conducts periodic safety update report (PSUR) assessments, demonstrating ongoing pharmacovigilance.[26] The approval of generic versions, such as Oxcarbazepine ADOH in 2022 via a decentralised procedure, confirms its established status within the EU market.[30]
• Health Canada: The initial authorization for Trileptal in Canada was granted on April 6, 2000.[12]

8.2 Dosing and Administration

The dosing of Oxcarbazepine is complex and must be individualized based on the indication, patient age, body weight, and renal function. Gradual dose initiation and titration are crucial for minimizing CNS side effects. The highly specific and weight-based dosing schedules, particularly for pediatric patients, reflect the extensive clinical experience gained with this mature drug.

8.2.1 Dose Titration, Conversion, and Discontinuation Strategies

• Titration: Therapy should always be initiated at a low dose and increased gradually over several weeks to the target maintenance dose to optimize tolerability.[15]
• Conversion to Monotherapy: When converting a patient from another AED to Oxcarbazepine monotherapy, Oxcarbazepine should be initiated while the dose of the concomitant AED is gradually tapered and completely withdrawn over a period of 3 to 6 weeks.[14]
• Discontinuation: To minimize the risk of rebound seizures, Oxcarbazepine should not be discontinued abruptly. The dose should be tapered down gradually under medical supervision.[10]

Table 8.1: Recommended Dosing Regimens for All Approved Indications

Indication	Patient Population	Starting Dose	Titration Schedule	Recommended Maintenance Dose
Adjunctive Therapy	Adults	600 mg/day (in 2 divided doses)	Increase by max. 600 mg/day at weekly intervals	1200 mg/day (Doses >1200 mg/day may have greater efficacy but poorer tolerability)
	Pediatrics (4-16 years)	8-10 mg/kg/day (not to exceed 600 mg/day) in 2 divided doses	Titrate over 2 weeks to target maintenance dose	20-29 kg: 900 mg/day 29.1-39 kg: 1200 mg/day >39 kg: 1800 mg/day
	Pediatrics (2 to <4 years)	8-10 mg/kg/day (in 2 divided doses)	Titrate over 2-4 weeks. Max dose should not exceed 60 mg/kg/day	Target maintenance dose based on clinical response, up to 60 mg/kg/day
Monotherapy (Conversion)	Adults	600 mg/day (in 2 divided doses)	Increase by max. 600 mg/day at weekly intervals. Withdraw concomitant AED over 3-6 weeks	2400 mg/day
	Pediatrics (4-16 years)	8-10 mg/kg/day (in 2 divided doses)	Increase by max. 10 mg/kg/day at weekly intervals. Withdraw concomitant AED over 3-6 weeks	Per weight-based ranges for adjunctive therapy
Monotherapy (Initiation)	Adults	600 mg/day (in 2 divided doses)	Increase by 300 mg/day every 3rd day	1200 mg/day
	Pediatrics (4-16 years)	8-10 mg/kg/day (in 2 divided doses)	Increase by 5 mg/kg/day every 3rd day	Per weight-based ranges for adjunctive therapy
Renal Impairment	Adults (CrCl <30 mL/min)	300 mg/day (in 2 divided doses)	Increase at a slower than usual rate	Based on clinical response
Table compiled and synthesized from prescribing information in.14 This is a summary; prescribers must consult the full official product label.

9.0 Conclusion and Expert Analysis

9.1 Synthesis of Oxcarbazepine's Therapeutic Profile

Oxcarbazepine stands as a prime example of successful second-generation drug development. It was rationally designed to address the known shortcomings of its parent compound, carbamazepine, and it largely succeeded in this goal. By incorporating a 10-keto functional group, its designers fundamentally altered its metabolic pathway, shunting it away from the complex and problematic cytochrome P450 system toward a cleaner, more predictable reductive pathway. This single chemical modification is the lynchpin of its entire therapeutic advantage, resulting in a drug with comparable efficacy for partial-onset seizures but with a significantly improved profile regarding drug-drug interactions, the absence of autoinduction, and a lower risk of certain severe adverse events. Its clinical utility is mediated almost entirely through its active metabolite, MHD, which effectively stabilizes hyperexcited neurons via voltage-gated sodium channel blockade.

9.2 Comparative Assessment and Place in Modern Therapy

In contemporary epilepsy management, Oxcarbazepine is firmly established as a valuable first- or second-line therapeutic option for patients with partial-onset seizures. Its primary therapeutic niche remains as a more tolerable alternative to carbamazepine. The advent of widespread generic availability has also made it a cost-effective choice, further solidifying its position in treatment guidelines. While newer agents have since been introduced, Oxcarbazepine maintains a crucial role due to its well-understood efficacy, manageable safety profile, and decades of clinical experience. The balance it strikes between efficacy, safety, and cost ensures its continued relevance in the therapeutic armamentarium.

9.3 Future Perspectives and Unanswered Questions

Despite its success, the story of Oxcarbazepine is still evolving. Several key questions will shape its future role:

• Competition with its Successor: What is the long-term place of Oxcarbazepine in an era where its own refined successor, Eslicarbazepine acetate (a prodrug for the more active S-enantiomer of MHD), is available? The choice between these agents will likely be driven by nuanced differences in efficacy, tolerability, and, critically, cost.
• Expansion of Indications: Will the common off-label uses of Oxcarbazepine, particularly in bipolar disorder and neuropathic pain, ever be supported by sufficient clinical trial data to gain formal regulatory approval? Such an expansion could significantly broaden its market, but would require substantial investment in new clinical development programs.
• Long-Term Pediatric Safety: As a drug used in children as young as two, long-term safety data is paramount. The recent EMA review of potential neurodevelopmental effects, while not establishing a clear causal link, highlights an area of ongoing surveillance and necessary future research.[26] Understanding the subtle, long-term consequences of AED use in the developing brain remains a critical and unanswered question for Oxcarbazepine and the field at large.

Ultimately, Oxcarbazepine represents a mature, reliable, and indispensable tool in neurology and psychiatry. Its history provides a valuable lesson in rational drug design, while its future will be defined by its relationship to its pharmacological relatives and the ongoing quest to refine the long-term safety of chronic antiepileptic therapy.

Works cited

1. Oxcarbazepine - StatPearls - NCBI Bookshelf, accessed August 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK482313/
2. Synthesis of oxcarbazepine by newer method - Der Pharma Chemica, accessed August 12, 2025, https://www.derpharmachemica.com/pharma-chemica/synthesis-of-oxcarbazepine-by-newer-method.pdf
3. Oxcarbazepine - Wikipedia, accessed August 12, 2025, https://en.wikipedia.org/wiki/Oxcarbazepine
4. Oxcarbazepine = 98 HPLC, solid 28721-07-5 - Sigma-Aldrich, accessed August 12, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/o3764
5. Oxcarbazepine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 12, 2025, https://go.drugbank.com/drugs/DB00776
6. Oxcarbazepine | C15H12N2O2 | CID 34312 - PubChem, accessed August 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Oxcarbazepine
7. [Table, CHEMICAL FORMULA AND STRUCTURE]. - LiverTox - NCBI Bookshelf, accessed August 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK548414/table/Oxcarbazepine.Tc/?report=objectonly
8. Oxcarbazepine [USAN:USP:INN:BAN] - PubChem, accessed August 12, 2025, https://pubchem.ncbi.nlm.nih.gov/substance/134996017
9. OXcarbazepine | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 12, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5535/OXcarbazepine
10. Oxcarbazepine Uses, Side Effects & Warnings - Drugs.com, accessed August 12, 2025, https://www.drugs.com/mtm/oxcarbazepine.html
11. Generic Trileptal Availability - Drugs.com, accessed August 12, 2025, https://www.drugs.com/availability/generic-trileptal.html
12. PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION PrTRILEPTAL® Oxcarbazepine Tablets, 300 mg and 600 mg, oral Novartis, accessed August 12, 2025, https://www.novartis.com/ca-en/sites/novartis_ca/files/trileptal_scrip_e.pdf
13. Oxcarbazepine - brand name list from Drugs.com, accessed August 12, 2025, https://www.drugs.com/ingredient/oxcarbazepine.html
14. TRILEPTAL (oxcarbazepine) - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021014s036lbl.pdf
15. Oxcarbazepine Basic Seizure Medication - Epilepsy Foundation, accessed August 12, 2025, https://www.epilepsy.com/tools-resources/seizure-medication-list/oxcarbazepine
16. Oxcarbazepine 202810 Clinical PREA - FDA, accessed August 12, 2025, https://www.fda.gov/files/drugs/published/Oxcarbazepine-202810-Clinical-PREA.pdf
17. A New Industrial Process for 10-Methoxyiminostilbene: Key ..., accessed August 12, 2025, https://pubs.acs.org/doi/10.1021/op900127v
18. EP2311812A1 - Method for chemical synthesis of oxcarbazepine ..., accessed August 12, 2025, https://patents.google.com/patent/EP2311812A1/en
19. patents.google.com, accessed August 12, 2025, https://patents.google.com/patent/EP2311812A1/en#:~:text=Method%20for%20chemical%20synthesis%20of%20oxcarbazepine%20comprises%20adding%205%2Dcyano,reaction%2C%20filtering%20after%20reacting%20completely%2C
20. Eslicarbazepine acetate - Wikipedia, accessed August 12, 2025, https://en.wikipedia.org/wiki/Eslicarbazepine_acetate
21. Multiple Sclerosis Completed Phase Trials for ... - DrugBank, accessed August 12, 2025, https://go.drugbank.com/indications/DBCOND0027885/clinical_trials/DB00776?phase=&status=completed
22. Oppositional Defiant Disorder Completed Phase 4 Trials for Oxcarbazepine (DB00776), accessed August 12, 2025, https://go.drugbank.com/indications/DBCOND0032311/clinical_trials/DB00776?phase=4&status=completed
23. Oxcarbazepine Withdrawn Phase 1 Trials for Metastatic Prostate Cancer Treatment, accessed August 12, 2025, https://go.drugbank.com/drugs/DB00776/clinical_trials?conditions=DBCOND0033188&phase=1&purpose=treatment&status=withdrawn
24. Oxcarbazepine (Trileptal) | National Alliance on Mental Illness (NAMI), accessed August 12, 2025, https://www.nami.org/about-mental-illness/treatments/mental-health-medications/types-of-medication/oxcarbazepine/
25. Oxcarbazepine Interactions Checker - Drugs.com, accessed August 12, 2025, https://www.drugs.com/drug-interactions/oxcarbazepine.html
26. Oxcarbazepine: CMDh scientific conclusions and grounds for the variation, amendments to the product information and timetable fo - EMA, accessed August 12, 2025, https://www.ema.europa.eu/en/documents/psusa/oxcarbazepin-cmdh-scientific-conclusions-and-grounds-variation-amendments-product-information-and-timetable-implementation-psusa00002235202108_en.pdf
27. Drug Approval Package: Trileptal (Oxcarbazepine) NDA#21-014 - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21-014_trileptal.cfm
28. Zebinix | European Medicines Agency (EMA), accessed August 12, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/zebinix
29. PSUSA/00002235/202408 - periodic safety update report single assessment - EMA, accessed August 12, 2025, https://www.ema.europa.eu/en/medicines/psusa/psusa-00002235-202408
30. Public Assessment Report Scientific discussion Oxcarbazepine ADOH 150 mg, 300 mg and 600 mg, film-coated tablets (oxcarbazepine) - Geneesmiddeleninformatiebank, accessed August 12, 2025, https://www.geneesmiddeleninformatiebank.nl/pars/h127890.pdf