Comprehensive Monograph: Cenobamate (DB06119)

Executive Summary and Core Drug Profile

Cenobamate is a third-generation antiseizure medication (ASM) representing a significant therapeutic advancement for adult patients with refractory partial-onset (focal) epilepsy.[1] It is distinguished by a novel, dual mechanism of action that involves both the inhibition of voltage-gated sodium channels and the positive allosteric modulation of

γ-aminobutyric acid type A (GABAA​) receptors.[2] This combined approach to reducing neuronal hyperexcitability and enhancing synaptic inhibition has translated into unprecedented efficacy in clinical trials, particularly in achieving high rates of seizure freedom in a difficult-to-treat patient population that has failed multiple prior therapies.[3]

The clinical use of cenobamate is defined by a characteristic safety and tolerability profile that necessitates a specific, slow-titration protocol. This regimen, which involves initiating treatment at a low dose of 12.5 mg daily and escalating every two weeks, was developed to mitigate the risk of serious adverse events, most notably Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).[4] Common adverse effects are primarily related to the central nervous system and include somnolence, dizziness, and fatigue.[1] Furthermore, cenobamate possesses a complex pharmacokinetic profile characterized by a long elimination half-life of 50-60 hours, which supports convenient once-daily dosing but also necessitates a gradual withdrawal period.[1] Its metabolism involves both UGT and CYP enzymes, leading to significant potential for drug-drug interactions that require active management of concomitant medications.[6]

Cenobamate is approved as Xcopri in the United States and Ontozry in the European Union, where it is positioned as a potent therapeutic option for patients with uncontrolled focal seizures.[1] Its successful application in clinical practice requires a comprehensive understanding of its pharmacology, a meticulous approach to its administration, and vigilant patient monitoring. Cenobamate thus stands as a highly effective but managerially complex agent within the modern ASM armamentarium.

Table 1: Core Drug Profile of Cenobamate

Attribute	Detail	Source Snippets
Generic Name	Cenobamate	8
Development Code	YKP-3089	8
DrugBank ID	DB06119	1
CAS Number	913088-80-9	1
Brand Names	Xcopri (US), Ontozry (EU)	1
Drug Class	Carbamate anticonvulsant; Tetrazole alkyl carbamate derivative	2
Therapeutic Indication	Adjunctive or monotherapy for partial-onset (focal) seizures in adults	1
Mechanism of Action	Dual: 1) Inhibitor of voltage-gated sodium channels (persistent current); 2) Positive allosteric modulator of GABAA​ receptors (non-benzodiazepine site)	2
Key Pharmacokinetics	Long half-life (50-60h), once-daily dosing, extensive metabolism (UGT & CYP), significant drug-drug interaction potential	1
Regulatory Status	US: Schedule V; EU: Rx-only	1

Chemical, Physicochemical, and Structural Analysis

Detailed Molecular Description

Cenobamate is a novel, synthetic organic, small molecule compound classified as a tetrazole-derived alkyl carbamate.[8] It possesses a single chiral center, with the pharmacologically active enantiomer being the (R)-isomer, as specified in its chemical name.[13] The molecular structure of cenobamate is distinct, featuring three key functional groups: a halogenated aromatic ring (2-chlorophenyl), a five-membered tetrazole heterocycle, and a carbamate group (

O−C(=O)NH2​).[15] The presence of the carbamate moiety is noteworthy, as this structural motif is shared by several other ASMs, including felbamate and carisbamate, which are also known to modulate sodium channels.[15] This shared feature suggests that the carbamate group may function as a pharmacophore contributing to the sodium channel-inhibiting activity of this class of compounds. However, the remarkable potency and dual mechanism of cenobamate indicate that the unique combination of the tetrazole ring and the specific (R)-1-(2-chlorophenyl)ethyl backbone confers its distinct pharmacological and pharmacokinetic properties, setting it apart from its structural predecessors.

Identifiers and Nomenclature

To ensure precise identification in scientific literature, regulatory filings, and clinical practice, cenobamate is defined by a comprehensive set of identifiers:

• International Union of Pure and Applied Chemistry (IUPAC) Name: carbamate.[1]
• Molecular Formula: C10​H10​ClN5​O2​.[1]
• Molecular Weight: The average molecular weight is 267.67 g·mol−1, and the monoisotopic mass is 267.0523023 Da.[1]
• Chemical Abstracts Service (CAS) Registry Number: 913088-80-9.[1]
• Synonyms and Development Codes: During its development by SK Pharmaceuticals, it was known by the code YKP-3089. Other international nonproprietary names include Cenobamato, Cénobamate, and Cenobamatum.[8]

Physicochemical Properties and Formulation Implications

The physical and chemical properties of cenobamate directly influence its formulation, administration, and pharmacokinetic behavior.

• Appearance: In its bulk drug substance form, cenobamate is a white powder.[13]
• Solubility: The compound is described as being slightly soluble to highly soluble in aqueous media across the physiological pH range.[17] A predicted Log S (ESOL) value of -2.59 further classifies it as "Soluble".[16] This favorable solubility is a critical property that underpins its formulation as an immediate-release oral tablet. More importantly, this solubility is a key clinical enabler, as it allows the tablets to be crushed and mixed with water to form a suspension for oral administration or delivery via a nasogastric (NG) tube.[12] The reliable dispersion in water facilitates administration for patients with dysphagia or those requiring enteral feeding, a common challenge in neurologically impaired populations. This versatility was formally recognized by the U.S. Food and Drug Administration (FDA) with an expanded approval in 2024 for these alternate administration methods, directly linking a fundamental physicochemical property to a tangible clinical benefit and a specific regulatory action.[20]
• Lipophilicity: The consensus Log Po/w​ (octanol-water partition coefficient) is 0.95, indicating moderate lipophilicity that balances aqueous solubility with the ability to cross biological membranes, including the blood-brain barrier.[16]
• Other Properties: The molecule has a Topological Polar Surface Area (TPSA) of 95.92 A˚2, five rotatable bonds, one hydrogen bond donor, and five hydrogen bond acceptors, properties which are consistent with established parameters for orally bioavailable drugs.[16]

Comprehensive Pharmacological Profile

Primary Mechanism of Action: Dual Modulation of Neuronal Excitability

The robust clinical efficacy of cenobamate is attributed to a unique dual mechanism of action that synergistically targets two fundamental pathways of neuronal signaling: voltage-gated sodium channels (VGSCs) and GABAA​ receptors. By simultaneously dampening pro-epileptic neuronal hyperexcitability and enhancing synaptic inhibition, it provides a more comprehensive approach to seizure control than many ASMs that act on a single pathway.

Voltage-Gated Sodium Channel (VGSC) Inhibition

Cenobamate effectively reduces repetitive neuronal firing by inhibiting voltage-gated sodium channels, a well-established target for antiseizure medications.[8] However, its action is distinguished by two key features. First, it preferentially inhibits the

persistent component of the sodium current (INaP​) over the transient component.[1] The persistent sodium current is a small, non-inactivating current that plays a critical role in setting the neuronal firing threshold and promoting the burst firing patterns characteristic of epileptic activity. By selectively targeting this current, with a reported half-maximal inhibitory concentration (

IC50​) of 53.1 μM, cenobamate can normalize the seizure threshold and prevent neuronal hyperexcitability with high potency.[7]

Second, cenobamate enhances both the fast and slow inactivation of VGSCs.[14] It demonstrates a higher binding affinity for the inactivated state of the channel compared to the resting state.[7] This voltage-dependent action means that its inhibitory effect is more pronounced in neurons that are already depolarized or firing at high frequencies, as is common in an epileptic focus. This targeted action increases the threshold required to generate an action potential and reduces the number of action potentials evoked by a depolarizing stimulus, thereby stabilizing neuronal membranes and preventing seizure propagation.[7]

Positive Allosteric Modulation of GABAA Receptors

In addition to its effects on sodium channels, cenobamate acts as a positive allosteric modulator of the γ-aminobutyric acid type A (GABAA​) ion channel, the primary mediator of fast synaptic inhibition in the central nervous system.[8] When GABA binds to the

GABAA​ receptor, it opens a chloride ion channel, leading to hyperpolarization of the neuron and making it less likely to fire. Cenobamate enhances this effect, thereby increasing inhibitory GABAergic neurotransmission.[1] A crucial aspect of this mechanism is that cenobamate binds to a site on the receptor that is distinct from the benzodiazepine binding site.[2] This non-benzodiazepine action suggests it can augment GABA-mediated inhibition through a different pathway, potentially avoiding some of the tolerance issues associated with long-term benzodiazepine use and offering an additive inhibitory effect when used with other GABAergic agents.

The combination of these two complementary mechanisms—reducing excitatory drive via VGSC inhibition and boosting inhibitory tone via GABAA​ modulation—is the most plausible pharmacological basis for the exceptionally high rates of seizure freedom observed with cenobamate in patients with refractory epilepsy.[2]

Pharmacodynamic Effects

Antiseizure Activity in Preclinical Models

The dual mechanism of action translates into a broad spectrum of anticonvulsant activity in preclinical studies. Cenobamate has demonstrated robust efficacy in a variety of established rodent seizure models, including the maximal electroshock (MES) test, which is predictive of efficacy against focal and secondarily generalized tonic-clonic seizures, and the subcutaneous pentylenetetrazol (PTZ) and picrotoxin tests, which are models for generalized absence and myoclonic seizures.[7] Its activity in the 6 Hz psychomotor seizure model further supports its utility in treating focal seizures that are resistant to other medications.[7] The observation that cenobamate was ineffective against seizures induced by bicuculline, a competitive

GABAA​ receptor antagonist, helps to further delineate its specific GABAergic mechanism, confirming that it acts as a modulator rather than a direct agonist.[7]

QT Interval Shortening

A distinct pharmacodynamic effect of cenobamate is a dose-dependent shortening of the corrected QT (QTc) interval on the electrocardiogram.[8] In a dedicated thorough QT study, a significantly higher percentage of subjects treated with cenobamate experienced a QTc shortening of greater than 20 milliseconds compared to placebo (31% at 200 mg and 66% at 500 mg vs. 6-17% for placebo).[5] While reductions below 300 milliseconds, a threshold associated with a significant risk of ventricular arrhythmias, were not observed, this effect is considered clinically significant.[5]

This QT shortening effect serves as a unique pharmacodynamic "fingerprint" for the drug and implies an interaction with cardiac ion channels, likely separate from its primary CNS targets. This has led to a clear, non-negotiable contraindication: cenobamate must not be used in patients with Familial Short QT syndrome, a rare genetic disorder that predisposes individuals to sudden cardiac death.[19] This contraindication requires specific patient screening based on personal and family medical history, making it a critical safety gatekeeper that is distinct from the management of more common, dose-related CNS side effects. Caution is also advised when co-administering cenobamate with other medications known to shorten the QT interval due to the potential for synergistic effects.[5]

Pharmacokinetic Profile: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of cenobamate is characterized by efficient absorption, moderate protein binding, extensive metabolism, and a long elimination half-life that underpins its once-daily dosing regimen. However, its non-linear kinetics and significant potential for drug-drug interactions are critical considerations for its safe and effective clinical use.

Absorption and Bioavailability

Following oral administration, cenobamate is well-absorbed from the gastrointestinal tract, with an absolute bioavailability of at least 88%.[4] Peak plasma concentrations (

Tmax​) are typically reached within 1 to 4 hours post-dose.[8] The absorption of cenobamate is not significantly affected by the presence of food, including high-fat meals, which provides flexibility for patients to take the medication at any time, with or without meals.[5]

The pharmacokinetics of cenobamate are non-linear, as the area under the concentration-time curve (AUC) increases in a greater-than-dose-proportional manner with increasing doses.[24] This non-linearity is particularly evident at doses higher than 300 mg per day and implies that dose increases can lead to disproportionately larger increases in drug exposure, which may contribute to the dose-dependent nature of its adverse effects.[27]

Distribution

Cenobamate has an apparent volume of distribution of approximately 40-50 L, suggesting it distributes beyond the plasma volume into tissues.[16] It is approximately 60% bound to plasma proteins, primarily serum albumin.[8] This binding is independent of drug concentration within the therapeutic range, meaning that changes in plasma concentration do not alter the fraction of bound versus unbound (active) drug.[8]

Metabolic Pathways and Enzymology

Cenobamate undergoes extensive metabolism in the liver, with less than 7% of the dose being excreted as unchanged drug.[6] Two main pathways are responsible for its biotransformation:

1. Glucuronidation: This is the primary metabolic pathway, mediated predominantly by the enzyme uridine 5'-diphospho-glucuronosyltransferase 2B7 (UGT2B7) and to a lesser extent by UGT2B4.[1]
2. Oxidation: A secondary pathway involves oxidation by multiple cytochrome P450 (CYP) enzymes. The main contributors are CYP2E1, CYP2A6, and CYP2B6, with minor roles played by CYP2C19 and CYP3A4/5.[1]

Importantly, no major circulating metabolites (defined as accounting for >10% of total drug-related material in plasma) have been identified in humans, indicating that the parent compound is primarily responsible for the pharmacological activity.[14]

Elimination and Half-Life

The terminal elimination half-life of cenobamate is long, ranging from 50 to 60 hours.[1] This long half-life is a major clinical advantage, as it supports a convenient once-daily dosing regimen that can improve patient adherence and provides stable plasma concentrations, minimizing fluctuations between doses. Steady-state plasma concentrations are achieved after approximately 14 days of consistent once-daily dosing.[1]

While advantageous for adherence, this long half-life is also a liability. It means that in the event of an adverse reaction, the drug and its effects will persist for several days after discontinuation. It also necessitates a very slow, gradual dose reduction over a period of at least two weeks when stopping the medication to avoid the risk of withdrawal seizures or status epilepticus.[19] This represents a critical trade-off between dosing convenience and clinical flexibility.

Elimination of cenobamate and its metabolites occurs primarily through the kidneys. Approximately 88% of an administered dose is recovered in the urine, with an additional 5% recovered in the feces.[8]

Drug-Drug Interaction (DDI) Potential

Cenobamate has a complex and clinically significant drug-drug interaction profile, acting as both an inhibitor and an inducer of key drug-metabolizing enzymes. This profile is not passive; it requires clinicians to actively manage concomitant medications to ensure safety and efficacy.

• Enzyme Induction: Cenobamate is a moderate inducer of CYP3A4 and CYP2B6.[1] This can significantly decrease the plasma concentrations and potential efficacy of drugs that are substrates of these enzymes. A critical example is the interaction with hormonal contraceptives, whose metabolism is induced by CYP3A4. This interaction can lead to contraceptive failure, and therefore, women of childbearing potential must be counseled to use additional or alternative non-hormonal methods of birth control.[16] Other ASMs, such as carbamazepine, and other medications, like midazolam and bupropion, may also have their concentrations reduced.[1] Cenobamate also appears to induce UGT enzymes, which can lead to decreased levels of other ASMs that are primarily metabolized via glucuronidation, such as lamotrigine.[16]
• Enzyme Inhibition: Conversely, cenobamate is an inhibitor of CYP2C19.[1] This can lead to increased plasma concentrations and potential toxicity of drugs metabolized by this enzyme. This is particularly relevant for several commonly co-prescribed ASMs, including phenytoin and phenobarbital, as well as the active metabolite of clobazam (N-desmethylclobazam).[6] When initiating cenobamate, it is often necessary to proactively reduce the dosage of these concomitant medications to avoid toxicity.[28]

The simultaneous induction of CYP3A4 and inhibition of CYP2C19 is a particularly challenging combination, as these are two of the most important enzymes in drug metabolism. This complexity elevates the level of pharmacological knowledge required for its safe prescription and positions it as a medication best managed by specialists familiar with navigating polypharmacy in epilepsy.

Table 2: Clinically Significant Drug-Drug Interactions with Cenobamate

Interacting Drug/Class	Effect of Cenobamate on Drug	Mechanism	Clinical Management Recommendation	Source Snippets
Oral Contraceptives	↓ Concentration / Efficacy	CYP3A4 Induction	Use additional or alternative non-hormonal birth control methods.	14
Phenytoin, Phenobarbital	↑ Concentration	CYP2C19 Inhibition	Monitor plasma levels. Gradually decrease phenytoin dose by up to 50%. Decrease phenobarbital dose as needed.	16
Clobazam	↑ Concentration of active metabolite (N-desmethylclobazam)	CYP2C19 Inhibition	Monitor for adverse effects. Decrease clobazam dose as needed.	6
Lamotrigine	↓ Concentration	UGT Induction	Monitor plasma levels. Increase lamotrigine dose as needed.	16
Carbamazepine	↓ Concentration	CYP3A4 Induction	Monitor plasma levels. Increase carbamazepine dose as needed.	16
Other CYP3A4 Substrates	↓ Concentration	CYP3A4 Induction	Monitor for reduced efficacy. Increase substrate dose as needed.	1
Other CYP2C19 Substrates	↑ Concentration	CYP2C19 Inhibition	Monitor for toxicity. Decrease substrate dose as needed.	1
CNS Depressants (Alcohol, Benzodiazepines)	Additive Sedative Effects	Pharmacodynamic Interaction	Advise patients to avoid or limit alcohol and use caution with other CNS depressants.	1

Clinical Efficacy in the Management of Partial-Onset Seizures

The clinical development program for cenobamate has established its potent efficacy as an adjunctive therapy for adults with uncontrolled partial-onset seizures. The results from its pivotal trials have been notable not only for the magnitude of seizure reduction but also for the unprecedented rates of seizure freedom achieved in a highly drug-resistant population.

Analysis of Pivotal Phase III Trials (Study C013 and Study C017)

The efficacy of cenobamate was demonstrated in two key multicenter, randomized, double-blind, placebo-controlled studies, C013 and C017.[4] The enrolled population consisted of adults with medically refractory focal epilepsy who were experiencing seizures despite stable treatment with one to three concomitant ASMs. These patients had a long history of epilepsy, with a mean duration of approximately 24 years, and a median baseline seizure frequency of 8.5 per 28 days, underscoring the severity and drug-resistant nature of their condition.[1]

Study C013

This study (N=221) compared a target dose of cenobamate 200 mg/day against placebo over a 12-week treatment period (6-week titration, 6-week maintenance).[4] The results were statistically significant and clinically profound:

• Median Percent Seizure Reduction: Patients in the cenobamate group experienced a 55.6% median reduction in seizure frequency from baseline, compared to a 21.5% reduction in the placebo group (p<0.0001).[4]
• Responder Rate: The proportion of patients achieving a ≥50% reduction in seizure frequency was more than double in the treatment arm, at 50% for cenobamate versus 22% for placebo (p<0.0001).[4]
• Seizure Freedom Rate: Most strikingly, during the 6-week maintenance phase, 28% of patients treated with cenobamate achieved 100% seizure freedom, a rate dramatically higher than the 1% observed in the placebo group (p=0.0001).[4]

Study C017

This larger dose-response study (N=437) evaluated three different target doses of cenobamate (100 mg, 200 mg, and 400 mg per day) against placebo over an 18-week treatment period (6-week titration, 12-week maintenance).[31] This trial confirmed the efficacy seen in C013 and established a clear dose-response relationship:

• Median Percent Seizure Reduction: All cenobamate doses were superior to placebo (24% reduction). The median reductions were 35.5% for the 100 mg group, 55% for the 200 mg group, and 55% for the 400 mg group.[31]
• Responder Rate: A dose-dependent increase in the ≥50% responder rate was observed: 40% for 100 mg, 56% for 200 mg, and 64% for 400 mg, all of which were statistically significant compared to the 25% rate for placebo.[4]
• Seizure Freedom Rate: The rate of complete seizure freedom during the 12-week maintenance phase also showed a clear dose-response: 4% for 100 mg, 11% for 200 mg (p=0.0022), and 21% for 400 mg (p<0.0001), compared to just 1% for placebo.[4]

The seizure freedom rates of 21-28% observed across these pivotal trials represent a paradigm shift in the treatment of refractory epilepsy. Historically, seizure freedom rates in placebo-controlled trials for third-line and later ASMs are typically in the low single digits. The performance of cenobamate suggests it is not merely an incremental improvement but a step-change in achievable outcomes for this challenging patient population, effectively redefining the benchmarks for efficacy.

Furthermore, a nuanced analysis of the Study C017 data reveals an interesting dose-efficacy relationship. While the median seizure reduction appeared to plateau at 200 mg (55% for both 200 mg and 400 mg arms), the proportion of patients achieving the best possible outcome—complete seizure freedom—nearly doubled from 11% at 200 mg to 21% at 400 mg.[4] This indicates that while 200 mg may provide the maximal "average" benefit for many patients, higher doses up to 400 mg are necessary to convert a significant number of responders into seizure-free individuals. This finding has important implications for clinical dosing strategy, justifying careful dose escalation in select patients despite the increased risk of adverse effects.

Long-Term Efficacy and Durability

The benefits of cenobamate treatment have been shown to be durable over time. Data from the open-label extension (OLE) phases of the pivotal studies, with follow-up extending up to 94 months, demonstrate that long-term adjunctive treatment is well-tolerated and maintains its efficacy.[32] Patient retention on the drug has been high, with approximately 68% of the overall population and 69% of older adults remaining on treatment at the 3-year mark.[36] Notably, the rates of 100% seizure reduction in the OLE studies appeared to increase over time, reaching over 50% in the overall population by 24 months of treatment, which suggests a continued or even improving benefit with long-term use.[36]

Efficacy in Special Populations

Cenobamate has also demonstrated efficacy in the most difficult-to-treat patient subgroups.

• Highly Refractory Epilepsy: Real-world retrospective analyses have been conducted in cohorts of patients with "ultra-refractory" epilepsy, defined as having failed six or more prior ASMs and often having undergone epilepsy surgery or vagus nerve stimulation, with highly active seizures (e.g., a median of 60 per month).[3] Even in this extremely challenging population, cenobamate produced meaningful seizure outcomes. One such study reported that 42.1% of patients achieved a 75-99% reduction in seizure frequency, and a remarkable 5.3% became completely seizure-free.[3]
• Older Adults (≥65 years): A post-hoc analysis of a large safety study showed that cenobamate has notable efficacy in older adults, a population often underrepresented in clinical trials. Seizure reduction rates were comparable to those seen in the overall study population, and rates of 100% seizure reduction were particularly high, reaching 78.6% by 24 months in this subgroup.[36]

Safety, Tolerability, and Risk Management

The clinical use of cenobamate is accompanied by a well-defined safety and tolerability profile. While generally considered favorable, particularly in the context of its high efficacy, it includes several important risks that require careful management, most notably the risk of DRESS, which has fundamentally shaped its administration protocol.

Common and Dose-Related Adverse Events

The most frequently reported treatment-emergent adverse events (TEAEs) are related to the central nervous system and are typically dose-dependent.[1] These adverse reactions are common to many ASMs and reflect the drug's mechanism of reducing neuronal excitability. The most common TEAEs observed in clinical trials include:

• Somnolence/Drowsiness: Reported in up to 37% of patients.[1]
• Dizziness: Reported in up to 33% of patients.[1]
• Fatigue: Reported in up to 24% of patients.[1]
• Diplopia (Double Vision): Reported in up to 15% of patients.[5]
• Headache: Reported in up to 19% of patients.[32]

Other neurological adverse reactions, such as ataxia, vertigo, and disturbances in gait and coordination, are also common and tend to increase in frequency and severity with higher doses.[5] The significant burden of these CNS side effects can impact a patient's quality of life and may be dose-limiting. However, for many patients with severe, uncontrolled epilepsy, this tolerability burden represents an acceptable trade-off for the potential of achieving significant seizure reduction or freedom. The clinical challenge, therefore, involves carefully titrating the dose to find a balance between efficacy and tolerability, often by concurrently reducing the dosage of other sedating ASMs.[3]

Serious Adverse Reactions and Mitigation Strategies

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

DRESS, also known as multiorgan hypersensitivity, is the most significant identified risk associated with cenobamate.[5] In early clinical development, cases of DRESS, including one fatality, were reported when cenobamate was initiated at higher starting doses (e.g., 50 mg or 100 mg) and titrated rapidly, typically on a weekly basis.[4] This serious, life-threatening adverse event could have potentially halted the drug's development.

However, a pivotal risk mitigation strategy was implemented. A large, open-label safety study (C021), which enrolled 1,339 patients, was conducted using a "start low, go slow" approach. In this study, cenobamate was initiated at a low dose of 12.5 mg/day and titrated slowly, with dose increases occurring only every two weeks.[4] Under this revised titration schedule,

zero cases of DRESS were reported.[4] This successful mitigation is a textbook example of pharmacologically-informed risk management. It demonstrated that the risk of this severe idiosyncratic reaction could be managed by allowing the body to acclimate to the drug over a prolonged period. Consequently, this slow titration schedule is now a mandatory and critical component of the prescribing information, transforming a simple dosing instruction into a core safety feature of the drug.[5]

Suicidal Behavior and Ideation

In line with a known class effect for all antiseizure medications, cenobamate carries an increased risk of suicidal thoughts or behavior.[5] Clinical studies have shown that patients taking ASMs have approximately twice the risk of suicidal behavior or ideation compared to patients taking placebo (a risk of about 1 in 500 people treated).[19] Therefore, all patients treated with cenobamate should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in mood or behavior.[5]

Contraindications and Precautions

• Absolute Contraindication: Cenobamate is absolutely contraindicated in patients with Familial Short QT syndrome.[19] This is due to the drug's dose-dependent QT-shortening effect, which could precipitate life-threatening ventricular arrhythmias in this genetically susceptible population.[34]
• Hypersensitivity: The drug is also contraindicated in patients with a known hypersensitivity to cenobamate or any of its excipients.[23]
• Precautions: Caution should be exercised when co-administering cenobamate with other drugs that are also known to shorten the QT interval, due to the potential for additive effects.[5]

Real-World Safety Data

Post-marketing surveillance, including analyses of the FDA Adverse Event Reporting System (FAERS) database, has largely confirmed the safety profile observed in clinical trials.[40] The most frequently reported adverse events in the real world are neurological disorders (e.g., seizure, fatigue) and injury-related events such as falls.[40] While the FAERS database has inherent limitations (e.g., underreporting, lack of a control group), the data substantiates that cenobamate is generally well-tolerated in clinical practice. One analysis even suggested that cenobamate may have a more favorable profile regarding the risk of falls in the elderly compared to some other commonly used ASMs.[41]

Table 3: Comprehensive Profile of Adverse Reactions by System Organ Class

System Organ Class	Very Common (≥10%)	Common (≥1% to <10%)	Uncommon (<1%)	Rare (<0.1%)	Source Snippets
Nervous System	Somnolence, Dizziness, Headache	Ataxia, Vertigo, Gait Disturbance, Nystagmus, Dysarthria, Memory Impairment	-	-	1
Eye Disorders	Diplopia	Vision Blurred	-	-	1
General Disorders	Fatigue	-	-	-	1
Psychiatric Disorders	-	Confusional State, Irritability, Suicidal Ideation (class effect)	-	-	5
Skin & Subcutaneous	-	Rash	Hypersensitivity	DRESS	1
Investigations	-	Elevated Potassium, Increased Transaminases	-	-	1

Dosing, Administration, and Clinical Patient Management

The safe and effective use of cenobamate is highly dependent on strict adherence to its specific dosing and administration guidelines. The titration protocol, in particular, is not merely a recommendation but a fundamental safety requirement designed to minimize the risk of serious adverse reactions.

Recommended Dosing and Titration Schedule

The dosing regimen for cenobamate is designed as a slow, stepwise escalation to allow for physiological adaptation. This rigid, 11-week titration to the initial maintenance dose is a direct consequence of the DRESS risk identified in early trials and is now considered an integral part of the drug's therapeutic identity.

• Initiation: Treatment must begin at a dose of 12.5 mg once daily for the first two weeks (Weeks 1 and 2).[5]
• Titration: The dose is then increased every two weeks according to the following mandatory schedule:
• Weeks 3 and 4: 25 mg once daily
• Weeks 5 and 6: 50 mg once daily
• Weeks 7 and 8: 100 mg once daily
• Weeks 9 and 10: 150 mg once daily.[5]
• Maintenance: The recommended maintenance dosage of 200 mg once daily is reached at Week 11 and continued thereafter.[5]
• Maximum Dose: If additional seizure control is needed based on clinical response and tolerability, the dose may be further increased above 200 mg. These increases should be made in increments of 50 mg once daily no more frequently than every two weeks, up to a maximum recommended dosage of 400 mg once daily.[5]

This recommended titration schedule should not be exceeded.[5] To facilitate patient adherence to this complex schedule, commercially available titration packs containing the appropriate tablet strengths for each two-week interval are provided.[28]

Administration Guidelines

• Cenobamate is administered orally once daily and can be taken with or without food.[5]
• The tablets are available in multiple strengths (12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg).[12]
• For patients who have difficulty swallowing, the tablets can be crushed and mixed with 25 mL of water to form a suspension. This suspension can be administered immediately either by mouth or via a nasogastric (NG) feeding tube.[20] Detailed instructions are provided in the prescribing information to ensure the full dose is administered.[19]

Dosage Adjustments in Specific Populations

• Hepatic Impairment: For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), drug exposure is increased. The maximum recommended dosage is therefore reduced to 200 mg once daily. Cenobamate is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).[5]
• Renal Impairment: Cenobamate should be used with caution in patients with mild, moderate, or severe renal impairment (creatinine clearance < 90 mL/min), and a dose reduction may be considered. It is not recommended for use in patients with end-stage renal disease or those undergoing hemodialysis.[5]
• Elderly: While no specific dose adjustment is required based on age alone, dosing should be cautious. Elderly patients are more likely to have comorbidities and may experience a higher incidence of certain adverse effects like somnolence, dizziness, and falls, which may necessitate a slower titration or lower maintenance dose.[30]

Patient Monitoring and Counseling

Proactive patient management is essential for the safe use of cenobamate.

• Monitoring: Clinicians should monitor patients for:
• Signs and symptoms of DRESS, particularly during the titration period (e.g., rash, fever, lymphadenopathy).[5]
• Suicidal behavior and ideation, as with all ASMs.[5]
• Neurological adverse reactions such as somnolence, dizziness, and coordination problems, which may require dose adjustment of cenobamate or concomitant ASMs.[5]
• It is also recommended to obtain baseline liver function tests before initiating therapy.[29]
• Counseling: Key counseling points for patients include:
• The critical importance of strictly adhering to the slow titration schedule to minimize safety risks.[23]
• To avoid driving or operating heavy machinery until they have gained sufficient experience to know how cenobamate affects them, due to the high incidence of dizziness and somnolence.[19]
• To use additional or alternative non-hormonal methods of birth control, as cenobamate can reduce the effectiveness of hormonal contraceptives.[19]
• To avoid abrupt discontinuation of the medication. If cenobamate is to be stopped, it should be tapered gradually over a period of at least two weeks, unless safety concerns warrant immediate withdrawal.[19]

The potent efficacy of cenobamate, combined with its significant DDI profile, means that its initiation often requires a re-optimization of the patient's entire ASM regimen. Clinicians must be prepared to proactively adjust the doses of other ASMs as cenobamate is titrated up, both to manage pharmacokinetic interactions (e.g., rising phenytoin levels) and to mitigate additive pharmacodynamic side effects (e.g., reducing other sedating ASMs to manage somnolence).[3] In many cases, the high efficacy of cenobamate may ultimately allow for a reduction in the overall "ASM load," simplifying a patient's regimen, which is a significant benefit for those burdened by polypharmacy.[36]

Regulatory and Commercial Landscape

Cenobamate has successfully navigated the regulatory pathways in major global markets and is positioned as a key therapeutic option for a specific segment of the epilepsy population.

Global Regulatory Approvals

• United States (FDA): Marketed under the brand name Xcopri, cenobamate was first approved by the U.S. Food and Drug Administration (FDA) on November 21, 2019.[12] The initial indication is for the treatment of partial-onset seizures in adults.[24] This approval was a landmark achievement for its developer, SK Life Science, as it marked the first time a Korean pharmaceutical company had independently guided a compound from discovery through to U.S. approval.[31] In April 2024, the FDA granted an expanded approval for alternate methods of administration (crushed tablet in suspension).[20]
• European Union (EMA): Marketed as Ontozry, cenobamate received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in January 2021, followed by full marketing authorization from the European Commission on March 26, 2021.[34] The European indication is more specific than the U.S. label, approved for the adjunctive treatment of focal-onset seizures with or without secondary generalization in adult patients with epilepsy who have not been adequately controlled despite a history of treatment with at least two anti-epileptic medicinal products.[39] This explicitly positions it for the drug-resistant epilepsy population.
• Other Regions: Following its approval in the U.S. and EU, cenobamate has received marketing authorization in other regions, including the United Kingdom (December 2021) and Canada (June 2023).[1] Exclusive licensing agreements are also in place for its development and commercialization in Japan (with Ono Pharmaceutical) and Latin America (with Eurofarma).[38]

Post-Approval Developments and Market Position

• Controlled Substance Scheduling: In the United States, cenobamate is classified as a Schedule V controlled substance by the Drug Enforcement Administration (DEA).[1] This is the least restrictive category of controlled substances and indicates a low potential for abuse or dependence relative to other scheduled drugs.[23]
• Commercialization: The drug is marketed by SK Life Science in the U.S. In Europe, the initial licensing partner was Arvelle Therapeutics, which was subsequently acquired by Angelini Pharma, the current commercializing entity.[38]
• Market Position: Cenobamate is firmly positioned as a high-efficacy therapy for patients with drug-resistant focal epilepsy.[3] The restrictive EU indication, combined with its complex management profile (slow titration, significant DDIs), reinforces its role not as a first- or second-line agent, but as a specialized, high-impact therapy. Its use is best suited for neurologists and epileptologists who manage patients that have failed multiple other treatments. The drug's unprecedented seizure freedom rates serve as its key differentiator in a competitive market. Clinical development is ongoing, with studies investigating its use as monotherapy and its potential efficacy in other seizure types, such as primary generalized seizures.[31]

Synthesis and Concluding Remarks

Cenobamate represents a landmark development in the pharmacotherapy of epilepsy. It is defined by the powerful combination of a novel dual mechanism of action—targeting both voltage-gated sodium channels and GABAA​ receptors—that translates into a level of clinical efficacy previously considered unattainable for many patients with drug-resistant focal epilepsy. The seizure-freedom rates of over 20% observed in its pivotal trials have established a new benchmark for success in this profoundly challenging patient population.

This profound efficacy, however, is inextricably linked to a complex management profile that demands a high degree of clinical expertise and patient adherence. Its long elimination half-life offers the convenience of once-daily dosing but necessitates a prolonged and careful withdrawal period. Its non-linear pharmacokinetics and significant potential for drug-drug interactions require proactive and vigilant management of a patient's entire medication regimen. Most critically, the identified risk of DRESS, a severe hypersensitivity reaction, has led to the adoption of a mandatory, rigid, and slow titration protocol that is central to its safe use. This titration schedule is not merely a guideline but an integral component of the drug's therapeutic identity, a procedural safeguard that is essential for mitigating serious harm.

The clinical value of cenobamate, therefore, lies in its ability to offer hope for seizure control to patients who have exhausted many other options. Harnessing this potential requires a sophisticated clinical approach that balances the pursuit of efficacy with meticulous attention to safety. This includes careful patient selection, comprehensive counseling on risks and benefits, proactive management of polypharmacy, and strict adherence to the prescribed administration protocol.

Future research will continue to define the ultimate place of cenobamate in therapy. The results of ongoing monotherapy trials may broaden its application, and further investigation is needed to determine if its promising preclinical activity in models of generalized epilepsy will translate to clinical efficacy in those seizure types. Additionally, the long-term impact of its potential neuroprotective properties remains an area for future exploration. In conclusion, cenobamate is a transformative but demanding therapeutic agent. Its legacy will be determined by how effectively the clinical community can navigate its inherent complexities to deliver its remarkable benefits to the patients with refractory epilepsy who need them most.

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