Clobazam (DB00349): A Comprehensive Monograph

I. Executive Summary & Drug Identification

Clobazam is a small molecule drug belonging to the 1,5-benzodiazepine class, functioning as a positive allosteric modulator of the gamma-aminobutyric acid type A (GABAA​) receptor. Its primary, FDA-approved indication is for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age and older.[1] Synthesized in the 1960s, clobazam has a long history of use globally as both an anxiolytic and an anticonvulsant. Its unique 1,5-benzodiazepine structure confers a distinct pharmacological profile, most notably a reduced sedative potential compared to traditional 1,4-benzodiazepines.[1] This is attributed to a preferential affinity for the

GABAA​ receptor α2​ subunit, which mediates anxiolytic and anticonvulsant effects, over the α1​ subunit associated with sedation.[1] The drug is extensively metabolized in the liver, primarily by cytochrome P450 (CYP) enzymes, to its major active metabolite, N-desmethylclobazam (norclobazam). This metabolite contributes significantly to the overall therapeutic effect and possesses a substantially longer elimination half-life than the parent compound, a critical factor in the drug's clinical pharmacology, time to steady state, and withdrawal management.[5] Clobazam is a DEA Schedule IV controlled substance, reflecting its potential for abuse, misuse, and dependence.[1]

The extensive catalog of identifiers associated with clobazam reflects its long history and comprehensive study across numerous chemical, biological, and clinical databases. This breadth of data underscores its well-established nature as a therapeutic agent, even though its specific approval by the U.S. Food and Drug Administration (FDA) for LGS is relatively recent, positioning it as a well-characterized compound repurposed for a critical, high-need indication.[1]

Table 1: Clobazam Key Identifiers and Physicochemical Properties

Property	Value	Source(s)
Drug Name	Clobazam	User Query
DrugBank ID	DB00349	1
Type	Small Molecule	User Query
CAS Number	22316-47-8	1
DEA Schedule	IV (Controlled Substance)	1
IUPAC Name	7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione	1
Molecular Formula	C16​H13​ClN2​O2​	62
Molecular Weight	300.74 g/mol	63
SMILES	CN1C(=O)CC(=O)N(C2=C1C=CC(=C2)Cl)C3=CC=CC=C3	1
InChIKey	CXOXHMZGEKVPMT-UHFFFAOYSA-N	1
Physical Description	White to Off-White Crystalline Solid	1
Melting Point	162-166 °C	34
Solubility	Slightly soluble in water; freely soluble in methylene chloride; soluble in DMSO and ethanol	34

II. Introduction: A Unique 1,5-Benzodiazepine

Historical Development and Regulatory Journey

Clobazam's history is one of a well-established medication that experienced a modern renaissance. First synthesized in 1966 and published in 1969, it emerged from the era of benzodiazepine discovery that followed the serendipitous synthesis of chlordiazepoxide.[1] It was initially developed with the goal of creating an anxiolytic with greater efficacy and fewer of the hallmark side effects of its predecessors, particularly sedation.[3] This led to its marketing as an anxiolytic in Europe and other global markets starting in 1975 and as an anticonvulsant since 1984.[1] For decades, it was used in over 100 countries for a range of anxiety and epilepsy indications, generating a substantial body of clinical experience.[3]

In stark contrast to its long international history, clobazam was not approved in the United States until October 21, 2011. On this date, the FDA granted approval for its use as an adjunctive treatment for the particularly challenging seizures associated with Lennox-Gastaut Syndrome (LGS) in patients aged two years and older.[1] This approval effectively repositioned clobazam in the U.S. market not as a general anxiolytic but as a specialized, evidence-based therapy for a severe and refractory form of epilepsy, making it a "rediscovered" therapeutic agent for a new generation of clinicians.[9]

The Significance of the 1,5-Benzodiazepine Structure

The unique clinical profile of clobazam is rooted in its distinct chemical structure. It is classified as a 1,5-benzodiazepine, a designation derived from the placement of nitrogen atoms at the 1 and 5 positions of its seven-membered diazepine ring.[2] This arrangement fundamentally distinguishes it from the vast majority of clinically used benzodiazepines, such as diazepam and clonazepam, which are 1,4-benzodiazepines with nitrogen atoms at the 1 and 4 positions.[2]

This seemingly subtle shift in one nitrogen atom's location is not a minor chemical detail; it is the molecular origin of clobazam's differentiated pharmacological and clinical properties. The change in the heterocyclic ring's geometry alters the molecule's three-dimensional shape and electron distribution. This, in turn, modifies how it interacts with its biological target, the GABAA​ receptor. The structural difference leads directly to an altered binding affinity for specific receptor subunits, which is the foundational reason for its reduced sedative potential relative to its 1,4-benzodiazepine counterparts. This structure-activity relationship provides a clear, mechanistic explanation for the clinical advantages that were sought during its initial development and have been borne out in clinical trials and practice.[1]

III. Clinical Pharmacology: Mechanism of Action and Pharmacodynamics

Positive Allosteric Modulation of the GABA-A Receptor

Clobazam exerts its therapeutic effects by modulating the primary inhibitory neurotransmitter system in the central nervous system. Like all benzodiazepines, it does not directly activate the GABAA​ receptor. Instead, it functions as a positive allosteric modulator.[3] The drug binds to a distinct site on the receptor complex, known as the benzodiazepine binding site, which is located at the interface between the

α and γ subunits.[4]

This binding event induces a conformational change in the receptor that increases its affinity for the endogenous neurotransmitter, gamma-aminobutyric acid (GABA). By enhancing GABA's natural effect, clobazam increases the frequency of the receptor's associated chloride ion channel opening.[15] The subsequent influx of negatively charged chloride ions (

Cl−) into the neuron leads to hyperpolarization of the cell membrane. This hyperpolarized state makes the neuron less likely to fire an action potential in response to excitatory stimuli, thereby dampening overall neuronal excitability and suppressing the abnormal, synchronous electrical activity that underlies epileptic seizures.[6]

Subunit Selectivity: The Key to a Favorable Profile

The key to clobazam's distinct clinical profile lies in its interaction with the diverse subtypes of the GABAA​ receptor. These receptors are heteropentameric complexes assembled from a variety of subunits (α,β,γ, etc.), and the specific subunit composition determines the receptor's pharmacological properties. Research has functionally segregated the roles of the most common α subunits: receptors containing the α1​ subunit are primarily associated with mediating sedative and amnesic effects, whereas those containing the α2​ subunit are more closely linked to the anxiolytic and anticonvulsant effects of benzodiazepines.[1]

Clobazam and its principal active metabolite, N-desmethylclobazam, exhibit a significantly greater binding affinity for GABAA​ receptors containing the α2​ subunit compared to those containing the α1​ subunit.[1] This is a critical point of differentiation from classic 1,4-benzodiazepines like clonazepam, which bind non-selectively and with high affinity to receptors containing

α1​,α2​,α3​, and α5​ subunits.[4] This preferential binding allows clobazam to more selectively enhance the inhibitory neurotransmission in circuits responsible for seizure control and anxiety reduction, while having a relatively lesser impact on the circuits that govern sedation and arousal.

Partial Agonist Activity

Further contributing to its favorable tolerability is the characterization of clobazam as a partial agonist at the GABAA​ receptor.[1] Unlike full agonists (e.g., diazepam), which elicit a maximal response upon binding, a partial agonist produces a submaximal response even when all available receptors are occupied. This property may create a "ceiling effect" for some of its pharmacological actions, particularly sedation.

The combination of these two pharmacodynamic properties—preferential α2​-subunit affinity and partial agonism—provides a powerful, two-pronged mechanistic explanation for clobazam's central clinical advantage. It achieves robust anticonvulsant efficacy by effectively targeting α2​-containing receptors, while the reduced affinity for and partial agonism at α1​-containing receptors mitigates the burden of sedation. This optimized pharmacology explains why patients in clinical trials reported less severe sedation compared to those treated with 1,4-benzodiazepines and why clobazam is often a more viable option for long-term therapy where cognitive side effects can be dose-limiting.[3]

IV. Pharmacokinetics: The Journey of Clobazam and its Active Metabolite

The clinical behavior of clobazam is dictated by a complex pharmacokinetic profile that is dominated by its primary active metabolite, N-desmethylclobazam. A thorough understanding of the absorption, distribution, metabolism, and excretion (ADME) of both the parent drug and this metabolite is essential for safe and effective prescribing.

Absorption and Distribution

Following oral administration, clobazam is rapidly and extensively absorbed, with peak plasma concentrations (Tmax​) occurring between 0.5 and 4 hours.[6] Its pharmacokinetics are linear and dose-proportional across the clinically relevant dose range of 5 to 160 mg/day, meaning that increases in dose lead to predictable increases in plasma concentration.[6] A key practical advantage is the negligible effect of food on its absorption; it can be administered as an intact tablet, crushed in applesauce, or as an oral suspension without significantly altering the extent of absorption, which offers considerable flexibility in administration, particularly for pediatric and dysphagic patients.[6]

As a lipophilic substance, clobazam has a large apparent volume of distribution of approximately 100 L, indicating that it distributes widely from the bloodstream into the body's tissues.[6] Both clobazam and its metabolite, N-desmethylclobazam, are highly bound to plasma proteins (approximately 90%), primarily albumin.[14]

Metabolism: The Central Role of CYP Enzymes

Clobazam undergoes extensive hepatic metabolism, with less than 3% of an administered dose being excreted unchanged.[14] The metabolic process is governed by the cytochrome P450 (CYP) enzyme system and proceeds along two main pathways.

The primary and most clinically significant pathway is N-demethylation, which converts clobazam into its active metabolite, N-desmethylclobazam (N-CLB), also known as norclobazam. This crucial conversion is catalyzed predominantly by CYP3A4, with minor contributions from CYP2C19 and CYP2B6.[6]

The second step involves the clearance of N-CLB. N-CLB is further metabolized via hydroxylation to inactive compounds. This elimination pathway is catalyzed almost exclusively by CYP2C19.[6] This heavy reliance on a single, highly polymorphic enzyme for the clearance of the main active moiety is a central feature of clobazam's pharmacology and a primary source of potential drug-drug and drug-gene interactions.

The Active Metabolite: N-desmethylclobazam (N-CLB)

The clinical pharmacology of clobazam cannot be understood without focusing on N-CLB. Following repeated administration, N-CLB becomes the major circulating active substance in the body.[7] At steady-state, plasma concentrations of N-CLB are typically

3 to 5 times higher than those of the parent compound, clobazam.[7] N-CLB itself is a potent anticonvulsant and, like its parent, exhibits a preferential affinity for

α2​- over α1​-containing GABAA​ receptors, contributing substantially to the overall therapeutic and side-effect profile of the drug.[4]

Excretion and Half-Life

The metabolites of clobazam are cleared from the body primarily through renal excretion, with approximately 82% of a dose recovered in the urine and 11% in the feces.[5] The elimination half-lives of the parent drug and its active metabolite are markedly different and have profound clinical implications. The mean elimination half-life (

t1/2​) of clobazam is approximately 36 to 42 hours. In contrast, the elimination half-life of N-CLB is significantly longer, ranging from 59 to 82 hours.[5]

This extended half-life of the dominant active metabolite dictates several key aspects of clobazam therapy. First, the time required to reach steady-state concentration, where the rate of drug administration equals the rate of elimination, is prolonged. While clobazam itself may reach steady state within about a week, the therapeutically crucial N-CLB can take up to three weeks to achieve its steady-state level.[14] This means that the full clinical effect of a dose adjustment may not be evident for several weeks, necessitating patience and a slow titration schedule. Second, the long half-life of N-CLB provides a degree of "auto-tapering" upon discontinuation, but it also means that withdrawal symptoms can be both delayed in onset and prolonged in duration. This underscores the absolute necessity of a very gradual, structured dose reduction when discontinuing the drug to allow the central nervous system to slowly re-adapt.

Table 2: Summary of Pharmacokinetic Parameters for Clobazam and N-desmethylclobazam

Parameter	Clobazam (Parent Drug)	N-desmethylclobazam (N-CLB, Active Metabolite)	Source(s)
Time to Peak (Tmax​)	0.5 - 4 hours	36 - 72 hours (after CLB dose)	6
Elimination Half-life (t1/2​)	36 - 42 hours	59 - 82 hours	5
Plasma Protein Binding	~90%	~90%	14
Primary Metabolic Enzyme	Formation: CYP3A4 (major), CYP2C19 (minor)	Elimination: CYP2C19 (major)	6
Steady-State Concentration	Lower	3-5 times higher than Clobazam	7

V. Clinical Efficacy in Lennox-Gastaut Syndrome

The approval of clobazam in the United States is predicated on robust evidence of its efficacy in Lennox-Gastaut Syndrome, one of the most challenging epilepsy syndromes to treat.

Lennox-Gastaut Syndrome (LGS): A Challenging Indication

LGS is a severe, rare, and complex form of childhood-onset epilepsy that constitutes an epileptic encephalopathy. It is defined by a triad of features: multiple, medically refractory seizure types, most notably tonic and atonic seizures that often result in sudden falls ("drop seizures"); a characteristic electroencephalogram (EEG) pattern of slow spike-and-wave complexes; and cognitive impairment or developmental delay.[2] The seizures are frequent, often occurring daily, and are notoriously difficult to control, persisting despite aggressive polypharmacy with multiple antiepileptic drugs (AEDs).[2]

The Pivotal Phase III CONTAIN Trial (OV-1012 / NCT00518713)

The cornerstone of clobazam's FDA approval for LGS is the CONTAIN trial, a large, multicenter, randomized, double-blind, placebo-controlled study designed to rigorously assess its efficacy and safety.[25]

• Study Design and Population: The trial enrolled 238 patients aged 2 to 60 years with a confirmed diagnosis of LGS who were experiencing frequent drop seizures despite treatment with other AEDs. Following a 4-week baseline period to establish seizure frequency, patients were randomized to one of three target doses of clobazam (low: 0.25 mg/kg/day; medium: 0.5 mg/kg/day; high: 1.0 mg/kg/day, with a maximum of 40 mg/day) or placebo. The treatment phase consisted of a 3-week titration period followed by a 12-week maintenance period.[27]
• Primary Efficacy Endpoint: The primary outcome was the percentage decrease in the mean weekly rate of drop seizures during the 12-week maintenance period compared to the 4-week baseline.[26]
• Efficacy Results: The trial met its primary endpoint, demonstrating a clear, statistically significant, and dose-dependent reduction in drop seizures. Compared to a 12.1% decrease in the placebo group, the average weekly drop seizure rate decreased by 41.2% in the low-dose group (p=0.012), 49.4% in the medium-dose group (p=0.0015), and 68.3% in the high-dose group (p<0.0001).[25]
• Responder Rates: This dose-dependent effect was also reflected in responder rates, defined as the percentage of patients achieving a ≥50% reduction in drop seizures. While 31.6% of placebo patients were responders, the rates were 43.4% (not significant), 58.6% (significant), and 77.6% (highly significant) for the low-, medium-, and high-dose clobazam groups, respectively.[25]
• Secondary Endpoints: In addition to seizure reduction, both physicians' and caregivers' global assessments of patients' overall condition showed significant improvement with clobazam treatment compared to placebo.[27]

Long-Term Efficacy and the Question of Tolerance

A critical concern with the chronic use of any benzodiazepine in epilepsy is the potential for the development of tolerance, where the drug's effectiveness wanes over time. The CONTAIN trial showed no evidence of tolerance during its 3-month maintenance period.[29] More importantly, data from subsequent open-label extension (OLE) studies, where patients continued on clobazam for extended periods, have demonstrated sustained efficacy.[25]

In the OV-1004 OLE study, patients who completed the pivotal trials were followed for up to several years. Interim results showed that the median percentage decrease in weekly drop seizures was not only maintained but appeared to improve over time, reaching 71.1% at 3 months and 91.6% at 24 months.[32] This evidence of durable, long-term efficacy directly challenges the conventional wisdom that benzodiazepine effectiveness in epilepsy is inevitably short-lived. This sustained effect is a key feature that distinguishes clobazam from many of its class counterparts and solidifies its role as a foundational adjunctive therapy in the long-term management of LGS.[2]

Table 3: Key Efficacy Outcomes from the Pivotal CONTAIN Trial

Efficacy Outcome	Placebo (n=57)	Clobazam Low-Dose (0.25 mg/kg/day; n=53)	Clobazam Medium-Dose (0.5 mg/kg/day; n=58)	Clobazam High-Dose (1.0 mg/kg/day; n=49)
Mean % Reduction in Weekly Drop Seizures	12.1%	41.2% (p=0.0120)	49.4% (p=0.0015)	68.3% (p<0.0001)
Responder Rate (≥50% Reduction)	31.6%	43.4% (p=0.3383)	58.6% (p=0.0159)	77.6% (p<0.0001)
Responder Rate (≥75% Reduction)	12%	Not Reported	38% (p≤0.05)	61% (p<0.001)

Data sourced from.[27]

VI. Broader Therapeutic Applications and Off-Label Use

While clobazam's U.S. approval is narrowly focused on LGS, its long history of global use reveals a much broader spectrum of anticonvulsant and anxiolytic activity. This wider utility is important for understanding its full therapeutic potential.

• Anxiety Disorders: Clobazam was originally developed and continues to be approved in many countries, including the United Kingdom and Australia, for the short-term (typically 2–4 weeks) relief of acute, severe, or disabling anxiety, with or without associated insomnia.[1]
• Other Epilepsy Syndromes (Off-Label in the U.S.): Clobazam's efficacy is not limited to the seizure types seen in LGS. Its established utility in other epilepsy syndromes highlights its broad-spectrum action.
• Dravet Syndrome: Although an off-label use in the U.S., clobazam is widely considered a first-line adjunctive agent for treating the refractory seizures associated with Dravet syndrome, another severe developmental and epileptic encephalopathy of childhood.[23]
• Refractory Epilepsy: Clobazam is used globally as an adjunctive therapy for various forms of treatment-resistant epilepsy in both children and adults. Health Canada, for example, has approved it as an add-on therapy for generalized tonic-clonic, myoclonic, and focal impaired awareness seizures.[1]
• Catamenial Epilepsy: The drug is also used off-label for catamenial epilepsy, a condition where seizure frequency increases in relation to the menstrual cycle.[37]
• Refractory Status Epilepticus: In some clinical settings, clobazam is employed as an adjunctive therapy for refractory status epilepticus.[37]

The broad spectrum of activity demonstrated across these varied indications suggests that clobazam's fundamental mechanism of enhancing GABAergic inhibition is effective against a wide range of neuronal hyperexcitability states. The specific FDA approval for LGS was a strategic regulatory decision based on the successful execution of a high-quality clinical trial in a well-defined orphan disease population. However, this narrow U.S. indication should not obscure the drug's wider, well-established utility in the broader field of epileptology.

VII. Safety, Tolerability, and Risk Management

The use of clobazam requires a comprehensive understanding of its safety profile, which includes common, manageable side effects as well as severe, life-threatening risks inherent to the benzodiazepine class.

Adverse Effects

• Common Adverse Effects: The most frequently reported adverse events in clinical trials are primarily related to CNS depression. These include somnolence (drowsiness) or sedation, lethargy, ataxia (poor coordination), and drooling. Other common effects include pyrexia (fever) and constipation.[29] Somnolence and sedation are notably dose-related, are most prominent during the first month of treatment, and may diminish with continued therapy as some degree of tolerance to this effect develops.[29]
• Serious Dermatological Reactions: Clobazam carries a risk of rare but potentially fatal skin reactions. These include Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which cause severe blistering and peeling of the skin and mucous membranes.[39] The risk for these reactions is highest during the first 8 weeks of treatment or upon re-initiation of therapy. Another serious reaction is Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a multiorgan hypersensitivity syndrome that typically presents with rash, fever, and internal organ involvement (e.g., liver, kidneys) and can be life-threatening.[29] Any patient developing a rash while on clobazam requires immediate medical evaluation, and the drug should be discontinued unless the rash is clearly not drug-related.

FDA Boxed Warnings: A Triad of Critical Risks

The FDA has mandated a boxed warning for all benzodiazepines, including clobazam, highlighting three critical, life-threatening risks.

1. Risks from Concomitant Use with Opioids: The concurrent use of clobazam with opioid medications, alcohol, or other CNS depressants (e.g., barbiturates, other sedatives) can result in profound sedation, severe respiratory depression, coma, and death.[29] This is an additive pharmacodynamic effect, and such combinations should be reserved only for patients for whom alternative treatment options are inadequate, using the lowest possible doses for the shortest duration.
2. Abuse, Misuse, and Addiction: As a DEA Schedule IV controlled substance, clobazam carries a risk of abuse, misuse, and addiction. These behaviors can lead to overdose and death, and the risk exists even when the medication is taken as prescribed.[41] Patients should be assessed for risk factors prior to prescribing and monitored for the development of substance use disorders during treatment.
3. Dependence and Withdrawal Reactions: The continued use of clobazam, even for short periods of several days to weeks, leads to the development of physical dependence. Abrupt discontinuation or an overly rapid dose reduction can precipitate a severe and potentially life-threatening withdrawal syndrome. Symptoms can include rebound seizures, status epilepticus, psychosis, hallucinations, tremors, and severe anxiety.[34]

Contraindications

Clobazam is contraindicated in patients with:

• A known history of hypersensitivity to clobazam or other benzodiazepines.[44]
• Myasthenia gravis, due to the risk of exacerbating muscle weakness.[5]
• Severe respiratory insufficiency.[5]
• Sleep apnea syndrome.[5]
• Severe hepatic insufficiency, due to the risk of precipitating encephalopathy.[5]

Precautions and Special Populations

• Suicidal Behavior and Ideation: Like all AEDs, clobazam carries a small but significant risk (approximately 1 in 500 patients) of increasing suicidal thoughts or behavior. Patients should be monitored for the emergence or worsening of depression, unusual changes in mood, or suicidality.[39]
• Pregnancy and Lactation: Use during pregnancy may pose risks to the fetus. Administration late in pregnancy can lead to neonatal sedation (respiratory depression, hypotonia) and withdrawal symptoms in the newborn, sometimes referred to as "floppy infant syndrome".[34] Clobazam is excreted in breast milk and should generally be avoided during breastfeeding.[34]
• Elderly and Patients with Organ Impairment: Elderly patients and those with renal or hepatic impairment may exhibit increased sensitivity to the effects of clobazam and may have reduced clearance. Lower starting doses and more cautious titration are recommended in these populations.[45]

Tolerance, Dependence, and Withdrawal Management

The safe management of clobazam therapy is critically dependent on understanding and mitigating the risks of tolerance, dependence, and withdrawal.

• Tolerance: Tolerance is a neuroadaptive process where the brain's response to a constant drug concentration diminishes over time, primarily through mechanisms like the downregulation of GABAA​ receptors.[47] While this can lead to a loss of efficacy, long-term studies in LGS suggest that tolerance to clobazam's anticonvulsant effects is less of a clinical limitation than with many other benzodiazepines.[2]
• Dependence: It is crucial to distinguish between physical dependence and addiction. Physical dependence is the physiological state of adaptation to the drug, where the body requires its continued presence to function normally. It is an expected outcome of continuous benzodiazepine therapy and can occur even with appropriate therapeutic use.[48] Addiction is a complex behavioral disorder characterized by compulsive drug use despite harmful consequences.
• Withdrawal Management: Due to physical dependence, clobazam must never be discontinued abruptly. A gradual and supervised dose reduction is mandatory to prevent a severe withdrawal syndrome. A common tapering strategy involves decreasing the total daily dose by 5–10 mg each week, allowing the central nervous system to gradually re-equilibrate to the absence of the drug.[38] The long half-life of N-CLB means that withdrawal symptoms may be delayed in onset and prolonged, requiring an extended tapering period.

The safety profile of clobazam presents a clinical dichotomy. Its unique pharmacology may offer better day-to-day tolerability with less sedation compared to its class counterparts. However, it carries the full weight of the severe, life-threatening risks common to all benzodiazepines, as highlighted in the FDA's boxed warnings. Safe prescribing is therefore a careful balance, requiring diligent patient selection, comprehensive counseling on the risks of concomitant CNS depressant use and addiction, and a meticulously planned, slow taper upon discontinuation.

VIII. Drug Interactions and Pharmacogenomics

The clinical effects of clobazam can be significantly altered by co-administered medications and by an individual's genetic makeup, primarily through interactions involving the cytochrome P450 enzyme system.

Pharmacodynamic Interactions

The most significant pharmacodynamic interactions involve additive CNS depression. When clobazam is combined with other CNS depressants—including opioids, alcohol, barbiturates, other benzodiazepines, and sedating antihistamines—the risk of sedation, cognitive and motor impairment, respiratory depression, and coma is substantially increased.[12] Notably, concomitant consumption of alcohol can also increase the bioavailability of clobazam by approximately 50%, further potentiating its effects.[5]

Pharmacokinetic Interactions (CYP450-Mediated)

Clobazam is both a substrate for and an inhibitor of CYP enzymes, creating a complex potential for bidirectional interactions.

• Clobazam as a Substrate:
• CYP3A4: Strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase plasma concentrations of the parent drug, clobazam. Conversely, strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, phenobarbital) can decrease clobazam levels but may paradoxically accelerate its conversion to the active metabolite, N-CLB.[20]
• CYP2C19: This pathway is of paramount clinical importance as it is responsible for clearing the highly active, long-acting N-CLB.
• Strong or moderate CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, omeprazole, cannabidiol) can significantly decrease the clearance of N-CLB, leading to its accumulation and an increased risk of dose-related adverse effects.[45] The interaction with CBD is particularly relevant as it is often co-prescribed with clobazam in patients with LGS and Dravet syndrome.
• CYP2C19 inducers (e.g., rifampin) can increase the clearance of N-CLB, potentially reducing the overall therapeutic efficacy of clobazam.[50]
• Clobazam as an Enzyme Inhibitor/Inducer:
• CYP2D6 Inhibition: Clobazam is a moderate inhibitor of CYP2D6. It can significantly increase the plasma concentrations of drugs that are substrates of this enzyme (e.g., dextromethorphan, many antidepressants, and antipsychotics). Co-administration may require a dose reduction of the CYP2D6 substrate.[16]
• CYP3A4 Induction: There is evidence suggesting clobazam is a weak inducer of CYP3A4, which could potentially reduce the effectiveness of certain co-administered drugs, including some hormonal contraceptives.[16]

Pharmacogenomics: The Role of CYP2C19 Polymorphisms

The gene encoding the CYP2C19 enzyme is highly polymorphic, leading to significant inter-individual variability in metabolic capacity. Individuals can be classified into several phenotypes, including ultrarapid metabolizers (UMs), normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs).[16]

This genetic variation has profound implications for clobazam therapy. CYP2C19 poor metabolizers (PMs), who have little to no functional CYP2C19 enzyme activity, are unable to efficiently clear N-CLB. Consequently, these individuals experience 3- to 5-fold higher plasma concentrations of N-CLB at steady state compared to normal metabolizers receiving the same dose.[51] This genetic predisposition places them at a significantly higher risk for dose-related toxicity, such as excessive sedation and ataxia.

Given this, for patients who are known to be CYP2C19 PMs, clinical guidelines recommend initiating clobazam at a lower starting dose (5 mg/day regardless of weight) and employing a slower, more cautious titration schedule to avoid adverse effects stemming from N-CLB accumulation.[49]

Table 4: Clinically Significant Drug-Drug Interactions with Clobazam

Interacting Drug/Class	Mechanism of Interaction	Effect on Clobazam/N-CLB or Co-administered Drug	Clinical Recommendation	Source(s)
Opioids, Alcohol, other CNS Depressants	Additive Pharmacodynamic CNS Depression	Increased risk of profound sedation, respiratory depression, coma, death	Avoid combination if possible. If necessary, use lowest effective doses and minimum duration; monitor closely.	43
Strong/Moderate CYP2C19 Inhibitors (e.g., fluconazole, fluvoxamine, omeprazole, cannabidiol)	Inhibition of N-CLB metabolism	Markedly increased plasma concentrations of N-CLB, increasing risk of toxicity	Dose reduction of clobazam may be necessary. Monitor for adverse effects.	45
Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin)	Induction of clobazam metabolism to N-CLB	Decreased clobazam levels; may increase N-CLB formation. Net effect on efficacy can be complex.	Monitor clinical response; dose adjustment may not be required but should be considered based on efficacy and tolerability.	20
CYP2D6 Substrates (e.g., dextromethorphan, paroxetine, metoprolol)	Inhibition of CYP2D6 by Clobazam	Increased plasma concentrations of the co-administered drug	Dose reduction of the CYP2D6 substrate may be necessary.	16

IX. Comparative Analysis: Clobazam in the Benzodiazepine Class

Clobazam's position within the therapeutic armamentarium for epilepsy is best understood by comparing it directly to the more traditional 1,4-benzodiazepines, such as clonazepam and diazepam. It is not merely an alternative but a distinct agent with a different profile of risks and benefits.

Clobazam vs. 1,4-Benzodiazepines (Clonazepam, Diazepam)

• Structure and Pharmacodynamics: The foundational difference is the 1,5-diazepine structure of clobazam versus the 1,4-diazepine structure of clonazepam and diazepam.[3] This leads to clobazam's key pharmacodynamic advantages: a preferential affinity for α2​-containing GABAA​ receptors and a partial agonist profile. In contrast, diazepam and clonazepam are non-selective, full agonists, binding with high affinity to multiple α subunits, including the sedation-mediating α1​ subunit.[1]
• Clinical Roles and Efficacy: These pharmacological differences translate into distinct clinical roles.
• Acute vs. Chronic Therapy: Intravenous diazepam and lorazepam are mainstays for the acute treatment of status epilepticus, where their rapid onset and potent, non-selective CNS depression are desired to terminate seizures quickly.[54] Clobazam, along with clonazepam, is primarily used for chronic, oral adjunctive therapy in refractory epilepsy.[54]
• Sustained Efficacy: Clobazam has demonstrated robust, long-term efficacy in the difficult-to-treat LGS population, with evidence suggesting that tolerance to its anticonvulsant effects is less of a clinical impediment than is often observed with the chronic use of clonazepam.[2]
• Side Effect Profile: The most significant clinical differentiator is clobazam's improved tolerability profile. Due to its targeted pharmacodynamic action, clobazam is associated with a lower incidence and severity of sedation, cognitive impairment, and amnesia compared to equipotent doses of 1,4-benzodiazepines.[1] Some studies have even suggested that in certain contexts, clobazam may enhance cognitive performance, a stark contrast to the well-documented cognitive-dulling effects of other benzodiazepines.[3]

This comparative analysis clarifies that different benzodiazepines are optimized for different clinical tasks. Diazepam is a tool for emergency intervention, designed for rapid and profound CNS depression. Clobazam, conversely, is a tool for long-term maintenance therapy, designed to provide sustained seizure control with minimal impact on daily functioning, cognition, and behavior. This distinction is particularly vital in pediatric populations like those with LGS, where preserving cognitive development is a paramount treatment goal.

X. Dosing, Administration, and Therapeutic Monitoring

Effective and safe use of clobazam requires adherence to established dosing guidelines, proper administration techniques, and, when necessary, the use of therapeutic drug monitoring.

Available Formulations

In the United States, clobazam is available in three oral formulations, providing flexibility for different patient needs [38]:

• Tablets (Onfi® and generics): Available in 10 mg and 20 mg strengths. The tablets are scored and can be swallowed whole, split in half, or crushed and mixed with a soft food like applesauce.[38]
• Oral Suspension (Onfi® and generics): A 2.5 mg/mL liquid formulation that allows for precise dose titration, which is particularly useful in pediatric patients and those requiring very low doses.[38]
• Oral Film (Sympazan®): A film strip placed on the tongue where it dissolves without the need for water. Available in 5 mg, 10 mg, and 20 mg strengths, it provides an alternative for patients with difficulty swallowing (dysphagia).[38]

Dosing and Administration

Dosing is initiated low and titrated gradually to effect, based on patient weight and clinical response.

• Patients weighing > 30 kg: The usual starting dose is 10 mg per day, administered in two divided doses (5 mg twice daily). The dose is then titrated upwards as needed and tolerated, typically on a weekly basis, to a maximum recommended dose of 40 mg per day.[38]
• Patients weighing ≤ 30 kg: The usual starting dose is 5 mg per day, given as a single dose. The dose is titrated as needed to a maximum recommended dose of 20 mg per day.[38]
• Special Populations:
• Elderly Patients: A starting dose of 5 mg per day is recommended due to potential for increased sensitivity and reduced clearance.[46]
• Known CYP2C19 Poor Metabolizers: A starting dose of 5 mg per day is recommended to mitigate the risk of toxicity from accumulation of N-desmethylclobazam.[51]

Therapeutic Drug Monitoring (TDM)

Measuring serum concentrations of clobazam and N-desmethylclobazam can be a valuable tool to optimize therapy, assess adherence, and investigate cases of unexpected toxicity or lack of efficacy.[21] Blood samples should be drawn at trough (just before the next scheduled dose) after steady state has been achieved (approximately 3 weeks).

The established therapeutic reference ranges are:

• Clobazam: 30–300 ng/mL [58]
• N-desmethylclobazam (N-CLB): 300–3000 ng/mL [58]

Concentrations are generally considered potentially toxic when clobazam levels exceed 500 ng/mL or N-CLB levels exceed 5000 ng/mL.[58] The fact that the therapeutic and toxic ranges for N-CLB are an order of magnitude higher than those for the parent drug numerically reinforces the pharmacokinetic data: N-CLB is the dominant circulating moiety. When interpreting TDM results, the N-CLB level is arguably the more critical value for assessing steady-state exposure and risk, particularly if a CYP2C19-mediated drug interaction or genetic polymorphism is suspected.

Table 5: Dosing Recommendations and Therapeutic Ranges

Patient Population	Starting Daily Dose	Maximum Daily Dose	Therapeutic Trough Range (Clobazam)	Therapeutic Trough Range (N-CLB)
Adults & Children > 30 kg	10 mg (5 mg BID)	40 mg	30 - 300 ng/mL	300 - 3000 ng/mL
Children ≤ 30 kg	5 mg (5 mg QD)	20 mg	30 - 300 ng/mL	300 - 3000 ng/mL
Elderly	5 mg (5 mg QD)	40 mg	30 - 300 ng/mL	300 - 3000 ng/mL
Known CYP2C19 Poor Metabolizers	5 mg (5 mg QD)	Titrate cautiously based on response and tolerability	30 - 300 ng/mL	300 - 3000 ng/mL (Target lower end of range)

Data sourced from.[38]

XI. Global Regulatory Status and Brand Information

Regulatory History

Clobazam has a bifurcated regulatory history, reflecting its long-standing use in many parts of the world and its more recent, specialized introduction to the U.S. market.

• International: It was first approved as an anxiolytic in the 1970s and as an anticonvulsant in the 1980s in Europe and other regions.[1] It is licensed in numerous countries for indications including short-term anxiety management and as an add-on therapy for refractory epilepsy.[35] In 2005, Health Canada approved clobazam as an add-on therapy for generalized tonic-clonic, myoclonic, and focal impaired awareness seizures.[1]
• United States: The U.S. Food and Drug Administration (FDA) approved clobazam on October 21, 2011. The approval was specifically for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients aged two years and older, based on the strength of the pivotal CONTAIN trial.[8]

International Brand Names

To aid in global identification, clobazam is marketed under several different brand names.

• United States: Onfi®, Sympazan® [38]
• Europe/International: Frisium®, Urbanyl®, Urbanol® [1]

Controlled Substance Status

Reflecting its potential for abuse and physical dependence, clobazam is a controlled substance in most jurisdictions. In the United States, it is classified as a Schedule IV drug under the Controlled Substances Act.[1] It holds similar classifications in other countries, such as Schedule IV in Canada and Class C in the United Kingdom, necessitating prescription controls and monitoring.[5]

XII. Conclusion

Clobazam (DB00349) is a 1,5-benzodiazepine with a unique and well-characterized profile that distinguishes it from classic 1,4-benzodiazepines. Its distinct molecular structure confers a preferential affinity for the α2​ subunit of the GABAA​ receptor and a partial agonist activity, a combination that provides robust anticonvulsant and anxiolytic effects with a reduced propensity for sedation and cognitive impairment.

Its pharmacokinetic profile is defined by its extensive hepatic metabolism via CYP3A4 and CYP2C19 and, most critically, by its long-acting, pharmacologically active metabolite, N-desmethylclobazam. This metabolite's high steady-state concentrations and prolonged elimination half-life are central to the drug's sustained therapeutic effect, its delayed time to full efficacy, and the imperative for a slow, gradual taper upon discontinuation to avoid a severe withdrawal syndrome.

Clinically, clobazam has demonstrated significant, dose-dependent, and durable efficacy as an adjunctive therapy for the debilitating drop seizures of Lennox-Gastaut Syndrome. While this is its primary U.S. indication, its long history of global use underscores a broader spectrum of activity in other refractory epilepsy syndromes and anxiety disorders.

The safe use of clobazam requires a comprehensive understanding of the serious risks common to the benzodiazepine class, as highlighted in the FDA's boxed warnings: profound CNS depression when combined with opioids, the potential for abuse and addiction, and the certainty of physical dependence with continued use. Management is further complicated by significant drug-drug interactions, primarily mediated by the CYP450 system, and by pharmacogenomic variability in the CYP2C19 gene, which can lead to dramatically elevated levels of its active metabolite in poor metabolizers.

In conclusion, clobazam represents a valuable therapeutic agent, particularly in the management of refractory epilepsy. It is not simply another benzodiazepine but a distinct entity whose unique pharmacology offers a more favorable balance of efficacy and tolerability for long-term use. However, its benefits can only be realized through careful patient selection, vigilant monitoring for adverse effects and interactions, comprehensive patient education, and a disciplined approach to initiation and, most importantly, discontinuation.

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