Clobazam
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Clobazam is a 1,5-benzodiazepine, meaning the two nitrogen atoms sit at positions 1 and 5 of the diazepine ring rather than at 1 and 4 as in diazepam, clonazepam and lorazepam, and that single structural shift changes what the molecule does at the receptor and what it costs the patient [21] [19]. It is approved as adjunctive therapy for drop seizures in Lennox-Gastaut syndrome and is used in many countries for anxiety. The pivotal phase III randomized trial in 217 evaluable patients with Lennox-Gastaut syndrome cut average weekly drop seizures by 41.2, 49.4 and 68.3 percent at 0.25, 0.5 and 1.0 mg/kg/day against 12.1 percent on placebo, with responder rates reaching 77.6 percent at the highest dose [1]. An earlier randomized dose-ranging trial in 68 patients had already shown the same dose dependence [2], and an open-label extension carried median drop-seizure reductions of 71.1 percent at three months and 91.6 percent at 24 months in patients who stayed on treatment [3]. Benefit held across baseline severity quartiles [4]. In refractory focal epilepsy a double-blind add-on trial produced greater than 75 percent seizure reduction in 40 percent of patients [6]. In anxious primary-care outpatients clobazam beat placebo on the Hamilton Anxiety Scale from the first week at a mean daily dose of 21 mg [13]. The distinguishing clinical feature is the sedation profile: in healthy volunteers clobazam produced significantly fewer psychomotor side effects than clonazepam [11] [9] and, unlike diazepam and lorazepam, did not impair memory in a placebo-controlled crossover [10]. Japanese expert consensus panels rank it among the standard adjunctive choices in childhood epilepsy [22]. Tolerance, dependence and withdrawal remain fully in force [16] [5].
- Randomized controlled evidence for drop seizure reduction in Lennox-Gastaut syndrome
- Dose dependent efficacy sustained past two years in open-label extension
- Effective add-on in refractory focal epilepsy
- Anxiolytic efficacy from the first week in controlled outpatient data
- Less psychomotor and memory impairment than clonazepam, diazepam and lorazepam in volunteers
- Minimal muscle relaxant and hypnotic activity relative to 1,4-benzodiazepines
- Somnolence and lethargy, dose related
- Falls and pneumonia in long term Lennox-Gastaut cohorts
- Tolerance to the anticonvulsant effect within the first months
- Physical dependence and withdrawal on discontinuation
- Headache, insomnia, tremor and anxiety after abrupt withdrawal
- Cognitive slowing at higher doses
- Serious skin reactions including Stevens-Johnson syndrome
- Additive respiratory and CNS depression with opioids or alcohol
evidence, by species22 cited papers
- Clobazam is a 1,5-benzodiazepine: its ring nitrogens sit at positions 1 and 5, not the 1 and 4 of diazepam, clonazepam and lorazepam.
- That ring shift shows up as receptor selectivity: clobazam and N-desmethylclobazam bind alpha2 GABA-A complexes with significantly greater affinity than alpha1 complexes, while clonazepam does not distinguish between them [7].
- The active metabolite N-desmethylclobazam outlives the parent by a wide margin, roughly 50 hours against 18, and reaches steady-state concentrations about eight times higher [20].
- In a placebo controlled crossover in healthy volunteers, diazepam and lorazepam produced anterograde amnesia while clobazam did not impair memory [10].
- In the phase III Lennox-Gastaut trial, 77.6 percent of patients on the highest clobazam dose halved their drop seizures, against 31.6 percent on placebo [1].
- Cannabidiol raises N-desmethylclobazam concentrations by inhibiting CYP2C19, which explains part of the sedation seen when the two are combined in children with refractory epilepsy [18].
Mechanism
Clobazam is a positive modulator at the benzodiazepine site of the -A receptor, increasing the frequency of chloride channel opening in response to GABA and thereby raising seizure threshold and reducing anxiety. What separates it from the 1,4-benzodiazepines is subunit preference rather than a different mechanism class. In radioligand binding work using rat brain homogenates and cloned human receptors expressed in HEK293 cells, both clobazam and its major N-desmethylclobazam showed significantly greater affinity for alpha2 subunit containing GABA-A receptor complexes than for alpha1 complexes, while the 1,4-benzodiazepine clonazepam showed no such distinction and zolpidem showed the opposite alpha1 preference [7]. Knock-in mouse work referenced in that study assigns anticonvulsant and anxiolytic action largely to alpha2 containing receptors and sedative and hypnotic action largely to alpha1, which supplies a coherent explanation for the clinical separation observed in volunteers. That separation was predicted preclinically: in a four-test comparison in mice against ten 1,4-benzodiazepines, clobazam had the widest ratio between anticonvulsant or anxiolytic ED50 and the ED50 for sedation and myorelaxation [8]. Clobazam behaves in practice as a partial rather than a full profile at the benzodiazepine site, producing anxiolysis and anticonvulsant effect with minimal muscle relaxant and hypnotic activity [20]. Metabolism matters as much as binding. Hepatic N-demethylation, largely by CYP3A4, yields N-desmethylclobazam, which is itself active and is cleared by CYP2C19. The parent has a half life of roughly 18 hours, the roughly 50 hours, and steady-state metabolite concentrations run about eight times parent [20]. In healthy volunteers and patients with epilepsy a single 30 mg dose of N-desmethylclobazam gave higher Cmax and AUC than the same dose of clobazam, and steady-state levels were higher in patients on concomitant antiepileptics [14]. Clearance falls with age in men, producing slower and more extensive accumulation of both parent and on repeated dosing [15]. Cannabidiol raises N-desmethylclobazam levels through CYP2C19 inhibition in children with refractory epilepsy [18].
receptor fingerprint
-A receptor alpha2 subunit containing complexpositive allosteric modulation at the benzodiazepine site
-A receptor benzodiazepine site, via N-desmethylclobazampositive allosteric modulation by the long lived active metabolite
-A receptor alpha1 subunit containing complexweaker positive allosteric modulation relative to alpha2
Cytochrome P450 2C19metabolic clearance pathway for N-desmethylclobazam
nothing. with no native signal there is nothing to modulate, so a resting target stays resting; this is the property a direct agonist does not have.
Safetyrisks and cautions, not medical advice
The nuance is attached, not optional. Somnolence, lethargy, pyrexia and upper respiratory infection were the most frequent adverse events in the pivotal Lennox-Gastaut trial, and sedation is dose related even though it is milder than with 1,4-benzodiazepines [1]. In the open-label extension the leading events over up to five years were upper respiratory tract infection at 18.4 percent, fall at 14.2 percent, pneumonia at 13.9 percent and somnolence at 12.7 percent [3]. Tolerance to the anticonvulsant effect is the principal efficacy limitation and it arrives early: in 183 patients with intractable complex partial seizures, complete remission was achieved initially in 61, but tolerance developed in 49.2 percent within the first three months, although 74.2 percent of those still seizure free at three months remained so at six [16]. Tolerance was noted in 56 percent of patients in the controlled focal epilepsy trial, with mild transient sedation in 40 percent [6], and this pattern is the standing critique of the drug in epilepsy [19]. Physical dependence and withdrawal are real. Abrupt discontinuation after steady-state dosing in phase I trials produced 193 withdrawal-related adverse events in 68 participants, with headache in 14 percent, insomnia in 12.6 percent, tremor in 10.1 percent and anxiety in 8.7 percent, and nearly half of the events followed supratherapeutic dosing; gradual taper over two to three weeks in the Lennox-Gastaut trials substantially reduced the burden [5]. Adverse effects appeared in 47 percent of Japanese clobazam cases, an incidence reduced by lower starting doses and slow titration [17]. Respiratory depression deserves specific mention: in healthy volunteers neither clobazam at 10 or 20 mg nor clonazepam altered the ventilatory response to carbon dioxide [11], but that is a single-dose volunteer finding and does not extend to overdose, to combination with opioids or alcohol, or to compromised patients. Cognitive and memory impairment is lower than with lorazepam or diazepam rather than absent [10] [12]. Serious skin reactions including Stevens-Johnson syndrome are a labelled risk.
Serious Drug: carries real danger of dependence, overdose or lasting harm; the site's own warning flag. Prescription: an approved medicine requiring a prescription in most jurisdictions.
The nuance is attached, not optional. Somnolence, lethargy, pyrexia and upper respiratory infection were the most frequent adverse events in the pivotal Lennox-Gastaut trial, and sedation is dose related even though it is milder than with 1,4-benzodiazepines [1]. In the open-label extension the leading events over up to five years were upper respiratory tract infection at 18.4 percent, fall at 14.2 percent, pneumonia at 13.9 percent and somnolence at 12.7 percent [3]. Tolerance to the anticonvulsant effect is the principal efficacy limitation and it arrives early: in 183 patients with intractable complex partial seizures, complete remission was achieved initially in 61, but tolerance developed in 49.2 percent within the first three months, although 74.2 percent of those still seizure free at three months remained so at six [16]. Tolerance was noted in 56 percent of patients in the controlled focal epilepsy trial, with mild transient sedation in 40 percent [6], and this pattern is the standing critique of the drug in epilepsy [19]. Physical dependence and withdrawal are real. Abrupt discontinuation after steady-state dosing in phase I trials produced 193 withdrawal-related adverse events in 68 participants, with headache in 14 percent, insomnia in 12.6 percent, tremor in 10.1 percent and anxiety in 8.7 percent, and nearly half of the events followed supratherapeutic dosing; gradual taper over two to three weeks in the Lennox-Gastaut trials substantially reduced the burden [5]. Adverse effects appeared in 47 percent of Japanese clobazam cases, an incidence reduced by lower starting doses and slow titration [17]. Respiratory depression deserves specific mention: in healthy volunteers neither clobazam at 10 or 20 mg nor clonazepam altered the ventilatory response to carbon dioxide [11], but that is a single-dose volunteer finding and does not extend to overdose, to combination with opioids or alcohol, or to compromised patients. Cognitive and memory impairment is lower than with lorazepam or diazepam rather than absent [10] [12]. Serious skin reactions including Stevens-Johnson syndrome are a labelled risk.
Do not combinehard conflicts this site holds; not a complete interaction list
other strong CNS depressants
for example Alprazolam, Diazepam, Zolpidem, Oxycodone, Phenobarbital, Pregabalin, Alcohol
two strong CNS depressants (opioid, benzodiazepine, z-drug, barbiturate, gabapentinoid, GABAergic or alcohol) add together on sedation and breathing; a leading cause of fatal respiratory depression.
Checking a whole stack? Run it through interactions + stacks.
History
Clobazam was synthesised in the 1960s and marketed from 1975 in Europe as Frisium and Urbanyl, initially as an anxiolytic positioned on the claim that a 1,5-benzodiazepine ring separates anxiolysis from sedation [20]. Its anticonvulsant use grew through the 1980s as controlled add-on studies in refractory focal epilepsy accumulated [6] [21], and Japan added it as a new antiepileptic drug in the 2000s [17]. The United States approved it only in October 2011, as Onfi, for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients two years and older, on the strength of the phase III trial [1] [7].
Reputation
Regarded within neurology as the benzodiazepine that behaves best in chronic use: real randomized evidence in Lennox-Gastaut syndrome, a comparatively gentle psychomotor profile, and a long international track record. The persistent reservation is tolerance to the anticonvulsant effect within months and the usual dependence and withdrawal burden of the class [19].
Resources
This entry is here for reference.
Research
- 1.Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome.
- 2.Clobazam in the treatment of Lennox-Gastaut syndrome.
- 3.Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study.
- 4.Clobazam is efficacious for patients across the spectrum of disease severity of Lennox-Gastaut syndrome: post hoc analyses of clinical trial results by baseline seizure-frequency quartiles and VNS experience.
- 5.Withdrawal-related adverse events from clinical trials of clobazam in Lennox-Gastaut syndrome.
- 6.Clobazam for refractory focal epilepsy. A controlled trial.
- 7.Clobazam and its active metabolite N-desmethylclobazam display significantly greater affinities for alpha2- versus alpha1-GABA(A)-receptor complexes.
- 8.Comparative study in mice of ten 1,4-benzodiazepines and of clobazam: anticonvulsant, anxiolytic, sedative, and myorelaxant effects.
- 9.Effects of clobazam and clonazepam on saccadic eye movements and other parameters of psychomotor performance.
- 10.Effects of single oral doses of clobazam, diazepam and lorazepam on performance tasks and memory.
- 11.Respiratory and sedative effects of clobazam and clonazepam in volunteers.
- 12.Effects of single oral doses of bromazepam, buspirone and clobazam on performance tasks and memory.
22 listed here; entry last updated August 2026
Reviews
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FAQ6 questions
What makes clobazam different from other benzodiazepines?
It is a 1,5-benzodiazepine rather than a 1,4-benzodiazepine, and it binds alpha2 containing GABA-A receptors with greater affinity than alpha1 containing ones. Since alpha1 carries most of the sedative signalling, clobazam delivers anticonvulsant and anxiolytic effect with less psychomotor and memory impairment.
Does clobazam actually work for Lennox-Gastaut syndrome?
Yes. A phase III randomized trial cut average weekly drop seizures by 68.3 percent at the highest dose against 12.1 percent on placebo, and an open-label extension sustained reductions past two years in patients who stayed on treatment.
What is N-desmethylclobazam?
The active metabolite formed by hepatic demethylation. It has a half life near 50 hours against about 18 hours for the parent and accumulates to roughly eight times parent concentration at steady state, so most of the sustained effect comes from it.
Does tolerance develop?
Frequently. Tolerance to the anticonvulsant effect appeared in about half of patients within three months in a 183 patient series and in 56 percent of patients in a controlled focal epilepsy trial, though patients still seizure free at three months often stayed that way.
Is clobazam less sedating in practice?
Less, not absent. Volunteer studies show fewer psychomotor effects than clonazepam and no memory impairment where diazepam and lorazepam impaired it, but somnolence, lethargy and falls were among the most common adverse events in the Lennox-Gastaut trials.
Why does cannabidiol matter?
Cannabidiol inhibits CYP2C19, which clears N-desmethylclobazam, so metabolite levels rise when the two are combined and sedation can increase.