Clobazam Stats - Substance Search

Pharmacology

DrugBank

State Solid Clearance Median estimated clearance = 2.49 L/h

Description

Clobazam belongs to the 1,5-benzodiazepine class of drugs and is expected to have a better side-effect profile compared to older 1,4-benzodiazepines. It has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984. The oral preparation was FDA approved on October 21, 2011. An oral suspension is expected to be available in 2013.

Mechanism of Action

Clobazam binds at distinct binding sites associated with the chloride ionopore at the post-synaptic GABA receptor. These GABA receptors are in various locations in the CNS (limbic, reticular formation) and clobazam increases the duration of time for which the chloride ionopore is open. As a result, hyper polarization and stabilization of the membrane occur as the post-synaptic inhibitory effect of GABA is enhanced.

Pharmacodynamics

Similar to other benzodiazepines, clobazam binds to the interface of the α and γ2-subunit of the GABA-A receptor. However, it is considered a partial agonist to GABA-A receptors which sets clobazam apart from 1,4-benzodiazepines which are full agonist. The significance of this difference is that one may experience less sedation with clobazam than with other benzodiazepines. Unlike the endogenous GABA ligand, clobazam binds allosterically to the GABA receptor to increase the frequency of the chloride channel opening and membrane permeability to chloride ions. Pharmacodynamic tolerance has been demonstrated in animal models.

Metabolism

Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation to form two major metabolites, N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, respectively. N-desmethylclobazam (norclobazam) retains pharmacological activity. Norclobazam is one-fourth the potency of clobazam. The main enzyme that facilitates the process of N-demethylation is CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6. Norclobazam itself is also metabolized via hydroxylation, primarily by CYP2C19. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19. A factor in determining extent of metabolism is the genetic profile of the individual patient as CYP2C19 is a polymorphic enzyme.

Absorption

After oral administration of clobazam, it is almost completely absorbed (87% of dose). Bioavailability relative to solution was almost at 100%. Food does not affect absorption. Tmax = 1-3 hours.

Toxicity

The most common adverse effects include somnolence, pyrexia, upper respiratory tract infection, and lethargy.

Indication

For treatment and management of epilepsy and seizures associated with Lennox-Gastaut syndrome, a difficult-to-treat form of childhood epilepsy.

Half-life

The mean elimination half life of an oral dose of clobazam 40 mg is 32 hours. It's main metabolite, norclobazam, as a half life of 57 hours. The half life in adult patients with epilepsy are higher than those that are healthy.

Protein Binding

Clobazam is the primary circulating entity in the serum and is highly protein-bound (80-90%).

Elimination

Clobazam is eliminated via the urine (~94%) as metabolites.

Volume of Distribution

Vdss = 100 L. This high volume of distribution suggests extensive distribution to body tissues.

Receptor Profile

Receptor Actions

Modulators

GABA-A receptor positive allosteric modulator (benzodiazepine site)

Other

preferential α2 subunit binding

Receptor Binding

Gamma-aminobutyric acid receptor subunit gamma-3 modulator

Gamma-aminobutyric acid receptor subunit alpha-1 antagonist

Effect Profile

Curated + 1 Reports

Benzodiazepine 6.7

Strong anxiolysis and cognitive impairment with moderate euphoria, mild sedation

Anxiolysis×3

10

Sedation / Relaxation×2

5

Motor / Cognitive Impairment×1

9

Euphoria / Mood Lift×1

6

Based on reports from:

Erowid Experience Reports PsychonautWiki Clobazam

Tolerance & Pharmacokinetics

drugs.wiki

Half-Life

Parent: ~36–42 hours; active metabolite (N‑desmethylclobazam): ~71–82 hours; metabolite exposure can be ~5× higher in CYP2C19 poor metabolizers.

Addiction Potential

Moderate to high. As with other benzodiazepines, clobazam carries a risk of dependence and a clinically significant withdrawal syndrome with prolonged or high-dose use.

Tolerance Decay

Full tolerance 14d Half tolerance 168d Baseline ~336d

Tolerance to hypnotic/anxiolytic effects tends to develop over weeks of daily use and decays slowly over weeks after cessation; seizure‑protective effects may persist variably. Data are drawn from class‑level evidence and clinical experience; individual variability is high.

Cross-Tolerances

Other benzodiazepines

100% ●●●

Z‑drugs (zolpidem, zopiclone, eszopiclone)

60% ●○○

Barbiturates (partial cross‑tolerance)

20% ●○○

Experience Report Analysis

Erowid

1 Reports

2013–2013 Date Range

1 With Age Data

Demographics

Gender Distribution

Age Distribution

Reports Over Time

Real-World Dose Distribution

62K Doses

From 6 individual dose entries

Oral (n=6)

Median: 30.0mg 25th: 22.5mg 75th: 30.0mg 90th: 65.0mg

Benzodiazepine Equivalence

20.0 mg Clobazam = 10.0 mg Diazepam

Potency ratio 0.5

Bioavailability Oral 85-90%

Clobazam - 20mg ~=10mg Diazepam.

⚠ All other CNS depressants

Harm Reduction

drugs.wiki

• N-desmethylclobazam, the active metabolite, has a mean half-life of ~71–82 hours (longer than parent), causing accumulation, next-day sedation, and prolonged impairment with repeated dosing; effects are markedly higher in CYP2C19 poor metabolizers.

• Cannabidiol (CBD) significantly increases clobazam exposure (~60%±80%) and increases N-desmethylclobazam by roughly 3–5×, frequently causing excessive sedation; dose reductions and monitoring are recommended when combined.

• Combining benzodiazepines with opioids, alcohol, GHB/GBL, barbiturates, Z‑drugs, or gabapentinoids greatly elevates risk of respiratory depression, aspiration, blackouts, and death; avoid such combinations. Community HR charts and clinical warnings align on high risk.

• Alcohol specifically increases clobazam absorption by about 50%, further intensifying CNS depression beyond simple additivity.

• Stiripentol (for Dravet/LGS adjunct therapy) inhibits CYPs and disproportionately raises norclobazam levels; adverse effects often resolve after reducing clobazam dose.

• Avoid abrupt discontinuation after regular use; benzodiazepine withdrawal can include seizures. Gradual tapers are recommended; clinical programs commonly use 10–25% dose reductions every 2–3 weeks, individualized to symptoms.

• December 2023 FDA alert identified rare but severe DRESS (drug reaction with eosinophilia and systemic symptoms) with clobazam; seek urgent care for rash with fever or systemic symptoms.

• Next‑day driving and fall risk persist, especially in older adults, those with hepatic/respiratory disease, and with polypharmacy; plan no driving or high‑risk tasks until fully unimpaired.

• Metabolism: clobazam is mainly N‑demethylated by CYP3A4 (also 2C19/2B6) to N‑desmethylclobazam, which is cleared predominantly by CYP2C19; inhibitors/inducers of these enzymes materially change exposure.

• Pregnancy and neonatal risk: benzodiazepines cross the placenta and can cause neonatal sedation or withdrawal; both clobazam and its metabolite are present in breast milk — weigh risks/benefits and monitor infants if exposed.

Clobazam Stats & Data