Clobazam was first synthesized in 1966 and first published in 1969. The primary goal for developing this drug was to provide greater efficacy with fewer benzodiazepine (BZD) related side effects. It was approved in Australia (in 1970), and France (in 1974) for anxiety. Marketing for epilepsy began in 1984.[1][2] In 2005, it received approval in Canada as an add on therapy for generalized tonic-clonic, myoclonic, and focal impaired awareness seizures. In the USA, the FDA approved clobazam in October 2011 as an adjunct treatment for seizures associated with Lennox-Gastaut syndrome (LGS) in individuals two years or older.

FDA indications[3]:

1. Adjunctive treatment of seizures associated with Lennox–Gastaut syndrome in patients two years or older

Non- FDA indications[4][5][6][7]:

1. Adjunctive therapy for seizures seen with Dravet syndrome
2. Adjunctive treatment for refractory status epilepticus
3. Adjunctive therapy of refractory focal epilepsy
4. Catamenial epilepsy (off-label)
5. Anxiety

Clobazam, in general, has a structural resemblance to typical BZD. The unique structural difference is that clobazam has nitrogen atoms at the 1st and 5th positions of the diazepine ring (instead of the usual 1st and 4th positions of typical BZD).

Due to this structural difference, clobazam is a partial agonist to gamma-aminobutyric acid (GABA) A receptors (compared to typical BZD, which are full agonists. It has a lower affinity for GABA-A (alpha1-beta2g2) receptor (BZ-1), thus leading to less sedative side effects. It also has a selective agonist for GABA-A (alpha2-beta3g2), thus exhibiting increased anxiolytic and anticonvulsant properties.[8] Enhancing the GABA activated chloride channel leads to an increase in chloride conduction leading to hyperpolarization of the neuronal membrane potential, thus inhibiting action potential generation and a decrease in neuronal hyperexcitability. It may have less effect on alpha5 subunits resulting in a lesser effect on cognition.[8] Both clobazam and its active metabolite N-desmethylclobazam have a similar mechanism.

Clobazam administration is oral, and there are three available formulations: oral tablets (10 mg, 20 mg), oral suspension (2.5 mg/ml), and newly developed oral films (5 mg, 10 mg, 20 mg).

The FDA recommended initial dosing for adults (greater than 30 kg bodyweight) is 10 mg/day divided into twice daily, which is titrated after one week to 20 mg/day and maintained at 40 mg/day by the second week. For children (under 30 kg body weight), the dosing initiation, titration, and maintenance is half of the adult dosing schedule. The dose escalation should proceed more slowly in the geriatric population, known CYP2C19 poor metabolizers and in those with mild to moderate hepatic impairment, in which the dose-escalation reduces by half of the recommended titration dosing schedule.

Clobazam undergoes extensive metabolism in the liver to N-desmethylclobazam (N-CLB), which is the active and significant circulating metabolite. N-CLB plasma concentration is 3.5 times higher than clobazam. It is rapidly absorbed with a bioavailability of 87% and has T-max (time to reach maximum concentration) in 0.5 to 4 hours. It exhibits 80 to 90% protein binding, and elimination half-life is 36 to 42 hours, while the active metabolite N-CLB has a prolonged half-life of 71 to 82 hours. It gets excreted in urine (approximately 82%) and feces (approximately 11%), with 3% excreted unchanged.

The most common adverse drug reactions (noted during the trials compared to placebo) were sedation, somnolence, drowsiness, headache, nausea, pyrexia, lethargy, aggression, drooling, irritability, ataxia, constipation, dry mouth, blurred vision, depression, insomnia, and amnesia.[9] When compared with other benzodiazepines (e.g., diazepam), the incidence of these side effects was much less with better tolerability. Tolerance to these side effects develops over time.

Other potential side effects include skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, suicidal thoughts, paradoxical behavioral aggression, withdrawal (seizures, hallucinations), and abuse potential (therefore a category IV drug).

There are no significant contraindications except for hypersensitivity to clobazam. The Canadian labeling mentions contraindications with myasthenia gravis, narrow-angle glaucoma, severe hepatic or respiratory disease, sleep apnea, history of substance abuse.

Warnings/precautions for clobazam generally include: History of drug/alcohol abuse, hepatic impairment, concomitant use of other sedating drugs (BZD, opioids), muscle weakness/ataxia, psychiatric diseases (as it can cause paradoxical reactions like aggressive behavior), respiratory disease, and use in special populations like geriatric and/or poor CYP2C19 metabolizers. As with other benzodiazepines, abrupt discontinuation of clobazam can lead to withdrawal seizures and behavioral changes.

Clobazam crosses the placenta. It was considered Category “C” in pregnancy per the previous FDA grading system for pregnancy. Both clobazam and N-CLB are present in breast milk, but there is no contraindication against breastfeeding.