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. 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 2 years or older.
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 increased anxiolytic and anticonvulsant properties. By enhancing the GABA activated chloride channel, it 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. Both clobazam and its active metabolite N-desmethylclobazam have a similar mechanism.
Clobazam is administered orally, and there are three available formulations: oral tablets (10mg, 20mg), oral suspension (2.5mg/ml) and newly developed oral films (5mg, 10mg, 20mg).
The FDA recommended initial dosing for adults (greater than 30kg body weight) is 10mg/day divided into twice daily which is titrated after 1 week to 20mg/day and maintained at 40mg/day by 2 weeks. For children (under 30kg body weight), the dosing initiation, titration, and maintenance is half of the adult dosing schedule. The dose escalation should proceed more slowly in 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 has 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. Its 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. 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 Steven-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 and is considered Category “C” in pregnancy. Both clobazam and N-CLB are present in breast milk, but there is no contraindication against breastfeeding.
Clobazam, like other benzodiazepines, does not require any ancillary monitoring, except for clinical monitoring for mental status/behavioral change or suicidality. The Canadian labeling recommends complete blood counts, liver and renal function tests, thyroid testing.
There is no established therapeutic index for clobazam, although some studies have suggested a clobazam range of 30 to 300 ng/ml. The routine monitoring for clobazam levels are indicated in specific scenarios, especially with it comes to anti-epileptic (AED) drug-drug interactions. In general, carbamazepine, phenytoin, and phenobarbital tend to decrease clobazam levels by up to 50%. While clobazam can unpredictably increase valproic acid (VPA) levels, it’s important to mention that with the recent approval of cannabidiol (CBD) for LGS and Dravet syndrome, CBD tends to increase the clobazam levels up to 60 to 80%.
Symptoms of clobazam overdose are almost similar to other typical benzodiazepines which include CNS depression, drowsiness, dizziness, hypotension, respiratory depression, confusion and lethargy, ataxia, and rarely coma or death. These symptoms can be aggravated with concomitant use of other CNS depressing agents/medications like alcohol. In general, overdose monitoring includes airway protection, hemodynamic monitoring, IV fluid replenishment for hypotension. The usual antidote for benzodiazepine overdose is flumazenil; however, its use in clobazam toxicity has not been well established.
Clobazam is one of the newer generation anti-epileptic medications introduced into the market with an FDA indication for add-on therapy for LGS. This approval came after the results from the Phase III randomized control trial in 2011. American Academy of Neurology (AAN) published practice parameters on the use of antiepileptic drugs (AED) for adult and pediatric epilepsy patients with LGS which concluded that based on 2 class II study data suggests clobazam is probably effective for LGS.
It’s worth noting that the efficacy of clobazam was dose-dependent in the trial, and the highest dose tried was 40mg/day. Thus, one clinical pearl from the results was that since escalating the dose from 10mg twice daily to 20mg twice daily resulted in a dose-dependent reduction in seizure frequency, higher doses (up to 60mg/day) may be beneficial if tolerated.
Clobazam has also proven its efficacy in treatment-resistant adult focal epilepsy (TRAFE), as 3 class III studies (small patient population and mixed epilepsy types) showed greater seizure frequency reduction compared to placebo but with higher side effects as mentioned above. AAN practice parameters on AED use for TRAFE concluded that it is probably effective as an add-on therapy for TRAFE.
Using clobazam for its indications (both approved and otherwise) require a multidisciplinary team approach because as with any benzodiazepine, there is risk associated with use. This team includes the prescribing physician or mid-level practitioner, the nursing staff, and the pharmacist. The team should communicate regarding drug interactions, adverse effects, and therapeutic effectiveness to provide optimal patient care. [Level V]
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