Clobazam

Mechanism of Action

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 fewer 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 decreasing 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.

Administration

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 the 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.

Adverse Effects

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] 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 misuse potential (therefore a category IV drug).

In December 2023, the FDA issued an alert that clobazam can cause a rare but serious and potentially life-threatening medication hypersensitivity reaction if it is not detected and promptly treated. Termed drug reaction with eosinophilia and systemic symptoms (DRESS), the reaction starts as a rash but can rapidly progress, causing internal organ injury leading to hospitalization and even death.

Contraindications

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.

Monitoring

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.

Although some studies have suggested a clobazam range of 30 to 300 ng/ml, there is no established therapeutic index for clobazam.[10] The routine monitoring for clobazam levels is indicated in specific scenarios, especially regarding 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 +/- 80% and more importantly N-CLB levels by 500  +/-  300%.[11]

Toxicity

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 become 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.

Enhancing Healthcare Team Outcomes

Clobazam is one of the newer generation antiepileptic 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.[6]

It is worth noting that the efficacy of clobazam was dose-dependent in the trial, and the highest dose tried was 40 mg/day. Thus, one clinical pearl from the results was that since escalating the dose from 10 mg twice daily to 20 mg 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.[6] 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) requires an interprofessional team approach because, as with any benzodiazepine, there is a risk associated with its use. This team includes the prescribing clinician or mid-level practitioner, the nursing staff, and the pharmacist. The pharmacist should verify dosing, perform a drug interaction check, and report any concerns to the prescriber. Nursing is in the best position to answer patient questions, counsel on dosing and adverse effects, and monitor these adverse effects, also informing the clinician f any issues present. The team should communicate regarding drug interactions, adverse effects, and therapeutic effectiveness to provide optimal patient care while minimizing adverse events. [Level 5]