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NCS Currents Sept 2016

NEUROCRITICAL CARE PHARMACY Clobazam (Onfi®) for Refractory Status Epilepticus By Akta Patel, PharmD, BCPS Refractory Status Epilepticus (RSE) is a medical emergency that has a mortality rate of 23- 61% at hospital discharge. Clinical practice guidelines define RSE as persistent status epilepticus (SE) despite the administration of standard treatment with adequate doses of an initial benzodiazepine followed by a second acceptable antiepileptic drug (AED). However, controversies exist regarding the definition of RSE (e.g. the number of AEDs patients need to have failed and the duration of SE after treatment initiation). Nevertheless, it is imperative to control the seizure immediately, as literature has shown that the longer the duration of the seizure, the worse the outcome. Patients with RSE are less likely to return to functional baseline than patients with SE. Return to baseline was seen in 39% of RSE patients at 3 months. Clobazam is rapidly and extensively absorbed – with peak concentrations occurring linearly half-hour to four-hours after oral administration – and has no significant drug interactions. Both clobazam and its active metabolite, N-desmethylclobazam are metabolized in the liver via the cytochrome-P450 pathway. The mean half-life of N-desmethylclobazam (71-82 hours) is nearly double the mean half-life of clobazam (36-42 hours). Clobazam, a 1,5-benzodiazepine, has a slightly different chemical structure from that of all other benzodiazepines on the market, which are 1,4-benzodiazepine. The anticonvulsant effects of clobazam are associated with the activation of the GABAA receptors, which are composed of five protein subunits: two copies of α subunit, two copies of β subunit and a γ subunit. From animal studies, authors have learned that sedating effects are mediated by the α1 subunit whereas the anticonvulsant effects are medicated by the α2 subunit. Clobazam has a higher affinity for the α2 subunit compared to the α1 subunit. Therefore, it is less likely to cause psychomotor impairments and sedation. In 1986, a small case series in Italy evaluated the use of clobazam in SE (six cases of absence, one case of myoclonic-absence, one case of tonic, and seven cases of complex partial). Clobazam was administered as a single dose (0.5 to 1.7 mg/kg). Fifteen of the 16 patients enrolled had termination of SE within 15 to 31 minutes after clobazam was administered. Drowsiness was observed in four patients. The authors concluded that clobazam is useful in the management of some forms of SE. Sivakumar et al, recently (2015) reported the use and efficacy of clobazam for RSE as a retrospective case series. RSE was defined as persistent SE despite adequate treatment with a benzodiazepine and one other AED with or without anesthetic infusions. Twenty-two patients who received clobazam were identified, of which five were excluded (three were on prior clobazam therapy and two did not received clobazam for SE). Of the 17 patients, the majority were adults (median age of 63 years) except one (14 years of age) with simple or complex partial or generalized convulsive seizure types. Demographic N (%) Comments Male 10 (58.8) African American 12 (70.6) History of epilepsy 11 (64.7) All were on home AEDs; 5 were taking more than one New onset of seizures 6 (35.3) 3 patients with acute symptomatic etiology, 2 with chronic etiology, and 1 was unknown Electrographic focal SE 15 (88.2%) Sixteen patients received a benzodiazepine as first-line therapy and 12 patients received intravenous anesthetics. Most common AEDs included phenytoin, valproic acid, lacosamide, levetiracetam, and phenobarbital. Clobazam was used as an add-on therapy in all patients, after failure of two or more AEDs in adequate dosing with or without anesthetics. Since clobazam is only available as an oral formulation, it was administered through a nasogastric tube for patients who were stuporous. A successful response, defined as termination of RSE within 24 hours of administration without addition or modification of concurrent AEDs and with successful wean of anesthetic infusions, was seen in 13 patients (76.5%). One patient had an unsuccessful response and three patients were categorized with indeterminate response. Two of the three patients had termination of SE with an intravenous benzodiazepine administered 24 hours prior to clobazam. Clobazam enabled the successful wean of anesthetic infusions without breakthrough seizures or recurrent SE in all three patients. Sedation was seen as a side effect in six (37.5%) of 16 patients. Clobazam was tapered and discontinued in these patients while the other ten patients were discharged on clobazam. The authors concluded that clobazam appears efficacious in the treatment of RSE and it should be further investigated in prospective, randomized trials. Result Median (range) Duration of SE prior to clobazam 4 days (1-161) Starting dose of clobazam 10 mg/day (10-40) Similar to FDA approved dose Maintenance dose of clobazam 20 mg/day (10-60) Number of failed AEDs 3 (2-6) Hospital length of stay 30 days (6-83) Discharge Glasgow Outcome Scale 3 (1-5) Clobazam tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce. It can be administered without regard to meals and via nasogastric tube for patients who cannot take it by mouth. Clobazam is also available in an oral suspension (2.5 mg/ml). Sixty of the 10-milligram tablets cost approximately $810-$1,044; 20-milligram tablets cost approximately $1,620-$2,088; and 120 ml of the suspension costs approximately $712-$914. Both tablets and oral suspension should be stored at controlled room temperature. This drug does require a prior authorization before discharge. 25


NCS Currents Sept 2016
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