Introduction to clobazam
On October 24, 2011, the U.S. Federal Drug Administration announced that clobazam (Onfi) was approved for use in the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Clobazam is a benzodiazepine which belongs to the same family of drugs that includes lorazepam (Ativan) ,diazepam (Valium), midazolam (Versed) and clonazepam (Klonopin). Clobazam is different from the other benzodiazepines because it is utilized for the long-term treatment of epilepsy due to its effectiveness and relatively low tendency to produce sedation. Outside of the United States, clobazam is one of the most commonly used anti-seizure medications in the world. It has been approved in several other countries, particularly Canada, Mexico and most of Europe. Because of this, the drug’s entry into the US comes with an extensive clinical experience that is often not seen with other recently approved agents.
Clobazam is being marketed in the United States under the trade name of Onfi. The FDA indication for clobazam is strictly for add-on therapy for treatment of seizures associated with Lennox-Gastaut syndrome in children from age 2 and older. The effectiveness for this drug was established in 2 multi-center control studies done specifically to bring the drug to the U.S. market. Both studies were similar in terms of the patient populations that were studied. The first study was a randomized, double-blind, placebo-controlled study that looked at patients who were aged 2 to 54 years with a current or prior diagnosis of Lennox-Gastaut syndrome. The patients were divided into 2 groups by weight, those who were less than 30 kg and those who were greater than 30 kg, and then they were randomized to 1 of 3 maintenance doses of the medication ( 5 mg- Low, 10 mg Medium and 20 mg High doses). The primary measure for the study was the percent seizure reduction and weekly frequency of various seizures that typify the syndrome, primarily drop, tonic, or myoclonic seizures over a 4-week baseline to a 12-week period of observation on the medication.
In the low-dose group, there was a 41.2% reduction of total seizures. In the medium-dose group, there was a 49.4% reduction in seizures, and in the high-dose group, a 68.3% reduction. The placebo group showed only a 12.1% reduction. Because this is a drug in the benzodiazepine family, they also looked at the issue of tolerance which is common to this drug group. Tolerance is defined as whether a drug maintains its effectiveness over time at a given dose. In other benzodiazepines, one often needs to take more of a given drug in order to maintain effectiveness. There was no significant development of tolerance over a 3-month period of observation.
In the second major study, also a randomized double-blind comparison study of high- and low-dose Onfi consisting of patients aged 2-25 years with a current or prior diagnosis of Lennox-Gastaut, divided into 2 weight groups and then randomized to either a low target dose of 5 mg or 10 mg depending on whether they weighed more or less than 30 kg. In the high dose group, the target daily dose of 20 mg for less than 30 kg body weight vs. 40 mg for more than a 30 kg body weight. Results showed a significant reduction in seizure frequency in the high dose compared to the low dose group with a median percent seizure reduction of 93% vs. 29%. Based on these analyses, the drug was approved.
In other studies done outside of the US, clobazam has been found to be effective amongst almost all seizure types. However, excitement over these findings has been tempered by the fact that the benefits can often be short-lived. In one large Canadian clobazam cooperative study, more than 40% of patients with a single seizure type had a 50% or greater reduction in seizure frequency and 60% of patients with multiple seizure types had improvement in at least one type of seizures; however, side effects did occur with the most common being drowsiness.
The mechanism of action for clobazam is not fully understood but is thought to involve what is known as potentiation of GABAergic neurotransmission resulting from binding at a benzodiazepine site at the GABA(A) receptor. The peak plasma level or the level of the drug in the blood is dose proportional over the dose range of 10-80 mg. Clobazam is broken down to a metabolite known as N-desmethylclobazam, which has about a fifth the activity of clobazam. The mean half-life or the amount of time that the drug spends in the system as well as for the main metabolite is 36-42 hours for clobazam itself and 71-82 hours for its main metabolite. The drug is rapidly absorbed after oral administration and it peaks in 30 minutes to 4 hours after single or multiple-dose administration. It is bioavailable. Food does not affect absorption. It can be easily crushed in items such as apple sauce or other foods. Clobazam is lipophilic and distributes rapidly throughout the body. It has a protein binding of 80-90% for clobazam and 70% for its main metabolites.
Clobazam is metabolized in the liver. The major metabolic pathway does involve CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6 isoenzymes. The main metabolite of the drug is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations of this can be 3 times higher than its parent compound. Eleven percent of the drug is excreted in feces and 82% is in the urine.
There is no apparent difference in the metabolism of clobazam between women and men. There is no significant effect of race on the clearance of clobazam either. Renal impairment has been evaluated and patients with severe renal impairment have not been studied extensively, but it apparently seems to be non-problematic in patients with mild or moderate renal impairment. In liver problems, there is limited data to address how things get affected with this condition; however, one needs to exercise caution with regards to its use in this situation. There is no specific recommendation from the company as to what should be done with people who have kidney or renal problems.
The most commonly reported side effect with this drug includes tiredness and sedation. In general, these tend to be dose related with the higher doses resulting in higher reports of adverse effects. . One needs to be careful about the use of this drug with other depressant drugs or alcohol. Also because it is a benzodiazepine, abrupt discontinuation should be avoided. This drug needs to be tapered slowly, otherwise withdrawal symptoms can occur. Withdrawal symptoms may include convulsions, hallucinations, behavioral disorder, tremor and anxiety. There is the chance of physical and psychological dependence on this drug. Similar to other seizure drugs, there is also the risk of suicidal thought or behaviors in patients who take this drug. The most common side effects that led to treatment stoppage in the control trials included lethargy, somnolence, ataxia, aggression, fatigue and insomnia. Other common side effects include gastrointestinal issues, decreased appetite and issues related to depression or psychiatric problems such as aggression or insomnia.
Onfi or clobazam is a pregnancy Category C drug. There are no adequate or well controlled studies of Onfi in pregnant women and no adequate developmental toxicity studies of clobazam in animals. Onfi is excreted in human milk. The effects of this exposure on infants are unknown. The drug has not been utilized in children under the age of 2 and therefore caution is needed with addressing this group of individuals.
Onfi or clobazam is a weak inducer of the CYP3A4 isoenzyme. Some hormonal contraceptives are metabolized by this pathway; therefore, their effectiveness may be diminished when given this drug, so additional non-hormonal forms of contraception are recommended when using this drug. Dosage adjustment of Onfi can be necessary if administered with other strong inhibitors including fluconazole or ticlopidine or even omeprazole. Alcohol increases the maximal plasma [exposure] of clobazam by almost 50%, so it is not wise to take this drug with alcohol or other similar agents.
Clobazam can increase the peak levels of dextromethorphan. It can also decrease midazolam levels. It does not affect valproic acid or lamotrigine. Ketoconazole can increase clobazam levels. Fluconazole, ticlopidine and omeprazole can increase the levels of the active metabolite of clobazam, so one may need to adjust the dosage for those medications. Other medications such as valproic acid, phenobarbital, phenytoin, carbamazepine, felbamate and oxcarbazepine do not impact this drug.
Dosage and Administration
Onfi is available in a number of dose sizes. It should be started slowly in a divided dose twice daily, and it should be done according to body weight. Serum levels of clobazam and its metabolites require 5-9 days to reach a steady state level. Clobazam will be available in the United States as a 5 mg, 10 mg and 20 mg tablet for oral administration. The highest dose was 20 mg for less than 30 kg body weight and 40 mg for greater than 30 kg body weight.
How Does Clobazam Compare to Other Medications?
Because clobazam has been out in the world for a considerable amount of time, it is likely that this agent could be quite an important addition to the armamentarium for patients with epilepsy. Given that it is one of the most frequently utilized medications, it would not be surprising that this drug will be used popularly, given its indication is for a very difficult to manage population of individuals with epilepsy. Because Onfi is a benzodiazepine, one will have to be careful about the side effect of sedation and the possibility of tolerance. We will also have to be extraordinarily careful about counseling individuals to not suddenly stop this medication as it could lead to significant problems including seizure emergencies.
How Can the Epilepsy Therapy Project Help?
The Epilepsy Therapy Project helps to bring new drug therapies to market as safely as feasible. By helping inform the public about various epilepsy treatments, hopefully the Epilepsy Therapy Project can help improve the quality of life of patients with epilepsy. It is unclear where clobazam will fall in the general spectrum of the various therapies for epilepsy management in the United States, but certainly the Epilepsy Therapy Project will be there to help guide individuals so that they can take charge of their own life and improve their seizure management.Back to top
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