Transitioning Epilepsy Patients From Clonazepam to Clobazam
Transitioning Epilepsy Patients From Clonazepam to Clobazam
Introduction In treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely.
Case presentations The following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox–Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic–clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke.
Conclusions From these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful.
Benzodiazepines have been used to treat seizures since 1965, when a group from Marseilles, led by Henri Gastaut, reported on the successful use of diazepam to treat non-convulsive (mainly absence) seizures and its utility in the treatment of status epilepticus. Prior to that, benzodiazepines such as diazepam and chlordiazepoxide had been employed primarily as anxiolytics and hypnotics. Despite the observations by Gastaut, the use of diazepam for absence epilepsy did not gain traction because the 1960s marked the emergence of succinimides such as ethosuximide, which seemed to be less sedating and better tolerated than diazepam. Subsequently, Henri Gastaut published that clonazepam was even more effective than diazepam in the treatment of status epilepticus.
The initial approval of clonazepam by the US Food and Drug Administration (FDA), as reviewed by Thomas Brown, suggested that it be used for the following types of seizures: absence (typical petit mal), infantile spasms (infantile myoclonic, massive spasms, salaam), atypical absence (atypical petit mal), akinetic (astatic, atonic, drop attack), "minor motor" attacks, and "Lennox–Gastaut syndrome," (LGS) but not for the treatment of grand mal, partial seizures with complex symptoms (for example, psychomotor, temporal lobe), or focal seizures. The more recent version of the prescribing information is more restrictive and states that, "It is useful alone or as an adjunct in the treatment of the LGS (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam (Klonopin™) may be useful. " Of interest, the initial experience described in the European literature was based on the use of intravenous clonazepam, which is not available in the USA.
Until the approval of clobazam (Onfiâ„¢) in the USA in October 2011 for adjunctive treatment of seizures associated with LGS, benzodiazepines had been used mainly as rescue medications for status epilepticus or acute repetitive seizures. In addition to concerns about excessive sedation, long-term benzodiazepine use raises questions about maintenance of efficacy because of potential development of tolerance. The indications section of the FDA prescribing information for clonazepam indicates, "In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may re-establish efficacy. "
In addition, of the various classes of anticonvulsant medications, benzodiazepines have been especially implicated in producing cognitive and behavioral adverse effects. However, clobazam, a 1,5-benzodiazepine, seems to differ in its spectrum of pharmacologic activities from traditional 1,4-benzodiazepines. Indeed, a recent study provided sustained efficacy results for clobazam in patients with LGS over 3 years with stable dosing.
Clinicians are considerably interested in switching some patients receiving clonazepam to clobazam to maintain or improve seizure control, while also improving tolerability and quality of life for the patient. However, no published guidelines assist clinicians in successfully accomplishing this change safely. In this report, we provide three case reports on this therapy transition, and summarize in the following discussion the known pharmacokinetic, pharmacologic, and clinical aspects of benzodiazepine action to arrive at a successful therapeutic solution to this problem.
Abstract and Introduction
Abstract
Introduction In treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely.
Case presentations The following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox–Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic–clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke.
Conclusions From these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful.
Introduction
Benzodiazepines have been used to treat seizures since 1965, when a group from Marseilles, led by Henri Gastaut, reported on the successful use of diazepam to treat non-convulsive (mainly absence) seizures and its utility in the treatment of status epilepticus. Prior to that, benzodiazepines such as diazepam and chlordiazepoxide had been employed primarily as anxiolytics and hypnotics. Despite the observations by Gastaut, the use of diazepam for absence epilepsy did not gain traction because the 1960s marked the emergence of succinimides such as ethosuximide, which seemed to be less sedating and better tolerated than diazepam. Subsequently, Henri Gastaut published that clonazepam was even more effective than diazepam in the treatment of status epilepticus.
The initial approval of clonazepam by the US Food and Drug Administration (FDA), as reviewed by Thomas Brown, suggested that it be used for the following types of seizures: absence (typical petit mal), infantile spasms (infantile myoclonic, massive spasms, salaam), atypical absence (atypical petit mal), akinetic (astatic, atonic, drop attack), "minor motor" attacks, and "Lennox–Gastaut syndrome," (LGS) but not for the treatment of grand mal, partial seizures with complex symptoms (for example, psychomotor, temporal lobe), or focal seizures. The more recent version of the prescribing information is more restrictive and states that, "It is useful alone or as an adjunct in the treatment of the LGS (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam (Klonopin™) may be useful. " Of interest, the initial experience described in the European literature was based on the use of intravenous clonazepam, which is not available in the USA.
Until the approval of clobazam (Onfiâ„¢) in the USA in October 2011 for adjunctive treatment of seizures associated with LGS, benzodiazepines had been used mainly as rescue medications for status epilepticus or acute repetitive seizures. In addition to concerns about excessive sedation, long-term benzodiazepine use raises questions about maintenance of efficacy because of potential development of tolerance. The indications section of the FDA prescribing information for clonazepam indicates, "In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may re-establish efficacy. "
In addition, of the various classes of anticonvulsant medications, benzodiazepines have been especially implicated in producing cognitive and behavioral adverse effects. However, clobazam, a 1,5-benzodiazepine, seems to differ in its spectrum of pharmacologic activities from traditional 1,4-benzodiazepines. Indeed, a recent study provided sustained efficacy results for clobazam in patients with LGS over 3 years with stable dosing.
Clinicians are considerably interested in switching some patients receiving clonazepam to clobazam to maintain or improve seizure control, while also improving tolerability and quality of life for the patient. However, no published guidelines assist clinicians in successfully accomplishing this change safely. In this report, we provide three case reports on this therapy transition, and summarize in the following discussion the known pharmacokinetic, pharmacologic, and clinical aspects of benzodiazepine action to arrive at a successful therapeutic solution to this problem.