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GTR Home > Conditions/Phenotypes > Clobazam response

Clobazam response

Synonyms
Onfi response; Sympazan response

Summary

Clobazam is approved by the FDA to treat seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older. The drug is widely used in the chronic treatment of focal and generalized seizures, and has application in the treatment of diverse epilepsy syndromes, including epileptic encephalopathies other than LGS, such as Dravet syndrome. Lennox-Gastaut syndrome is characterized by different types of seizures that typically begin in early childhood and may be associated with intellectual disability. Clobazam has been shown in controlled clinical trials to reduce drop (atonic) seizures in children with LGS, but there is evidence that it is effective for other seizure types as well. Clobazam is a 1,5-benzodiazepine that acts as a positive allosteric modulator of GABAA receptors. It is often used in combination with other drugs, including stiripentol, cannabidiol, and many others. Clobazam is extensively metabolized in the liver by cytochrome P450 (CYP) and non-CYP transformations. The major metabolite is N-desmethylclobazam (norclobazam), which has similar activity to clobazam on GABAA receptors and is an active antiseizure agent. During chronic treatment, levels of norclobazam are 8–20 times higher than those of the parent drug so that seizure protection during chronic therapy is mainly due to this metabolite. Norclobazam is principally metabolized by CYP2C19. Individuals who lack CYP2C19 activity (“CYP2C19 poor metabolizers”) have higher plasma levels of norclobazam and are at an increased risk of adverse effects. The FDA-approved drug label states that for patients known to be CYP2C19 poor metabolizers, the starting dose of clobazam should be 5 mg/day. Dose titration should proceed slowly according to weight, but to half the standard recommended doses, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21. [from Medical Genetics Summaries]

Available tests

11 tests are in the database for this condition.

Clinical tests (11 available)

Molecular Genetics Tests

Genes See tests for all associated and related genes

  • Also known as: CPCJ, CYP2C, CYPIIC17, CYPIIC19, P450C2C, P450IIC19, CYP2C19
    Summary: cytochrome P450 family 2 subfamily C member 19

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted1information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2019 Statement from the US Food and Drug Administration (FDA)

2.5 Dosage Adjustments in CYP2C19 Poor Metabolizers

In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21.

[…]

8.6 CYP2C19 Poor Metabolizers

Concentrations of clobazam's active metabolite, N-desmethylclobazam, are higher in CYP2C19 poor metabolizers than in normal metabolizers. For this reason, dosage modification is recommended

[…]

12.5 Pharmacogenomics

The polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active N- desmethylclobazam. Compared with CYP2C19 normal metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3–5 times higher in poor metabolizers (e.g., subjects with *2/*2 genotype) and 2 times higher in intermediate metabolizers (e.g., subjects with *1/*2 genotype). The prevalence of CYP2C19 poor metabolism differs depending on racial/ethnic background. Dosage in patients who are known CYP2C19 poor metabolizers may need to be adjusted.

The systemic exposure of clobazam is similar for both CYP2C19 poor and normal metabolizers.

Please review the complete therapeutic recommendations that are located here: (1).

Table 1. The FDA (2019) Drug Label for Clobazam: Recommended Total Daily Dosing by Weight Group
Less than or equal to 30 kg body weightGreater than 30 kg body weightCYP2C19 poor metabolizers
Starting dose5 mg10 mgIn patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the recommended total daily doses presented in this table, as tolerated. If necessary, and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21.
Starting day 710 mg20 mg
Starting day 1420 mg40 mg

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.

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