Clobazam

Clobazam
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]

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Overview

Clobazam is a Benzodiazepine that is FDA approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Common adverse reactions include constipation, somnolence or sedation, pyrexia, lethargy, and drooling.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Seizures associated with Lennox-Gastaut syndrome (LGS)

• A daily dose of ONFI greater than 5 mg should be administered in divided doses twice daily
• 5 mg daily dose can be administered as a single dose.
• Dose patients according to body weight.

• Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Clobazam in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Seizures associated with Lennox-Gastaut syndrome (LGS) (2 years of age or older)

• A daily dose of ONFI greater than 5 mg should be administered in divided doses twice daily
• 5 mg daily dose can be administered as a single dose.
• Dose patients according to body weight.

• Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Clobazam in pediatric patients.

Contraindications

• ONFI is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
• Hypersensitivity reactions have included serious dermatological reactions.

Warnings

Somnolence or Sedation

• ONFI causes somnolence and sedation.
• In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.
• In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment.
• Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants.
• Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of ONFI is known.

Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants

• Since ONFI has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.

Withdrawal Symptoms

• Abrupt discontinuation of ONFI should be avoided.
• ONFI should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation.
• Withdrawal symptoms occurred following abrupt discontinuation of ONFI; the risk of withdrawal symptoms is greater with higher doses.
• As with all antiepileptic drugs, ONFI should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
• Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines.
• The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation.
• Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.

Serious Dermatological Reactions

• Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with ONFI in both children and adults during the post-marketing period.
• Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy.
• ONFI should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.
• If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Physical and Psychological Dependence

• Patients with a history of substance abuse should be under careful surveillance when receiving ONFI or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Suicidal Behavior and Ideation

• Antiepileptic drugs (AEDs), including ONFI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. *Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
• Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
• There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
• The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
• Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
• The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
• The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

• The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
• Anyone considering prescribing ONFI or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
• Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
• Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
• Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
• Behaviors of concern should be reported immediately to healthcare providers.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• During its development for the adjunctive treatment of seizures associated with LGS, ONFI was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more.
• The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2). Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on ONFI at several doses to placebo.

Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1)

• The adverse reactions associated with ONFI treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.

Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1) Table 3 lists the adverse reactions that occurred in ≥5% of ONFI treated patients (at any dose), and at a rate greater than placebo treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).

Postmarketing Experience

These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.

Blood Disorders

• Anemia
• Eosinophilia
• Leukopenia
• Thrombocytopenia

Eye Disorders

• Diplopia
• Vision blurred

Gastrointestinal Disorders

• Abdominal distention

General Disorders and Administration Site Conditions

• Hypothermia

Investigations

• Hepatic enzyme increased

Musculoskeletal

• Muscle spasms

Psychiatric Disorders

• Agitation
• Anxiety
• Apathy
• Confusional state
• Depression
• Delirium
• Delusion
• Hallucination

Renal and Urinary Disorders

• Urinary retention

Respiratory Disorders

• Aspiration
• Respiratory depression

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Angioedema
• Facial and lip edema

Drug Interactions

There is limited information regarding Clobazam Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Clobazam in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clobazam in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Clobazam during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Clobazam in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Clobazam in pediatric settings.

Geriatic Use

Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation. The starting dose should be 5 mg/day for all elderly patients. Then titrate elderly patients 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 weight) may be started on day 21 [see Use in Specific Populations (8.5)].

Gender

There is no FDA guidance on the use of Clobazam with respect to specific gender populations.

Race

There is no FDA guidance on the use of Clobazam with respect to specific racial populations.

Renal Impairment

No dose adjustment is required for patients with mild and moderate renal impairment. There is no experience with ONFI in patients with severe renal impairment or end stage renal disease (ESRD). It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Hepatic Impairment

ONFI is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of ONFI. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups. Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group). There is inadequate information about metabolism of ONFI in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be given [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Clobazam in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Clobazam in patients who are immunocompromised.

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 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.5)].

Administration and Monitoring

Administration

• Oral

Important Administration Instructions

Instruct patients to read the "Instructions for Use" carefully for complete directions on how to properly dose and administer ONFI oral suspension.

ONFI Tablet Oral Administration ONFI tablets can be taken with or without food. ONFI tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.

ONFI Oral Suspension Oral Administration ONFI oral suspension can be taken with or without food [see Clinical Pharmacology (12.3)].

Shake ONFI Oral Suspension well before every administration. When administering the oral suspension, use only the oral dosing syringe provided with the product. Each carton includes two syringes, but only one syringe should be used for dosing. The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost. Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose. After removing the syringe from the bottle adapter, slowly squirt ONFI Oral Suspension into the corner of the patient's mouth. Replace the cap after each use. The cap fits over the adapter when the adapter is properly placed. See ONFI Oral Suspension "Instructions for Use" for complete instruction on how to properly dose and administer the ONFI Oral Suspension.

Monitoring

There is limited information regarding Clobazam Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Clobazam and IV administrations.

Overdosage

There is limited information regarding Clobazam overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Clobazam Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Clobazam Mechanism of Action in the drug label.

Structure

There is limited information regarding Clobazam Structure in the drug label.

Pharmacodynamics

There is limited information regarding Clobazam Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Clobazam Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Clobazam Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Clobazam Clinical Studies in the drug label.

How Supplied

There is limited information regarding Clobazam How Supplied in the drug label.

Storage

There is limited information regarding Clobazam Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Clobazam Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Clobazam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Clobazam Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Clobazam Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Clobazam

File:Clobazam-2D-skeletal.png
File:Clobazam3d.png
Clinical data
Pregnancy category	?
Routes of administration	Oral
ATC code	N05BA09 (WHO)
Legal status
Legal status	Schedule IV (US) Class C (New Zealand) Class C/Sch.4 (UK)
Pharmacokinetic data
Bioavailability	90%
Metabolism	Hepatic
Elimination half-life	18 hours
Excretion	Renal
Identifiers
IUPAC name 7-Chloro-1,5-dihydro-1-methyl-5-phenyl- 1,5-benzodiazepine-2,4(3H)-dione
CAS Number	22316-47-8
PubChem CID	2789
DrugBank	APRD00307
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C16H13ClN2O2
Molar mass	300.74

Clobazam is a drug which is a benzodiazepine derivative. It has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984.

Pharmacology

Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4). Like other 1,5-benzodiazepines (arfendazam, lofendazam, e.g.), it has less affinity for the ω₁-allosteric binding site on the GABA_A receptor compared to the 1,4-benzodiazepines. It has selective affinity for the ω₂ site, where it has agonistic activity.

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10mg or 20 mg of clobazam was shown to be much less sedating than either 0.5mg or 1 mg of clonazepam.

The ω₁-receptor, which is found on the α₁ subtype of the GABA_A receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α₁ receptors were insensitive to diazepam. It would seem, then, that the anticonvulsant properties of clobazam are due to its selective affinity for ω₂.

In 1996, Nakamura et al reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride currents at GABA_A-receptor-coupled Cl^- channels. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts most efficiently in GABA-deficient brain tissue.

Nine years earlier, Kilpatrick et al noted that there was a correlation between plasma levels of norclobazam and therapeutic effects, although this was not true with the parent compound.

According to Valli and colleagues in 1984, clobazam lowered prolactin levels elevated by sulpiride, a typical antipsychotic. Hyperprolactinemia (i.e. elevated blood prolactin) occurs occasionally in people using antipsychotics, (particularly the typical ones), and can lead to cardiovascular disease, breast cancer, galactorrhea, infertility, amenorrhea, dysmenorrhea, osteopenia, osteoporosis, loss of libido, impotence, and hypogonadism.

Antipsychotics block type 2 dopamine receptors and at least 65% of central D₂ receptors need to be occupied to produce a response; >72% D₂ receptor occupancy was found to be associated with development of hyperprolactinemia.

Peak plasma protein binding occurs around 83%.

Metabolism

Clobazam has two major metabolites: N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-hydroxyclobazam by CYP2C18 and CYP2C19.

Dependence

Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken for, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.

Uses

Canada

As of 2005, clobazam (Frisium®) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures.

France

Clobazam (Urbanyl®) is approved for adjunctive therapy in complex partial seizures certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for treatment of anxiety.

India

Clobazam (Frisium®, Aventis Pharma India, Ltd.) is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety.

Japan

Clobazam (Mystan®) is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.

New Zealand

Marketed as: Frisium®

United Kingdom

Clobazam (Frisium®) is approved in the United Kingdom for short-term (2-4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression.

It is also approved for adjunctive therapy for epilepsy in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.

In addition to epilepsy and severe anxiety, clobazam is also approved as an adjunctive agent in schizophrenia and other psychotic disorders.

Clobazam is sometimes used for refractory epilepsies however, long term prophylactic treatment of epilepsy has considerable drawbacks, most importantly loss of antiepileptic effects due to tolerance which may render long term therapy useless. Other antiepileptic drugs may therefore be preferred for the long term management of epielpsy. Also benzodiazepines have the draw back after long term use of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.

Dosage

Clobazam is available in oral form only, due to its insolubility in water.

Side effects

Common

• Ataxia
• Somnolence
• Diplopia
• Dysarthria

Rare

• Gelastic seizures
• Urticaria
• Rashes

Contraindications

Clobazam should be used with great care in patients with the following disorders:

• Myasthenia gravis
• Sleep apnea
• Severe liver diseases such as cirrhosis and hepatitis
• Respiratory problems, including hypoventilation

Drug Interactions

• Alcohol increases bioavailability by 50%
• Cimetidine increases the effects of clobazam
• valproates

Abuse potential

Clobazam in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.

External links

• Inchem - Clobazam
• Mystan Prescribing Information Sheet (Japanese)

References

• Ochoa, Juan G. (2005). "GABA Receptor Agonists". Antiepileptic Drugs: An Overview. eMedicine.com, Inc. Retrieved 10 July.