Clobazam

Clobazam is an Antiseizure agent belonging to the Long-acting benzodiazepine class.

Clobazam is a benzodiazepine used as adjunct treatment in seizures associated with Lennox-Gastaut syndrome.

Clobazam rapidly and extensively absorbed from the gastrointestinal tract. The bioavailability is approximately 100% (tab). Time to peak plasma concentrations is about 0.5-4 hours (tab) and 0.5-2 hours (oral suspension). Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively. Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.

Clobazam shows side effects like Tiredness, problems with coordination, difficulty speaking or swallowing, drooling, change in appetite, vomiting, constipation, cough, joint pain.

Clobazam is available in the form of Oral Tablet, Oral suspension, and oral film.

Clobazam is available in India, Canada, the US, France, Ireland, Germany, Italy, Denmark, Spain, and Iceland.

Clobazam belongs to Long-acting benzodiazepine class and acts as Antiseizure Agent.

Clobazam long-acting benzodiazepine. Clobazam is a 1,5 benzodiazepine which binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.

The Onset of action of Clobazam is not clinically established.

The Time to peak plasma concentration of Clobazam is approximately 0.5-4 hours (tab); 0.5-2 hours (oral suspension).

Clobazam is available in the form of Oral Tablet, Oral suspension, and oral film.

Clobazam Tablet, suspension is taken orally usually in divided dose.

Clobazam oral film is placed on top of tongue where it dissolves.

Clobazam is used to control seizures in adults and children 2 years of age and older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often causes developmental delays).

Clobazam is an Antiseizure agent belonging to the Long-acting benzodiazepine class.

Clobazam is in a class of medications called benzodiazepines. It works by decreasing abnormal electrical activity in the brain.

Clobazam is approved for use in the following clinical indications

• Anxiety disorders
• Catamenial epilepsy
• Lennox-Gastaut
• Seizures, treatment refractory

• Anxiety disorders

Oral: 20 to 30 mg/day in 2 to 3 divided doses; may gradually increase based on response and tolerability to 80 mg/day.

• Catamenial epilepsy

Oral: 20 to 30 mg daily for 10 days during the perimenstrual period.

• Lennox-Gastaut

Oral: Initial: 5 mg twice daily for ≥1 week, then increase based on response and tolerability to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter.

• Seizures, treatment refractory

Oral: Initial: 5 to 15 mg/day; may gradually increase based on response and tolerability to 40 mg/day. Alternatively, a maximum dose of 80 mg/day has also been recommended. Daily doses of up to 30 mg may be taken as a single dose at bedtime; higher doses should be divided.

Clobazam is available in various strengths as 10 mg; 20 mg; 2.5 mg/mL; 5 mg.

Clobazam is available in the form of Oral Tablet, Oral suspension, and oral film.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment: Initial: 5 mg once daily for ≥1 week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily; after ≥1 week may increase to 20 mg twice daily based on patient tolerability and response; maximum: 40 mg/day.

Severe impairment: There are no dosage adjustments provided.

Clobazam is contraindicated in patients with

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

• Anterograde amnesia

Benzodiazepines have been associated with anterograde amnesia.

• CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Paradoxical reactions

Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders.

• Skin reactions

Serious reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Monitor patients closely for signs and symptoms (eg, burning sensation, pleomorphic rash, petechiae, vesicles, bullae) especially during the first 8 weeks or when reintroducing therapy. Permanently discontinue immediately if rash is suggestive of SJS/TEN.

• Sleep-related activities

Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines.

• Suicidal ideation

Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression.

• Depression

Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus).

• Hepatic impairment

Use with caution in patients with hepatic impairment; dose adjustment may be necessary.

• Respiratory disease

Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.

Clobazam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Clobazam, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

There are no adequate and well-controlled studies of Clobazam in pregnant women. In animal studies, administration of clobazam during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Common

Drowsiness, lethargy, drooling, aggressive behavior, irritability, Upper respiratory tract infection, Fever, Ataxia, sedation, insomnia, psychomotor agitation, fatigue, dysarthria, Constipation, vomiting, decreased appetite, increased appetite, dysphagia, Urinary tract infection, Cough, pneumonia, bronchitis.

• Rare

Abdominal distention, agitation, anemia, angioedema, anxiety, apathy, behavioral changes, blurred vision, confusion, delirium, delusions, depression, diplopia, eosinophilia, facial edema, hallucination, hypothermia, increased liver enzymes, leukopenia, lip edema, mood changes, muscle spasm, pulmonary aspiration, respiratory depression, skin rash, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, thrombocytopenia, toxic epidermal necrolysis, urinary retention, urticaria, withdrawal syndrome.

Alcohol (Ethyl)

May enhance the CNS depressant effect of Clobazam. Alcohol (Ethyl) may increase the serum concentration of Clobazam. Management: Patients taking clobazam should avoid alcohol consumption. If combined, patients should be informed that the CNS depressant effects of alcohol and clobazam may be potentiated.

Atogepant

CYP3A4 Inducers (Weak) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided.

Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if co-administering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be co-administered with blonanserin.

Buprenorphine

CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.

Cannabidiol

Clobazam may enhance the hepatotoxic effect of Cannabidiol. Cannabidiol may increase serum concentrations of the active metabolite(s) of Clobazam. Cannabidiol may increase the serum concentration of Clobazam.

Cannabinoid-Containing Products

CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.

Chlormethiazole

May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.

Clozapine

Benzodiazepines may enhance the adverse/toxic effect of Clozapine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined.

Dexmedetomidine

CNS Depressants may enhance the CNS depressant effect of Dexmedetomidine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants and consider dose reductions of either agent to avoid excessive CNS depression.

Droperidol

May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use.

Fenfluramine

Clobazam may increase the serum concentration of Fenfluramine. Management: Limit the fenfluramine dose to a maximum daily dosage of 0.2 mg/kg twice daily (17 mg/day) when used in combination with stiripentol and clobazam.

Flunitrazepam

CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available.

Hormonal Contraceptives

CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability.

Hydroxyzine

May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant.

Methadone

Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution.

Methotrimeprazine

May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression.

Olanzapine

Benzodiazepines may enhance the adverse/toxic effect of Olanzapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended.

Opioid Agonists

CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Oxycodone

CNS Depressants may enhance the CNS depressant effect of Oxycodone. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Ropeginterferon Alfa-2b

CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania).

Suvorexant

CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended.

Thioridazine

CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication.

Yohimbine

May diminish the therapeutic effect of Antianxiety Agents.

Zolpidem

CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.

Zuranolone

May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects.

The common side effects of Clobazam include the following

Common side effects

Tiredness, problems with coordination, difficulty speaking or swallowing, drooling, change in appetite, vomiting, constipation, cough, joint pain.

Rare side effects

Difficult, painful, or frequent urination, cough, difficulty breathing, fever, sores in your mouth, rash, hives, peeling or blistering skin, fever.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Clobazam in pregnant women. In animal studies, administration of clobazam during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Clobazam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Clobazam, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in patients less than 2 years of age have not been established.

• Geriatric Use

Clinical studies of Clobazam did not include enough subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day. Patients should be titrated initially to 10-20 mg/day. Patients may be titrated further to a maximum daily dose of 40 mg if tolerated.

Overdose and intoxication with benzodiazepines, including Clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.

Management:

The management of Clobazam overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs. Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents. The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in Clobazam overdose has not been assessed. The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.

• Pharmacodynamic

Clobazam belongs to the benzodiazepine class of drugs. Clobazam acts on the GABAA receptor to increase GABAnergic transmission, particularly chloride conductance in neurons. This causes neuronal hyperpolarization, resulting in an increase in the action potential threshold and reducing neuron firing frequency. Consequently, the general neuronal activity of the central nervous system is depressed; therefore, clobazam can be used to treat diseases caused by excessive excitatory action potentials.

• Pharmacokinetics

Absorption

Clobazam rapidly and extensively absorbed from the gastrointestinal tract. The bioavailability is approximately 100% (tab). Time to peak plasma concentrations is about 0.5-4 hours (tab) and 0.5-2 hours (oral suspension).

Distribution

Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein

binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.

Metabolism and Excretion

Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203993s005lbl.pdf
• https://go.drugbank.com/drugs/DB00349
• https://www.uptodate.com/contents/clobazam-drug-information?search=clobazam&source=panel_search_result&selectedTitle=1~27&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://medlineplus.gov/druginfo/meds/a612008.html
• https://www.drugs.com/dosage/clobazam.html