Clobazam is indicated for the management of acute and chronic anxiety conditions, particularly when symptoms such as anxiety, tension, restlessness, excitement, irritability, sleep disturbances related to emotional causes, psychovegetative and psychosomatic disorders (e.g., cardiovascular or gastrointestinal), and emotional instability are present.

In patients with depression or anxiety associated with depression, Clobazam should only be used alongside appropriate concurrent therapy. Use of benzodiazepines alone in such patients may increase the risk of suicidal tendencies. Therefore, it is essential to assess whether the patient has an underlying depressive disorder before initiating treatment for anxiety associated with emotional instability.

In patients with schizophrenia or other psychotic disorders, benzodiazepines should be used only as adjunctive therapy and not as primary treatment.

Clobazam may also be used as adjunctive therapy in patients with epilepsy who are not adequately controlled with anticonvulsant monotherapy.

Clobazam acts by binding to specific sites associated with the chloride ion channel of the post-synaptic GABA receptor. These receptors are widely distributed in the central nervous system, including the limbic system and reticular formation. Clobazam enhances the duration of chloride channel opening, leading to increased chloride ion influx. This results in hyperpolarization and stabilization of neuronal membranes, thereby strengthening the inhibitory effects of GABA.

General Dosage: Dosage and duration of treatment must be adjusted to the indication, the severity of the condition and the individual clinical response. Due regard must be paid to the possibility of interference with alertness and reaction time. The fundamental principle is to keep the dose as low as possible.

Treatment of anxiety states-

Adults and adolescents over 15 years of age: The initial dose is usually 20 mg clobazam daily. If necessary, the daily dose may be increased. Generally, it is recommended that a total daily dose of 30 mg is not exceeded.

Elderly: Increased responsiveness and higher susceptibility to adverse effects may be present in elderly patients and require low initial doses and gradual dose increments under careful observation. A maintenance dose of 10 to 15 mg clobazam daily is frequently sufficient.

Children from 3 to 15 years of age: Increased responsiveness and higher susceptibility to adverse effects may be present in children and require low initial doses and gradual dose increments under careful observation. A daily dose of 5 to 10 mg clobazam is frequently sufficient. Benzodiazepines must not be given to children without careful assessment of the need for their use.

Secondary dosage adjustment: After the improvement of the symptoms, the dose may be reduced.

Timing of doses: If the dose is to be spread throughout the day, it is recommended that the larger portion be taken in the evening.

Duration of treatment: The duration of treatment must be as short as possible. The patient must be reassessed after a period not exceeding 4 weeks and regularly thereafter in order to evaluate the need for continued treatment, especially where the patient is free of symptoms. Generally, the overall duration of treatment (i.e. including tapering-of process) must not exceed 8 to 12 weeks. In certain cases, extension beyond the maximum treatment period may be necessary; treatment must not be extended without a re-evaluation of the patient's status using special expertise. It is strongly recommended that prolonged periods of uninterrupted treatment be avoided, since they may lead to dependence.

Discontinuation of treatment: It is strongly recommended that after prolonged treatment clobazam is not withdrawn suddenly but rather that the dose is reduced gradually under medical supervision; otherwise, withdrawal symptoms may occur.

Treatment of epilepsy in combination with one or more other anticonvulsants-

Adults and adolescents over 15 years of age: It is recommended that administration be started at small doses (5 to 15 mg daily), if necessary, increasing the dose gradually to a maximum daily dose of about 80 mg.

Children from 3 to 15 years of age: It is recommended that normally treatment be started at 5 mg daily. A maintenance dose of 0.3 to 1.0 mg/kg body weight daily is usually sufficient. Higher susceptibility to adverse effects may be present in children and require gradual dose increments under careful observation. Benzodiazepines must not be given to children without careful assessment of the need for their use.

Elderly: Higher susceptibility to adverse effects may be present in elderly patients and require low initial doses and gradual dose increments under careful observation.

Timing of doses: If the dose is spread throughout the day, it is recommended that the larger portion be taken in the evening. Doses of up to 30 mg clobazam can also be administered as a single evening dose.

Duration of treatment: The patient must be re-assessed after a period not exceeding 4 weeks and regularly thereafter in order to evaluate the need for continued treatment.

Discontinuation of treatment: At the end of treatment- to include cases in which response to therapy has been poor- it is strongly recommended that clobazam is not withdrawn suddenly but rather that the dose is reduced gradually; otherwise an increased susceptibility to seizures as well as other withdrawal symptoms may occur.

Administration

The tablets can be administered whole, or crushed and mixed in applesauce. The 10 mg tablets can be divided into equal halves of 5 mg. Clobazam can be given with or without food.

Alcohol: Concomitant intake of alcohol may increase the bioavailability of clobazam by approximately 50%, leading to enhanced effects.

Central nervous system depressants: When clobazam is used, especially at higher doses, it may have additive effects with other CNS depressants such as antipsychotics, anxiolytics, certain antidepressants, anticonvulsants, sedative antihistamines, anesthetics, hypnotics, narcotic analgesics, or other sedatives. Extra caution is required in cases of intoxication or when used with lithium.

Opioids: Concurrent use of benzodiazepines, including clobazam, with opioids increases the risk of sedation, respiratory depression, coma, and death due to additive CNS depressant effects. Dose and duration should be limited.

Anticonvulsants: When used with other anticonvulsants, dosage adjustments and regular monitoring (e.g., EEG) are necessary. Valproic acid levels may increase slightly to moderately, and phenytoin levels may also rise. Carbamazepine and phenytoin may enhance the metabolism of clobazam. Stiripentol increases levels of clobazam and its active metabolite via CYP3A and CYP2C19 inhibition; monitoring is recommended.

Narcotic analgesics: Concomitant use may enhance euphoria, increasing the risk of psychological dependence.

Muscle relaxants: Effects of muscle relaxants and nitrous oxide may be increased.

CYP2C19 inhibitors: Strong or moderate inhibitors may increase exposure to the active metabolite N-desmethylclobazam; dose adjustment may be required (e.g., cannabidiol, fluvoxamine, ticlopidine, omeprazole).

CYP2D6 substrates: Clobazam is a weak CYP2D6 inhibitor; dose adjustments of drugs metabolized by CYP2D6 (e.g., dextromethorphan, pimozide, paroxetine, nebivolol) may be needed.

Clobazam must not be used in:

• Patients with hypersensitivity to clobazam or any of its excipients.
• Patients with myasthenia gravis (risk of worsening muscle weakness).
• Patients with severe respiratory insufficiency.
• Patients with sleep apnea syndrome.
• Patients with severe hepatic impairment (risk of encephalopathy).
• Breastfeeding women (unless clearly necessary and carefully assessed).
• Children aged between 6 months and 3 years, except in exceptional cases for anticonvulsant therapy.

Metabolism and nutrition disorders: Common: decreased appetite

Psychiatric disorders: Common: irritability, aggression, restlessness, depression (may reveal pre-existing depression), development of tolerance (especially with prolonged use), agitation

Nervous system disorders: Very common: drowsiness, especially at the start of therapy and with higher doses; Common: sedation, dizziness, impaired attention, slowed speech/dysarthria (particularly with high doses or long-term use and usually reversible), headache, tremor, ataxia

Eye disorders: Uncommon: double vision (especially at higher doses or with long-term use and generally reversible)

Respiratory, thoracic and mediastinal disorders: Not known: respiratory depression or failure (particularly in patients with pre-existing respiratory compromise such as asthma or brain injury)

Gastrointestinal disorders: Common: dry mouth, nausea, constipation

Skin and subcutaneous disorders: Uncommon: rash; Not known: photosensitivity, urticaria, Stevens–Johnson syndrome, toxic epidermal necrolysis (including rare fatal cases)

Musculoskeletal and connective tissue disorders: Not known: muscle spasms, muscle weakness

General disorders and administration site conditions: Very common: fatigue, especially at treatment initiation or with higher doses; Not known: delayed response to stimuli, hypothermia

Investigations: Uncommon: weight gain (particularly with higher doses or prolonged use)

Pregnancy: Clobazam is not recommended during the first trimester or in women of childbearing potential not using contraception. It should only be used during pregnancy if the expected benefit outweighs the potential risk to the fetus. Animal studies have shown reproductive toxicity, and clobazam crosses the placenta. While large cohort data have not shown a clear increase in malformations, some studies suggest a higher incidence of cleft lip and palate with benzodiazepines. Use in late pregnancy or during labor may lead to neonatal respiratory depression, hypotonia, hypothermia, sedation, feeding difficulties, and “floppy infant syndrome.” Prolonged use during late pregnancy may also cause neonatal dependence and withdrawal symptoms. Careful assessment and monitoring are required. If continued, use the lowest effective dose.

Lactation: Clobazam should not be used during breastfeeding, as it passes into breast milk.

Serious Skin Reactions: Severe skin reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in both children and adults during post-marketing use. Most cases were associated with concomitant use of other drugs, particularly antiepileptics known to cause serious skin reactions. These conditions may be life-threatening. Patients should be closely monitored for early signs and symptoms of SJS/TEN, especially within the first 8 weeks of treatment. If suspected, clobazam must be discontinued immediately and should not be restarted; alternative therapy should be considered.

Respiratory depression: Clobazam may cause respiratory depression, particularly at higher doses. Patients with acute or chronic respiratory insufficiency require careful monitoring and possible dose adjustment. It is contraindicated in severe respiratory insufficiency.

Muscle weakness: Clobazam may induce muscle weakness and should not be used in patients with myasthenia gravis.

Renal and hepatic impairment: In patients with impaired renal or hepatic function, sensitivity to clobazam and the risk of adverse effects are increased. Dose adjustment may be required, and regular monitoring is recommended, especially during long-term therapy.

Elderly patients: Elderly patients are more susceptible to adverse effects such as drowsiness, dizziness, and muscle weakness, increasing the risk of falls and serious injury. Dose reduction is advised.

Tolerance in epilepsy: During long-term treatment of epilepsy with benzodiazepines, including clobazam, reduced anticonvulsant efficacy may occur due to the development of tolerance.

CYP2C19 poor metabolizers: Patients who are poor metabolizers of CYP2C19 may have higher levels of the active metabolite N-desmethylclobazam. Dose adjustment (e.g., lower starting dose with careful titration) may be necessary.

Suicidality: Some studies indicate an increased risk of suicidal thoughts and behavior in patients treated with benzodiazepines. Although data for clobazam are limited, such cases have been reported. Close monitoring is essential.

Concomitant use of CYP2C19 inhibitors: Use of clobazam with CYP2C19 inhibitors (e.g., cannabidiol-containing medicinal or recreational products) may increase exposure to N-desmethylclobazam, leading to enhanced adverse effects such as sedation. Dose adjustment may be required, and such combinations should be used cautiously.

Benzodiazepine hypnotics

Do not use after the expiry date. Store below 30°C and protect from light. Keep out of reach of children.