Clobazam

Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam (N-CLB), the active metabolite of clobazam. Dosage adjustment of clobazam may be necessary when co-administered with strong (e.g. fluconazole, fluvoxamine, ticlopidine) or moderate (e.g. omeprazole) CYP2C19 inhibitors.

Clobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol may be necessary.

In patients with impairment of renal function, responsiveness to clobazam and susceptibility to adverse effects are increased, and a dose reduction may be necessary. In long term treatment renal function must be checked regularly.

It is recommended that patients abstain from drinking alcohol during treatment with clobazam (increased risk of sedation and other adverse effects.

Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50%.

In patients with impairment of hepatic function, responsiveness to clobazam and susceptibility to adverse effects are increased, and a dose reduction may be necessary. In long term treatment hepatic function must be checked regularly.

The effects of muscle relaxants and nitrous oxide may be enhanced.

If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.

Concomitant use of clobazam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as clobazam with opioids should be reserved for patients for whom alternative treatment options are not possible.

If a decision is made to prescribe clobazam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms.

Addition of clobazam to established anticonvulsant medication (e.g phenytoin, valproic acid) might cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dose of clobazam should be determined by monitoring the EEG and the plasma levels of the other drugs checked.

Phenytoin and carbamazepine may cause an increase in the metabolic conversion of clobazam to the active metabolite N–desmethyl clobazam which may result in adverse reactions.

Stiripentol increases plasma levels of clobazam and its active metabolite N-desmethylclobazam, through inhibition of CYP3A and CYP2C19. Monitoring of blood levels is recommended, prior to initiation of stiripentol, and then once new steady-state concentration has been reached, i.e. after 2 weeks approximately.

When cannabidiol and clobazam are co-administered, bi-directional PK interactions occur. Based on a healthy volunteer study, elevated levels (3-to 4-fold) of N-desmethylclobazam (an active metabolite of clobazam) can occur when combined with cannabidiol, likely mediated by CYP2C19 inhibition. Increased systemic levels of these active substances may lead to enhanced pharmacological effects and to an increase in adverse drug reactions. Concomitant use of cannabidiol and clobazam increases the incidence of somnolence and sedation. Reduction in dose of clobazam should be considered if somnolence or sedation are experienced when clobazam is co-administered with cannabidiol.

Concomitant administration of drugs, inhibit the monooxygenase system, such as cimetidine and erythromycin, can enhance the effects of clobazam.

Benzodiazepines including clobazam, should be used with extreme caution in patients with a history of alcohol or drug abuse.

A lower dose is recommended for patients with chronic or acute respiratory insufficiency due to the risk of respiratory depression (respiratory functions must be monitored and a dose reduction may be necessary).

In patients who are CYP2C19 poor metabolisers, levels of the active metabolite N-desmethylclobazam are expected to be increased as compared to extensive metabolizers. Dosage adjustment of clobazam may be necessary (e.g. low starting dose with care dose titration.

Clobazam may cause muscle weakness, therefore, in patients with pre-existing muscle weakness or spinal or cerebellar ataxia, special observation is required and a dose reduction may be necessary. Clobazam is contraindicated in patients with myasthenia gravis.

There are limited amount of data from the use of clobazam in pregnant women. Nevertheless, a large amount of data collected from cohort studies has not demonstrated evidence of the occurrence of major malformations following exposure to benzodiazepines during the first trimester of pregnancy, although incidences of cleft lip and palate were reported in certain case-control studies.

Clobazam is not recommended during pregnancy and in women of childbearing potential not using contraception. Clobazam crosses the placenta. Animal studies have demonstrated reproductive toxicity.

Women of childbearing potential should be informed of the risks and benefits of the use of clobazam during pregnancy.

Women of childbearing potential should be informed to contact her physician regarding discontinuation of the product if they are pregnant or intend to become pregnant. If clobazam treatment is continued, it should be used at the lowest effective dose.

Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines during the second and/or third trimester of pregnancy.

If clobazam is administered during the late phase of pregnancy or during childbirth, effects on the neonate, such as respiratory depression (including respiratory distress and apnea), sedation signs, hypothermia, hypotonia, and feeding difficulties in the newborn (so-called “floppy infant syndrome”) are to be expected.

Moreover, infants born to mothers who have taken benzodiazepines over longer periods during the later stages of pregnancy may have developed physical dependence and may be at risk of developing a withdrawal syndrome in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.

Since benzodizepines are found in the breast milk, clobazam must not be used in breast-feeding women.

Fertility

There is insufficient information to assess effects of clobazam on fertility in humans.

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased.

Metabolism and nutrition disorders

Common: decreased appetite

Psychiatric disorders

Common: irritability, aggression, restlessness, depression (pre-existing depression may be unmasked), drug tolerance (especially during prolonged use), agitation

Uncommon: abnormal behaviour, confusional state, anxiety, delusion, nightmare, loss of libido (particularly with high doses or in long-term treatment and is reversible)

Not known: dependence (especially during prolonged use), initial insomnia, anger, hallucination, psychotic disorder, poor quality sleep, suicidal ideation

Nervous system disorders

Very common: somnolence, especially at the beginning of treatment and when higher doses are used

Common: sedation, dizziness, disturbance in attention, slow speech/dysarthria/ speech disorder (particularly with high doses or in long-term treatment, and are reversible), headache, tremor, ataxia

Uncommon: emotional poverty, amnesia (may be associated with abnormal behaviour), memory impairment, anterograde amnesia (in (in the normal dose range, but especially at higher dose levels)

Not known: cognitive disorder, altered state of consciousness (particularly in elderly patients, may be combined with respiratory disorders), nystagmus (particularly with high doses or in long-term treatment), gait disturbance (particularly with high doses or in long-term treatment and is reversible)

Eye Disorders

Uncommon: diplopia (particularly with high doses or in long-term treatment and is reversible)

Respiratory, thoracic and mediastinal disorders

Not known: respiratory depression respiratory failure (particularly in patients with pre-existing compromised respiratory function e.g. in patients with bronchial asthma or brain damage)

Gastrointestinal disorders

Common: dry mouth, nausea, constipation

Skin and subcutaneous tissue disorders

Uncommon: rash

Not known: urticaria; Steven-Johnson syndrome, toxic epidermal necrolysis (including some cases with fatal outcome);

Musculoskeletal and connective tissue disorders

Not known: muscle spasms, muscle weakness

General disorders and administration site conditions

Very common: fatigue, especially at the beginning of treatment and when higher doses are used

Not known: slow response to stimuli, hypothermia

Investigations

Uncommon: weight increased (particularly with high doses or in long-term treatment) Injury poisoning and procedural complications

Uncommon: fall