Frisium

/ Sanofi

Treatment of anxiety: The usual anxiolytic dose for adults is 20-30 mg daily in divided doses or as a single dose given at night. Doses up to 60mg daily have been used in the treatment of adult in-patients with severe anxiety. The lowest dose that can control symptoms should be used. After improvement of the symptoms, the dose may be reduced. It should not be used for longer than 4 weeks. Long term chronic use as an anxiolytic is not recommended. In certain cases, extension beyond the maximum treatment period may be necessary; treatment must not be extended without 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. Treatment should always be withdrawn gradually. Patients who have taken Clobazam for a long time may require a longer period during which doses are 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.
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. Doses of 10-20 mg daily in anxiety may be used in the elderly, who are more sensitive to the effects of psychoactive agents.
Patients with renal or hepatic impairment: Increased responsiveness and higher susceptibility to adverse effects may be present in these patients and require low initial doses and gradual dose increments under careful observation.
Method of Administration: Tablets can be administered whole, or crushed and mixed in apple sauce. The 10mg tablets can be divided into equal halves of 5mg. Clobazam can be given with or without food.

Short-term relief (2-4 weeks) only of anxiety in adults patients that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short term psychosomatic, organic or psychotic illness. The use of Clobazam to treat short-term “mild” anxiety is inappropriate and unsuitable.
Before treatment of anxiety states associated with emotional instability, it must first be determined whether the patient suffers from a depressive disorder requiring adjunctive or different treatment. Indeed, in patients with anxiety associated with depression, Clobazam must be used only in conjunction with adequate concomitant treatment. Use of benzodiazepine (such as Clobazam) alone, can precipitate suicide in such patients.
In adult patients with schizophrenic or other psychotic illnesses, use of benzodiazepines is recommended only for adjunctive, i.e. not for primary treatment.

Patients with hypersensitivity to benzodiazepines or any of the excipients of this drug. Patients with any history of drug or alcohol dependence (increased risk of development of dependence), Patients with myasthenia gravis (risk of aggravation of muscle weakness), Patients with severe respiratory insufficiency (risk of deterioration), Patients with sleep apnea syndrome (risk of deterioration), Patients with severe hepatic insufficiencies (risk of precipitating encephalopathy), During the first trimester of pregnancy, Breast-feeding women.

Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who are depressed and aggressive behaviour towards self and others may be precipitated. Extreme caution should therefore be used in prescribing benzodiazepines in patients with personality disorders.
Alcohol: It is recommended that patients abstain from drinking alcohol during treatment with Clobazam (increased risk of sedation and other adverse effects).
Amnesia: Anterograde amnesia may occur  even if benzodiazepines are used in the normal dose range, but especially at higher dose levels. In case of loss or bereavement psychological adjustment may be inhibited by benzodiazepines.
Muscle weakness: Clobazam can cause muscle weakness. Therefore, in patients with pre-existing muscle weakness or spinal or cerebellar ataxia or sleep apnea, special observation is required and a dose reduction may be necessary. Clobazam is contraindicated in patients with myasthenia gravis.
Dependance: Use of benzodiazepines – including Clobazam- may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Therefore the duration of treatment should be as short as possible (see Posology). Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (or rebound phenomena). Rebound phenomena are characterised by a recurrence in enhanced form of the symptoms which originally led to Clobazam treatment. This may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. A withdrawal syndrome may also occur when abruptly changing over from a benzodiazepine with a long duration of action (for example, Clobazam) to one with a short duration of action.
Serious Skin Reactions: Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults during the post-marketing experience. A majority of the reported cases involved the concomitant use of other drugs, including antiepileptic drugs that are associated with serious skin reactions.
Respiratory depression: Respiratory function should be monitored in patients with chronic or acute severe respiratory insufficiency and a dose reduction of Clobazam may be necessary.
Renal and hepatic impairement: In patients with impairment of renal or hepatic function, responsiveness to clobazam and susceptibility to adverse effects are increased, and a dose reduction may be necessary. In long-term treatment renal and hepatic function must be checked regularly.
Elderly patients: In the elderly, due to the increased sensitivity to adverse reactions such as drowsiness, dizziness, muscle weakness, there is an increased risk of fall that may result in serious injury. A dose reduction is recommended.
CYP2C19 poor metabolizers: In patients who are CYP2C19 poor metabolizers, 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 careful dose titration). In the treatment of epilepsy with benzodiazepines – including clobazam – consideration must be given to the possibility of a decrease in anticonvulsant efficacy (development of tolerance) in the course of treatment. 
For full details see prescribing information.

Nervous system disorders: Sedation, leading to tiredness and sleepiness, especially at the beginning of treatment and when higher doses are used. Slowing of reaction time, drowsiness, numbed emotions, confusion, headaches, dizziness, muscle weakness, ataxia, or a fine tremor of the fingers may occur. Slowed or indistinct speech (disorders of articulation), unsteadiness of gait and other motor functions, or loss of libido may occur.
Such reaction occur particularly with high doses or in long- term treatment, and is reversible.
After prolonged use of benzodiazepines, impairment of consciousness, sometimes combined with respiratory disorders, has been reported in very rare
cases, particularly in elderly patients: it sometimes persists for some length of time. Anterograde amnesia may occur, especially at higher dose levels. Amnesia effects may be associated with inappropriate behaviour.
Psychiatric disorders: Especially in the elderly, paradoxical reactions, may occur such as restlessness, irritability, difficulty in sleeping, acute agitational states, anxiety, aggressiveness, delusion, fits of rage, nightmares, hallucinations, psychotic reactions, suicidal tendencies or frequent muscle spasms. In the event of such reactions, treatment with clobazam must be discontinued. Pre-existing depression may be unmasked during benzodiazepine use. Tolerance and physical and/or psychic dependence may develop, especially during prolonged use. Discontinuation of the therapy may result in withdrawal or rebound phenomena. Abuse of benzodiazepines has been reported.
Eye disorders: Visual disorders (diplopia, nystagmus). Such reactions occur particulary with high doses or in long-term treatment, and are reversible.
Respiratory, thoracic and mediatinal disorders: Respiratory depression, especially if administered in high doses. Therefore, particularly in patients with pre-existing compromised respiratory function (i.e., in patients with bronchial asthma) or brain damage, respiratory insufficiency may occur or deteriorate.
Gastrointestinal disorders: Dry mouth, constipation, decreased appetite, nausea.
Skin and subcutaneous tissue disorders: Isolated cases of skin reactions, such as rashes or urticaria, have been observed. Stevens-Johnson syndrome, Toxic Epidermal Necrolysi including some cases with fatal outcome.
Metabolism and nutrition disorders: Weight gain, may occur particularly with high doses or in long-term treatment. This reaction is reversible.
General disorders: Fall. When used as an adjuvant in the treatment of epilepsy, this preparation may in rare cases cause restlessness and muscle weakness.
Additional adverse events reported postmarketing: urinary retention, hypothermia.
For full details see prescribing information.

Central nervous system depressant drugs: Especially when clobazam is administered at higher doses, an enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anticonvulsant drugs, anaesthetics and sedative antihistamines. Special caution is also necessary when clobazam is administered in cases of intoxication with such substances or with lithium.
Alcohol: Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% and therefore increase the effects of clobazam (e.g.; sedation). This affects the ability to drive or use machines.
Anticonvulsants: Addition of clobazam to established anticonvulsant medication (eg, phenytoin, valproic acid) may cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dosage of Frisium 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. Stiripentol increases plasma levels of clobazam and its active metabolite Ndesmethylclobazam, 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. Clinical monitoring is recommended and dose adjustment may be necessary.
Muscle relaxants: The effects of muscle relaxants, analgesics and nitrous oxide may be enhanced.
Narcotic analgesics: If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.
CYP 2C19 inhibitors: Strong and moderate inhibitors of CYP2C19 may result in increased exposure to Ndesmethylclobazam (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.
CYP 2D6 substrates: Clobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol) may be necessary.

Pregnancy: If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the product if she intends to become pregnant or suspects that she is pregnant.
Lactation: Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.
For full details see prescribing information.

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death. As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol). In the management of overdose, it is recommended that the possible involvement of multiple agents be taken into consideration. Following overdose with oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious, or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care. Secondary elimination of clobazam (by forced diuresis or haemodialysis) is ineffective. Consideration should be given to the use of flumazenil as a benzodiazepine antagonist.

Storage: Store below 25°C.