Frisium (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis France (France)

Manufactured By

Opella Healthcare International, SAS (France)

ATC Code

N05BA09 (Clobazam)

Active Substance

Clobazam (Rec.INN registered by WHO)

Dosage Form

Frisium

Tablets 10 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex, with a score and engravings “B” and “GL” on one side and an engraved “Hoechst” logo on the other side of the tablet.

Excipients: lactose monohydrate, corn starch, talc, colloidal silicon dioxide, magnesium stearate.

20 pcs. – blisters (5) – cardboard packs.

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Benzodiazepine derivatives

Pharmacological Action

Anticonvulsant, anxiolytic agent, a 1,5-benzodiazepine derivative. When taken in a single dose of up to 20 mg or a divided dose of up to 30 mg, Clobazam does not affect psychomotor functions, skilled work performance, memory, or higher mental functions.

Pharmacokinetics

After oral administration, Clobazam is rapidly and completely absorbed. The time to reach C_max in blood plasma is 0.5-4 hours. Administration with food or liquid slows absorption by approximately 1 hour but does not affect the overall extent of absorption. Concurrent use of alcohol may increase the bioavailability of clobazam by 50%.

After a single 20 mg dose, interindividual variability in C_max in blood plasma (222-709 ng/ml) was observed after 0.25-4 hours. Clobazam is a lipophilic substance and is rapidly distributed throughout the body.

According to pharmacokinetic analysis, the apparent V_d at steady state is approximately 102 L and is independent of concentration within the therapeutic range.

Plasma protein binding is approximately 80-90%. Accumulation of clobazam to steady-state concentration occurs over 2-3 doses, whereas the active metabolite N-desmethylclobazam accumulates approximately 20 times longer after administration of clobazam twice daily. Steady-state concentrations are reached approximately within 2 weeks.

Clobazam is rapidly and extensively metabolized in the liver. The metabolism of clobazam occurs mainly by demethylation in the liver to N-desmethylclobazam, mediated by cytochrome CYP3A4 and to a lesser extent by CYP2C19. N-desmethylclobazam is an active metabolite and the main circulating metabolite detected in human plasma. N-desmethylclobazam undergoes further metabolism in the liver to form 4-hydroxy-N-desmethylclobazam mainly under the action of CYP2C19.

In patients with low CYP2C19 metabolic activity, a five-fold increase in the concentration of N-desmethylclobazam was noted compared to patients with high CYP2C19 metabolic activity.

Clobazam is a weak inhibitor of CYP2D6. Concurrent administration with dextromethorphan leads to an increase in AUC by 90% and C_max values by 59% for dextromethorphan.

Concomitant administration of 400 mg ketoconazole (a CYP3A4 inhibitor) increased the AUC of clobazam by 54% without affecting C_max. These changes are not considered clinically significant.

According to pharmacokinetic analysis, the T_1/2 of clobazam and the main metabolite N-desmethylclobazam from blood plasma is 36 hours and 79 hours, respectively.

Clobazam is cleared primarily by metabolism in the liver followed by renal elimination. Approximately 80% of the administered clobazam dose is recovered in urine and approximately 11% in feces. Less than 1% of unchanged clobazam and less than 10% of unchanged N-desmethylclobazam is excreted by the kidneys.

Indications

Symptomatic treatment of acute and chronic states of tension, agitation, and anxiety; epilepsy (as adjunctive therapy in patients who have not achieved remission on therapy with one or more antiepileptic drugs).

ICD codes

Dosage Regimen

A treatment break may be required if a “wearing-off” phenomenon develops; therapy should then be resumed by prescribing the minimum dose. When completing treatment (also in patients who did not respond to therapy), it is recommended to reduce the drug dose gradually, as the risk of developing a “withdrawal” (“rebound”) syndrome is higher after abrupt discontinuation of the drug.

Adverse Reactions

Psychiatric disorders frequent – irritability, aggressiveness, agitation, depression (signs of pre-existing depressive disorder may manifest), habituation to the drug (especially with long-term use), agitation; infrequent – abnormal behavior, confusion, anxiety, delirium, nightmares, obsessions, loss of libido (especially when used in high doses for a long time); frequency unknown – drug dependence (especially with long-term use), insomnia, anger, hallucinations, psychotic disorders, decreased sleep quality, suicidal thoughts.

Nervous system disorders very frequent – drowsiness, especially at the beginning of therapy and when used in high doses; frequent – sedative effect, dizziness, attention disturbance, slowed speech/articulation disorder/speech function disorders (especially at high doses or with long-term use, reversible), headache, tremor, ataxia; infrequent – emotional burnout, amnesia (may be accompanied by abnormal behavior), memory impairment, anterograde amnesia (at usual doses, more often at higher doses); frequency unknown – cognitive disorders, altered state of consciousness (especially in elderly patients, may be combined with respiratory disorders), nystagmus (especially at high doses or with long-term use), gait disturbance (especially at high doses or with long-term use, reversible), delayed reaction to stimuli.

Eye disorders infrequent – diplopia (especially at high doses or with long-term use, reversible).

Respiratory system disorders frequency unknown – respiratory depression, breathing impairment in patients with a history of impaired respiratory function, for example, bronchial asthma or cerebrovascular accident.

Gastrointestinal disorders frequent – dry mouth, nausea, constipation.

Metabolism and nutrition disorders frequent – decreased appetite; infrequent – weight gain (especially at high doses or with long-term use); frequency unknown – hypothermia.

Skin and subcutaneous tissue disorders infrequent – rash; frequency unknown – photosensitivity reactions, urticaria, toxic epidermal necrolysis (including fatal outcome), Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders frequency unknown – muscle spasm, muscle weakness.

General disorders very frequent – feeling of fatigue (especially at high doses or with long-term use).

Contraindications

Hypersensitivity to clobazam, benzodiazepine derivatives; states of acute alcohol intoxication, overdose of hypnotics or analgesics, neuroleptics, antidepressants, lithium salts; spinal and cerebellar ataxia; severe pancreatic dysfunction; severe hepatic insufficiency (risk of hepatic encephalopathy), severe liver disease (especially drug-induced hepatitis) in the patient’s history and/or in his/her close blood relatives (risk of encephalopathy); history of drug or alcohol dependence (increased risk of dependence); myasthenia gravis (risk of worsening muscle weakness); severe respiratory failure (risk of deterioration); sleep apnea syndrome (risk of deterioration); Stevens-Johnson syndrome and toxic epidermal necrolysis; pregnancy; breastfeeding period; children under 3 years of age.

With caution

Mild and moderate hepatic insufficiency and history of pancreatic dysfunction; congenital enzymopathies; bone marrow hematopoiesis suppression (leukopenia, thrombocytopenia, anemia); renal insufficiency (dose adjustment required); concurrent use of several anticonvulsant drugs (due to increased risk of liver damage); concurrent use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures); concurrent use of neuroleptics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepines (possibility of potentiating their effects).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: hepatic insufficiency (risk of hepatic encephalopathy), severe liver disease (especially drug-induced hepatitis) in the patient’s history and/or in his/her close blood relatives (risk of encephalopathy).

Use in Renal Impairment

With caution: renal insufficiency (dose adjustment required).

Pediatric Use

Contraindicated for use in children under 3 years of age.

Geriatric Use

In elderly patients, due to increased sensitivity to adverse reactions such as drowsiness, dizziness, muscle weakness, there is an increased risk of fainting or falling, which can lead to serious injuries. Dose reduction is recommended.

Special Precautions

Taking benzodiazepines can cause amnesia. In case of memory loss or severe amnesia, the use of benzodiazepines may hinder psychological adaptation.

In patients with muscle weakness, spinal or cerebellar ataxia, or a history of sleep apnea, a reduction in the clobazam dose may be required.

In patients with depression and aggressive behavior towards themselves and others, a tendency to suicide may be noted, so special caution should be exercised when prescribing benzodiazepines to patients with personality disorders.

The use of benzodiazepines (including Clobazam) may lead to the development of physical and mental dependence. The risk of dependence increases with increasing dosage and duration of treatment, and is also increased in patients with a history of alcohol or drug dependence. Therefore, the duration of treatment should be as short as possible.
In case of physical dependence development, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms (or “rebound” syndrome). Withdrawal syndrome is characterized by a recurrence in an intensified form of the initial indications for clobazam use, which may be accompanied by other reactions, including mood changes, anxiety, or sleep disturbances. Withdrawal syndrome may also occur when abruptly switching from a benzodiazepine with a long duration of action (e.g., Clobazam) to drugs with a short duration of action.

During post-marketing surveillance of clobazam use in both children and adults, serious skin adverse reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Most reported cases are associated with concomitant use of other medications that can lead to the development of serious skin adverse reactions, including antiepileptic drugs.

Stevens-Johnson syndrome and toxic epidermal necrolysis can be fatal. Patients should be carefully monitored for signs or symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis, especially during the first 8 weeks of treatment. Clobazam administration should be immediately discontinued if Stevens-Johnson syndrome and toxic epidermal necrolysis are suspected. If all signs or symptoms indicate the development of Stevens-Johnson syndrome and toxic epidermal necrolysis, the use of clobazam cannot be resumed, and the possibility of prescribing alternative therapy should be considered.

Clobazam is contraindicated in patients with severe respiratory failure. In patients with chronic or acute respiratory failure, respiratory function should be carefully monitored, and a reduction in the clobazam dose may be required.

In patients with impaired renal or hepatic function, sensitivity to clobazam and the risk of adverse reactions are increased. In these cases, a reduction in the drug dose may be required. During long-term treatment, liver and kidney function should be regularly monitored.

When treating epilepsy with benzodiazepines, including Clobazam, the possibility of a reduction in the anticonvulsant effect (development of tolerance) during treatment should be taken into account.

In patients with slow metabolism of the CYP2C19 isoenzyme, the concentration of the active metabolite N-desmethylclobazam is expected to be increased compared to patients who are rapid metabolizers of the CYP2C19 isoenzyme. Since this may lead to an increase in adverse events, adjustment of the clobazam dose is necessary (e.g., low initial dose with careful dose titration).

Patients are advised to refrain from consuming alcohol during treatment with clobazam (increased risk of sedative effect and other adverse reactions).

Concurrent use of opioids and benzodiazepines, including Clobazam, may lead to sedative effect, respiratory depression, coma, and death. Thus, concurrent prescription of opioids and benzodiazepines may only be considered in patients for whom alternative treatment options are ineffective. If a decision is made to prescribe clobazam treatment concurrently with opioids, it is necessary to use the minimum effective doses and for the minimum duration, and to carefully observe patients for signs and symptoms of respiratory depression and sedative symptoms.

Effect on ability to drive vehicles and operate machinery

Driving vehicles and operating machinery is contraindicated.

Drug Interactions

Concomitant alcohol consumption may increase the bioavailability of clobazam by 50% and, consequently, enhance the effect of clobazam, for example, the sedative effect.

Drugs affecting the central nervous system (CNS)
Especially when using clobazam in higher doses, enhancement of the central depressant effect may be observed in cases of concurrent use with antipsychotics, hypnotics, anxiolytics or sedatives, antidepressants, narcotic analgesics, anticonvulsants, anesthetics, and sedative antihistamines. Special caution is also necessary when prescribing clobazam in cases of intoxication with the listed agents or lithium.

Enhancement of the depressant effect on the CNS, especially when clobazam is used in increased doses, may be observed in cases of simultaneous use with antipsychotics, hypnotics, anxiolytics or sedatives, antidepressants, narcotic analgesics, anticonvulsants, anesthetics, and sedative antihistamines. Special caution is also necessary when prescribing clobazam in cases of intoxication with the listed agents or lithium.

Concomitant use of benzodiazepines, including clobazam, and opioid analgesics increases the risk of sedative effect, respiratory depression, coma, and fatal outcome due to the additive effect on the CNS. It is necessary to reduce the dose and duration of simultaneous use of benzodiazepines and opioids.

Concomitant use of clobazam with anticonvulsant drugs (for example, phenytoin, valproic acid) may cause a change in the plasma concentration of these drugs. When used as adjunctive therapy for the treatment of epilepsy, the dosage of clobazam should be titrated by monitoring the EEG and the concentration of other drugs in the plasma.

Phenytoin and carbamazepine may cause an increase in the metabolic conversion of clobazam to the active metabolite N-desmethylclobazam.

Stiripentol increases the plasma concentrations of clobazam and its active metabolite N-desmethylclobazam by inhibiting CYP3A and CYP2C19. Monitoring of clobazam and active metabolite plasma levels is recommended before starting stiripentol and then, after reaching a new steady-state concentration, i.e., approximately after 2 weeks. Clinical monitoring is recommended, and a dose adjustment may be required.

The effect of muscle relaxants, analgesics, and nitrous oxide may be enhanced.

Strong and moderate inhibitors of CYP2C19 may lead to an enhanced effect of N-desmethylclobazam, the active metabolite of clobazam. A dose adjustment of clobazam may be required when used concomitantly with strong (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate (e.g., omeprazole) inhibitors of CYP2C19.

Clobazam is a weak inhibitor of the CYP2D6 isoenzyme. A dose adjustment of drugs metabolized by the CYP2D6 isoenzyme (e.g., dextromethorphan, pimozide, paroxetine, nebivolol) may be required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.