Active ingredients: Clobazam
FRISIUM 10 mg hard capsules
Indications Why is Frisium used? What is it for?
Pharmacotherapeutic group
Anxiolytics; benzodiazepines.
Therapeutic indications
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome. Insomnia.
Benzodiazepines are indicated only when the disorder is severe, disabling and subjects the subject to severe discomfort
Contraindications When Frisium should not be used
Hypersensitivity to the active substance, to benzodiazepines in general or to any of the excipients.
Myasthenia gravis.
Severe respiratory failure (e.g. severe chronic obstructive pulmonary disease).
Severe hepatic insufficiency.
Sleep apnea syndrome.
Spinal and cerebellar ataxia.
Patients with a history of drug or alcohol abuse, due to an increased risk of addiction.
Contraindicated during pregnancy and lactation (see "Pregnancy and Lactation").
Benzodiazepines should not be given to children without careful consideration of the actual need for treatment. Frisium should not be used in children under 3 years of age.
Precautions for use What you need to know before taking Frisium
Alcohol
Patients are advised to avoid alcohol intake during clobazam therapy, due to the increased risk of sedation and other undesirable effects.
Tolerance
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines can lead to the development of physical and psychological dependence on these drugs. The risk of dependence increases with dose and duration of treatment; it is greater in patients with a history of drug or alcohol abuse. The risk of dependence is also present with the daily intake of clobazam for a period of only a few weeks and is valid not only for possible abuse at particularly high doses, but also for the recommended therapeutic dosage. It is strongly recommended to avoid prolonged periods of uninterrupted treatment as they can lead to addiction.
Withdrawal symptoms
Once physical dependence has developed, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms. These may consist of headache, body aches, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following may occur. symptoms: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations and symptomatic psychosis or seizures. Other symptoms are: depression, insomnia, increased dreams, sweating, persistent tinnitus, involuntary movements, nausea, vomiting, paraesthesia, perceptual changes, abdominal and muscle cramps, tremor, myalgia, agitation, palpitations, tachycardia, panic attacks, dizziness, hyper-reflexia, short-term memory loss, hyperthermia.
Rebound insomnia and anxiety:
A transient syndrome in which symptoms that led to treatment with benzodiazepines recur in an aggravated form may occur upon discontinuation of treatment. It may be accompanied by other reactions, including mood changes, anxiety, restlessness or sleep disturbances. withdrawal or rebound symptoms is greater after abrupt cessation of treatment, it is suggested to make a gradual decrease of the dosage. It is also "important that the patient is informed of the possibility of rebound phenomena, in order to minimize the anxious reaction that the "Any occurrence of such symptoms could be triggered when Frisium is discontinued.
Duration of treatment
The duration of treatment should be as short as possible (see "Dose, method and time of administration") depending on the indication, but should not exceed four weeks for insomnia and eight to twelve weeks for anxiety, including a gradual withdrawal period. Extension of therapy beyond these periods should not occur without reassessment of the clinical situation. It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage should be progressively decreased, as abrupt discontinuation can lead to withdrawal symptoms such as agitation, anxiety and insomnia. It is also important that the patient is informed of the possibility of rebound phenomena, thus minimizing the anxiety about these symptoms should they occur upon discontinuation of the drug. There are elements to predict that, in the case of benzodiazepines with a short duration of action, withdrawal symptoms may become manifest within the dosing interval between doses, particularly for high doses. When using benzodiazepines with a long duration of action (eg Frisium), it is important to warn the patient that abrupt change to a benzodiazepine with a short duration of action is not recommended, as withdrawal symptoms may occur. benzodiazepines, in case of prolonged treatment it is advisable to evaluate the therapeutic benefit against the risk of addiction and dependence.
Amnesia
Benzodiazepines can induce antegrade amnesia whether used in the normal dosage range, but especially at high doses. This occurs most often several hours after ingestion of the drug and, therefore, to reduce the risk it should be ensured that patients can have an uninterrupted sleep of 7 to 8 hours (see "Side Effects").
Psychiatric and paradoxical reactions
When benzodiazepines are used it is known that reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes can occur. Should this occur, use of the medicinal product should be discontinued. These reactions are more likely to occur in children and the elderly as well as in patients with organic brain syndrome.
Specific groups of patients
Pediatric patients
Benzodiazepines should not be given to children without careful consideration of the actual need for treatment; the duration of treatment should be as short as possible. Elderly patients In the elderly, benzodiazepine use may be associated with an increased risk of falls due to side effects such as ataxia, muscle weakness, dizziness, sleepiness, tiredness and fatigue. Falls can lead to serious injuries and therefore it is recommended that elderly patients be treated with caution. The elderly should take a reduced dose (see "Dose, method and time of administration).
Patients with poor CYP2C19 metabolism
Levels of the active metabolite N-desmethylclobazam are expected to be higher in patients with poor CYP2C19 metabolism than in those with extensive metabolism. The dose of clobazam may need to be adjusted (eg a low starting dose with careful titration of the dose). Patients with chronic respiratory failure A lower dose is recommended in patients with chronic respiratory failure due to the risk of respiratory depression (see also "Contraindications"). In patients with acute respiratory failure, respiratory function should be monitored. Clobazam is contraindicated in patients with severe respiratory insufficiency (see "Contraindications").
Muscle weakness
Clobazam can cause muscle weakness. Therefore, special observation is required in patients with pre-existing muscle weakness and a reduction in dosage may be necessary. Clobazam is contraindicated in patients with myasthenia gravis (see "Contraindications"). Patients with severe hepatic insufficiency It is recommended to treat with caution patients with severe hepatic insufficiency and / or encephalopathy as Frisium like all benzodiazepines can precipitate hepatic encephalopathy. In patients with impaired hepatic and renal function it is advisable to reduce the dosage since there is an increase in both reactivity to clobazam and susceptibility to undesirable effects.In case of prolonged treatment it is advisable to carry out periodic checks of liver and kidney function.
Benzodiazepines are not recommended for the primary treatment of psychotic illness
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide can be precipitated in such patients). Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse. In the case of somatic affections with a psycho-emotional component, it is advisable for the doctor to investigate the possibility of an organic cause.
Interactions Which drugs or foods can modify the effect of Frisium
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Not recommended
Alcohol: concomitant intake with alcohol should be avoided. Concomitant consumption of alcohol may increase the bioavailability of clobazam by 50%, resulting in an increase in its effects. This adversely affects the ability to drive or use machines.
Pay attention
CNS depressant drugs: the central depressive effect may be enhanced in cases of concomitant use with antipsychotics, hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics and sedative antihistamines. Particular caution is required with the use of clobazam. in case of intoxication with such drugs or with lithium.
Anticonvulsants:
If clobazam is used concomitantly with anticonvulsants in the treatment of epilepsy, the dosage should be adjusted under close medical supervision (EEG monitoring) as there may be interactions with anticonvulsant therapy. In patients receiving concomitant therapy with valproic acid, an increase may occur. mild to moderate plasma concentration of valproic acid. Plasma levels of phenytoin may increase with concomitant therapy with clobazam. It is recommended, where possible, to monitor the plasma levels of valproic acid or phenytoin given concomitantly. Carbamazepine and phenytoin can lead to increased biotransformation from clobazam to the active metabolite, Ndesmethylclobazam. Stiripentol: increased plasma concentrations of clobazam and its active metabolite N-desmethylclobazam by inhibition of its hepatic metabolism, with risk of overdose. Clinical surveillance, plasma benzodiazepine dosage and possible dosage adjustment are recommended;
Narcotic analgesics
If clobazam is used concomitantly with narcotic analgesics, an increase in euphoria can occur, leading to an increase in psychic dependence.
Muscle relaxants
The effect of muscle relaxants and nitrous oxide can be enhanced.
CYP2C19 inhibitors
Strong and moderate inhibitors of CYP2C19 may lead to increased exposure to N-desmethylclobazam, the active metabolite of clobazam. A dose adjustment of clobazam may be required when given with strong drugs (eg fluconazole, fluvoxamine, ticlopidine). ) or moderate (e.g. omeprazole) inhibitors of CYP2C19.
CYP2D6 substrates
Clobazam is a weak inhibitor of CYP2D6. Dose adjustment of drugs metabolised by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol) may be required.
The following associations should be carefully considered:
- buprenorphine: increased risk of respiratory depression, which can be fatal. Carefully evaluate the risk / benefit ratio of this association. Inform the patient of the need to respect the prescribed doses;
- clozapine: increased risk of collapse with respiratory and / or cardiac arrest.
Administration of theophylline or aminophylline may reduce the effects of benzodiazepines.
Warnings It is important to know that:
This medicine contains lactose, so if your doctor has told you that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Pregnancy and Breastfeeding
Frisium, like all benzodiazepines, should not be administered during pregnancy, childbirth and breastfeeding. If the product is prescribed to a woman of childbearing age, she should contact her doctor, whether or not she intends to become pregnant. , or if you suspect you are pregnant, regarding discontinuation of the medicinal product. If, for serious medical reasons, the product is administered during the last period of pregnancy or during labor, respiratory depression (which includes respiratory distress and apnea), which may be associated with other disorders such as symptoms of sedation, hypothermia, hypotonia and feeding difficulties (floppy infant syndrome). Additionally, infants born to mothers who have taken benzodiazepines chronically during late pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. Appropriate monitoring of neonates in the postnatal period is recommended. Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers.
Effects on ability to drive and use machines
At higher doses and in the case of particular individual sensitivity, Frisium can influence the ability to react; this should be borne in mind in particular in the case of simultaneous consumption of alcoholic beverages. Sedation, amnesia, impaired concentration and muscle function can adversely affect the ability to drive and use machines. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see "Interactions").
Dosage and method of use How to use Frisium: Dosage
The dosage and duration of treatment should be adapted case by case in the opinion of the physician, based on the indications, the severity of the clinical picture and the variability of the individual response. Treatment should be started with the lowest dose. The maximum dose should not be exceeded. The patient should be monitored regularly at the start of treatment to decrease the dose or frequency of intake if necessary to prevent overdose due to accumulation.
Adults
Generally, adults are given 2 capsules a day, increasing, if necessary, to 3 capsules a day. In particularly severe forms, the daily dosage can be increased according to the doctor's judgment. Once the clinical picture has improved, the dosage can be In elderly or debilitated subjects, administration of 1 capsule per day is often sufficient. If the daily dose is spread over the day, the higher single dose should be administered in the evening before going to bed. Daily doses up to 30 mg can also be administered as a single dose in the evening.
Patients with impaired hepatic and / or renal function:
in these patients there may be marked reactivity and a higher sensitivity towards adverse effects. Consequently, it is necessary to start therapy with reduced doses, which can be gradually increased by continuing the treatment which, however, must always be carried out under careful medical supervision. Predisposed subjects, if treated at high doses and for prolonged periods, may be addictive, as occurs with other drugs with hypnotic, sedative and tranquilizing activity.
Elderly patients
In these patients there may be increased reactivity and higher sensitivity to adverse effects. Consequently, it is necessary to start therapy with reduced doses which can be gradually increased under careful medical supervision
Anxiety
Treatment should be as short as possible. The patient should be re-evaluated regularly and the need for continued treatment should be carefully considered, particularly if the patient is symptom-free. The overall duration of treatment should generally not exceed 8-12 weeks, including a gradual withdrawal period. In certain cases, extension beyond the maximum treatment period may be necessary, in which case this should not be done without reassessment of the patient's condition.
Insomnia
Treatment should be as short as possible. The duration of treatment generally ranges from a few days to two weeks, up to a maximum of four weeks, including a gradual withdrawal period.
In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without reassessment of the patient's condition.
The drug should be taken at bedtime.
The administration of Frisium for the treatment of insomnia to patients under the age of 18 is not recommended without a careful assessment of its actual need. The single dose for patients under 18 depends on their age, weight and general condition of the patient.
Overdose What to do if you have taken too much Frisium
In case of accidental ingestion / intake of an excessive dose of Frisium, notify your doctor immediately or go to the nearest hospital. In case of intoxication, on the basis of the symptoms, the necessary measures must be taken to ensure vital functions.
As with other benzodiazepines, an overdose should not be life-threatening unless concomitant other CNS depressants (including alcohol) are taken. In the treatment of overdose of any drug, consideration should be given to possibility that other substances were taken at the same time.
Following an overdose of oral benzodiazepines, vomiting should be induced (within one "hour) if the patient is conscious or gastric lavage with respiratory protection undertaken if the patient is unconscious. Secondary elimination. of clobazam (with forced diuresis or hemodialysis) is ineffective. If no improvement is seen with stomach emptying, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in emergency therapy. Overdosage of benzodiazepines usually manifests with varying degrees of central nervous system depression ranging from drowsiness, mental confusion and lethargy.
In severe cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma, and very rarely death. "Flumazenil" can be useful as an antidote.
Side Effects What are the side effects of Frisium
Like all medicines, Frisium can cause side effects, although not everybody gets them. Undesirable effects are grouped according to frequency using the following convention:
Very common (≥ 1/10)
Common (≥ 1/100,
Uncommon (≥ 1/1000,
Rare (≥ 1 / 10,000,
Very rare (
Disorders of the immune system
Common: Quincke's edema
Rare: anaphylactic / anaphylactoid reactions
Psychiatric disorders
Common: anxiety and decreased libido
Paradoxical reactions such as agitation, difficulty falling asleep or sleeping, irritability, acute agitation, anxiety, aggression, delirium, anger attacks, nightmares, hallucinations, psychotic reactions, suicidal tendencies or frequent muscle spasms If these reactions occur, treatment with Frisium should be discontinued.
A pre-existing depressive state may be unmasked during benzodiazepine use. Tolerance and dependence may develop, especially during prolonged use (see section "Precautions for use").
Nervous system disorders
Very common: headache
Common: dizziness, sedation, somnolence, attention disturbance, amnesia, speech disturbances, dysgeusia and psycho-motor slowing
Drowsiness during the day, dulling of emotions, decreased alertness, confusion, fatigue, dizziness, ataxia, fine finger tremor have been reported.
Instability in gait and other motor functions may occur. Such reactions occur particularly at high doses or in long-term treatments and are reversible.
After prolonged use of benzodiazepines, loss of consciousness may occur in very rare cases, particularly in the elderly, sometimes in association with respiratory disorders; these effects sometimes persist for a considerable period of time.
Anterograde amnesia may also occur.
The effects of amnesia can be associated with inappropriate behavior.
Eye disorders
Common: visual disturbances (diplopia, nystagmus). These reactions occur particularly at high doses or in long-term treatments and are reversible.
Respiratory, thoracic and mediastinal disorders
Clobazam can cause respiratory depression, especially in high doses. Therefore, particularly in patients with pre-existing impaired respiratory function (eg in patients with bronchial asthma) or with brain damage, "respiratory failure" may occur or worsen.
Cardiac pathologies
Common: tachycardia
Gastrointestinal disorders
Common: vomiting, nausea, pain in the upper abdomen, constipation and dry mouth, decreased appetite.
Skin and subcutaneous tissue disorders
Common: pruritus In very rare cases, skin reactions such as rash or hives may develop.
Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis,
Metabolism and nutrition disorders
Weight gain. This reaction occurs particularly in high doses or in long-term treatments and is reversible.
Musculoskeletal and connective tissue disorders
Muscle weakness
Renal and urinary disorders
Common: disturbances in urination
General disorders and administration site conditions
Common: asthenia and sweating
Falls
Adverse reactions of the benzodiazepine class (bdz)
Dependence
The use of benzodiazepines (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy can cause rebound or withdrawal phenomena (see "Precautions for use"). Psychic dependence can occur. Abuse of benzodiazepines has been reported. Once physical dependence has developed, abrupt cessation of treatment may be accompanied by withdrawal symptoms. These may consist of extreme anxiety, tension, restlessness, confusion, irritability, headache and muscle pain. In severe cases they may appear. the following symptoms: derealization, depersonalization, hallucinations, paraesthesia of the limbs, hypersensitivity to light, noise and physical contact, hyperacusis and seizures. There is evidence that, in the case of use of benzodiazepines with short duration of action, they may withdrawal symptoms become manifest between dose intervals especially at high doses. This is unlikely to occur with Frisium, because its elimination half-life is approximately 20 hours.
Rebound insomnia
Upon discontinuation of treatment, a transient syndrome such as insomnia may occur, which recurs in an aggravated form following treatment with benzodiazepines. Since, after abrupt discontinuation of treatment, the risk of rebound / withdrawal phenomena is higher, it is recommended to gradually decrease the dose. The patient should be informed of the possibility of rebound phenomena in order to minimize anxiety. caused by these symptoms, which can appear when benzodiazepines are stopped.
Depression
During the use of benzodiazepines a pre-existing depressive state can be unmasked. Benzodiazepines and benzodiazepine-like compounds can cause reactions such as: restlessness, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, behavioral changes. quite severe and are more likely in children and the elderly.
In addition, other adverse reactions have been reported rarely with benzodiazepines, including: increased bilirubin, jaundice, increased liver transaminases, increased alkaline phosphatase, thrombocytopenia, agranulocytosis, pancytopenia, SIAD (syndrome of inappropriate antidiuretic hormone secretion). of the instructions in the package leaflet reduces the risk of side effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety of this medicine.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Do not store above 25 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
Composition and pharmaceutical form
Composition
One hard capsule contains:
Active ingredient: clobazam 10 mg.
Excipients: lactose, corn starch, talc, magnesium stearate.
Capsule components: gelatin, titanium dioxide (E 171).
Pharmaceutical form and content
Hard capsules.
Box of 30 capsules.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
FRISIUM 10 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One hard capsule contains:
Active principle: clobazam 10 mg
Excipients with known effects: lactose 107.75 mg
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsules.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome. Insomnia.
Benzodiazepines are indicated only when the disorder is severe, disabling and subjects the subject to severe distress.
04.2 Posology and method of administration
The dosage and duration of treatment must be adapted case by case, in the opinion of the physician, on the basis of the indications, the severity of the clinical picture and the variability of the individual response.
Treatment should be started with the lowest dose.
The maximum dose should not be exceeded.
The patient should be monitored regularly at the start of treatment to decrease the dose or frequency of intake if necessary to prevent overdose due to accumulation.
Adults:
Generally, adults are given 2 capsules per day, increasing if necessary to 3 capsules per day.
In particularly severe forms, the daily dosage can be increased in the opinion of the doctor.
Once the clinical picture has improved, the dosage can be reduced.
In elderly or debilitated subjects, administration of 1 capsule a day is often sufficient.
If the daily dose is spread over the day, the higher single dose should be given in the evening before going to bed. Daily doses up to 30 mg can also be given as a single dose in the evening.
Patients with impaired hepatic and / or renal function
In these patients, accentuated reactivity and higher sensitivity to adverse effects may occur. Consequently, it is necessary to start therapy with reduced doses, which can be gradually increased by continuing the treatment which, however, must always be carried out under careful medical supervision.
Elderly patients
In these patients there may be increased reactivity and higher sensitivity to adverse effects. Consequently, it is necessary to start therapy with reduced doses which can be gradually increased under careful medical supervision.
Anxiety
Treatment should be as short as possible. The patient should be re-evaluated regularly and the need for continued treatment should be carefully considered, particularly if the patient is symptom-free. The overall duration of treatment should generally not exceed 8-12 weeks, including a gradual withdrawal period.
In certain cases, extension beyond the maximum treatment period may be necessary, in which case this should not be done without reassessment of the patient's condition.
Insomnia
Treatment should be as short as possible. The duration of treatment generally ranges from a few days to two weeks, up to a maximum of four weeks, including a gradual withdrawal period.
In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without reassessment of the patient's condition.
The drug should be taken at bedtime.
The administration of Frisium for the treatment of insomnia to patients under the age of 18 is not recommended without a careful assessment of its actual need. The single dose for patients under 18 depends on their age, weight and general condition of the patient.
04.3 Contraindications
Hypersensitivity to the active substance, to benzodiazepines in general or to any of the excipients listed in section 6.1.
Myasthenia gravis.
Severe respiratory failure (e.g. severe chronic obstructive pulmonary disease)
Severe hepatic insufficiency.
Sleep apnea syndrome.
Spinal and cerebellar ataxia.
Patients with a history of drug or alcohol abuse, due to an increased risk of addiction.
Contraindicated during pregnancy and lactation (see 4.6 pregnancy and lactation).
Benzodiazepines should not be given to children without careful consideration of the actual need for treatment. Frisium should not be used in children under 3 years of age.
04.4 Special warnings and appropriate precautions for use
Alcohol
Patients are advised to avoid alcohol intake during clobazam therapy, due to the increased risk of sedation and other undesirable effects (see section 4.5).
Tolerance
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines can lead to the development of physical and psychological dependence on these drugs. The risk of dependence increases with dose and duration of treatment, and is greater in patients with a history of drug or alcohol abuse.
The risk of dependence is also present with the daily intake of clobazam for a period of only a few weeks and is valid not only for possible abuse at particularly high doses, but also for the recommended therapeutic dosage.
It is strongly recommended to avoid prolonged periods of uninterrupted treatment as they can lead to addiction.
Withdrawal symptoms
Once physical dependence has developed, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms. These may consist of headache, body aches, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following may occur. symptoms: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations and symptomatic psychosis or epileptic seizures.
Other symptoms are: depression, insomnia, increased dreams, sweating, persistent tinnitus, involuntary movements, nausea, vomiting, paraesthesia, perceptual changes, abdominal and muscle cramps, tremor, myalgia, agitation, palpitations, tachycardia, panic attacks, dizziness, hyper-reflexia, short-term memory loss, hyperthermia.
Rebound insomnia and anxiety
A transient syndrome in which symptoms that led to treatment with benzodiazepines recur in an aggravated form may occur upon discontinuation of treatment. It may be accompanied by other reactions, including mood changes, anxiety, restlessness or sleep disturbances. withdrawal or rebound symptoms is greater after abrupt cessation of treatment, it is suggested to make a gradual decrease in dosage. It is also important that the patient is informed of the possibility of rebound phenomena, in order to minimize the anxious reaction. any occurrence of such symptoms could trigger when Frisium is discontinued.
Duration of treatment
The duration of treatment should be as short as possible (see 4.2) depending on the indication, but should not exceed four weeks for insomnia and eight to twelve weeks for anxiety, including a gradual withdrawal period. "extension of therapy beyond these periods should not occur without re-evaluation of the clinical situation. It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage should be progressively decreased, as abrupt discontinuation can lead to withdrawal symptoms such as agitation, anxiety and insomnia.
It is also important that the patient is informed of the possibility of rebound phenomena, thus minimizing anxiety about these symptoms should they occur when the drug is discontinued.
There is evidence that, in the case of benzodiazepines with a short duration of action, withdrawal symptoms may become manifest within the dosing interval between doses, particularly for high doses.
When using benzodiazepines with a long duration of action (eg Frisium), it is important to warn the patient that abrupt change to a benzodiazepine with a short duration of action is not recommended, as withdrawal symptoms may occur.
As with other benzodiazepines, in the case of prolonged treatment it is advisable to evaluate the therapeutic benefit against the risk of addiction and dependence.
Amnesia
Benzodiazepines can induce antegrade amnesia whether used in the normal dosage range, but especially at high doses. This occurs most often several hours after ingestion of the drug and, therefore, to reduce the risk it should be ensured that patients can have an uninterrupted sleep of 7 to 8 hours (see 4.8).
Psychiatric and paradoxical reactions
When benzodiazepines are used it is known that reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes can occur. Should this occur, use of the medicinal product should be discontinued. These reactions are more likely to occur in children and the elderly as well as in patients with organic brain syndrome.
Specific groups of patients
Pediatric patients
Benzodiazepines should not be given to children without careful consideration of the actual need for treatment; the duration of treatment should be as short as possible.
Elderly patients
In the elderly, the use of benzodiazepines may be associated with an increased risk of falls due to undesirable effects such as ataxia, muscle weakness, dizziness, somnolence, tiredness and fatigue. Falls can lead to serious injury and therefore it is recommended to treat with caution. elderly patients Elderly patients should take a reduced dose (see 4.2 and 4.8).
Patients with poor CYP2C19 metabolism
Levels of the active metabolite N-desmethylclobazam are expected to be higher in patients with poor CYP2C19 metabolism than in those with extensive metabolism. The dose of clobazam may need to be adjusted (eg a low starting dose with careful titration of the dose).
Patients with chronic respiratory failure: a lower dose is recommended in patients with chronic respiratory failure due to the risk of respiratory depression (see also 4.3 "Contraindications"). In patients with acute respiratory failure, respiratory function should be monitored.
Clobazam is contraindicated in patients with severe respiratory insufficiency (see section 4.3).
Muscle weakness
Clobazam can cause muscle weakness. Therefore, special observation is required in patients with pre-existing muscle weakness and a reduction in dosage may be necessary. Clobazam is contraindicated in patients with myasthenia gravis (see section 4.3).
Patients with severe hepatic insufficiency: it is recommended to treat patients with severe hepatic insufficiency and / or encephalopathy with caution as Frisium like all benzodiazepines can precipitate hepatic encephalopathy.
In patients with impaired hepatic and renal function it is advisable to reduce the dosage as there is an increase in both reactivity to clobazam and susceptibility to undesirable effects. In case of prolonged treatment it is advisable to carry out periodic checks of the liver and kidney function.
Benzodiazepines are not recommended for the primary treatment of psychotic illness. Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide can be precipitated in such patients). Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse.
In the case of somatic affections with a psycho-emotional component, it is advisable for the doctor to investigate the possibility of an organic cause.
The medicine contains lactose therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose / galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Not recommended
• Alcohol: concomitant intake with alcohol should be avoided. Concomitant consumption of alcohol may increase the bioavailability of clobazam by 50% (see 5.2), resulting in increased effects of the same (see 4.4). This negatively affects the ability to driving or operating machinery.
Pay attention
• CNS depressant drugs: the central depressive effect may be enhanced in cases of concomitant use with antipsychotics, hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics and sedative antihistamines.
Particular caution is required with the use of clobazam in case of intoxication with such drugs or with lithium.
• Anticonvulsants: if clobazam is used concomitantly with anticonvulsants in the treatment of epilepsy, the dosage should be adjusted under close medical supervision (EEG monitoring) as there may be interactions with anticonvulsant therapy.
In patients on concomitant therapy with valproic acid, a mild to moderate increase in plasma concentrations of valproic acid may occur.
Plasma levels of phenytoin may increase with concomitant therapy with clobazam.
It is recommended, where possible, to monitor the plasma levels of valproic acid or phenytoin given concomitantly.
Carbamazepine and phenytoin can lead to increased biotransformation from clobazam to the active metabolite, N-desmethylclobazam.
Stiripentol: increased plasma concentrations of clobazam and its active metabolite N-desmethylclobazam by inhibition of its hepatic metabolism, with risk of overdose. Clinical surveillance, plasma benzodiazepine dosage and possible dosage adjustment are recommended;
• Narcotic analgesics
If clobazam is used concomitantly with narcotic analgesics, an increase in euphoria can occur, leading to an increase in psychic dependence.
• Muscle relaxants
The effect of muscle relaxants and nitrous oxide can be enhanced.
• CYP2C19 inhibitors
Strong and moderate inhibitors of CYP2C19 may lead to increased exposure to N-desmethylclobazam, the active metabolite of clobazam. A dose adjustment of clobazam may be required when given with strong drugs (eg fluconazole, fluvoxamine, ticlopidine). ) or moderate (e.g. omeprazole) inhibitors of CYP2C19.
• CYP2D6 substrates
Clobazam is a weak inhibitor of CYP2D6. Dose adjustment of drugs metabolised by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol) may be required.
The following associations should be carefully considered:
• buprenorphine: increased risk of respiratory depression, which can be fatal. Carefully evaluate the risk / benefit ratio of this association. Inform the patient of the need to respect the prescribed doses;
• clozapine: increased risk of collapse with respiratory and / or cardiac arrest.
Administration of theophylline or aminophylline may reduce the effects of benzodiazepines.
04.6 Pregnancy and lactation
Frisium, like all benzodiazepines, should not be administered during pregnancy, childbirth and breastfeeding;
If the product is prescribed to a woman of childbearing age, she should contact her doctor, both if she intends to become pregnant and if she suspects that she is pregnant, regarding discontinuation of the medicine.
If, for serious medical reasons, the product is administered during late pregnancy or during labor, respiratory depression (including respiratory distress and apnea) may occur in the newborn, which may be associated with other disorders such as symptoms of sedation, hypothermia , hypotonia and feeding difficulties (floppy infant syndrome).
Additionally, infants born to mothers who have taken benzodiazepines chronically during late pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. Appropriate monitoring of neonates in the postnatal period is recommended.
Since benzodiazepines are excreted in breast milk, they should not be administered to breastfeeding mothers (see section 5.2).
04.7 Effects on ability to drive and use machines
At higher doses and in case of particular individual sensitivity, Frisium can influence the ability to react; this should be borne in mind in particular in the case of simultaneous consumption of alcoholic beverages.
Sedation, amnesia, impaired concentration and muscle function can adversely affect the ability to drive and use machines. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see 4.5).
04.8 Undesirable effects
Undesirable effects are grouped according to frequency using the following convention:
Very common (≥ 1/10)
Common (≥ 1/100,
Uncommon (≥ 1/1000,
Rare (≥ 1 / 10,000,
Very rare (
Disorders of the immune system
Common: Quincke's edema
Rare: anaphylactic / anaphylactoid reactions
Psychiatric disorders
Common: anxiety and decreased libido
Paradoxical reactions such as agitation, difficulty falling asleep or sleeping, irritability, acute agitation, anxiety, aggression, delirium, anger attacks, nightmares, hallucinations, psychotic reactions, suicidal tendencies or frequent muscle spasms If these reactions occur, treatment with Frisium should be discontinued.
A pre-existing depressive state may be unmasked during the use of benzodiazepines.
Tolerance and dependence may develop, especially during prolonged use (see section 4.4).
Nervous system disorders
Very common: headache
Common: dizziness, sedation, somnolence, attention disturbance, amnesia, speech disturbances, dysgeusia and psycho-motor slowing.
Drowsiness during the day, dulling of emotions, decreased alertness, confusion, fatigue, dizziness, ataxia, fine finger tremor have been reported.
Instability in gait and other motor functions may occur. Such reactions occur particularly at high doses or in long-term treatments and are reversible.
After prolonged use of benzodiazepines, loss of consciousness may occur in very rare cases and particularly in the elderly, sometimes in association with respiratory disorders; these effects sometimes persist for a considerable period of time.
Anterograde amnesia may also occur. The effects of amnesia can be associated with inappropriate behavior.
Eye disorders
Common: visual disturbances (diplopia, nystagmus). These reactions occur particularly at high doses or in long-term treatments and are reversible.
Respiratory, thoracic and mediastinal disorders
Clobazam can cause respiratory depression, especially in high doses. Therefore, particularly in patients with pre-existing impaired respiratory function (eg in patients with bronchial asthma) or with brain damage, "respiratory failure" may occur or worsen.
Cardiac pathologies
Common: tachycardia
Gastrointestinal disorders
Common: vomiting, nausea, pain in the upper abdomen, constipation and dry mouth, decreased appetite.
Skin and subcutaneous tissue disorders
Common: itching
In very rare cases, skin reactions such as rash or hives may develop.
Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis.
Metabolism and nutrition disorders
Weight gain. This reaction occurs particularly in high doses or in long-term treatments and is reversible.
Musculoskeletal and connective tissue disorders
Muscle weakness
Renal and urinary disorders
Common: disturbances in urination
General disorders and administration site conditions
Common: asthenia and sweating
Falls (see section 4.4)
ADVERSE REACTIONS OF THE BENZODIAZEPINE CLASS (BDZ)
Dependence
The use of benzodiazepines (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy can cause rebound or withdrawal phenomena (see 4.4 "Special warnings and precautions for use"). Psychic dependence can occur. Abuse of benzodiazepines has been reported. Once physical dependence has developed, abrupt cessation of treatment may be accompanied by withdrawal symptoms. These may consist of extreme anxiety, tension, restlessness, confusion, irritability, headache and muscle pain. In severe cases they may appear. the following symptoms: derealization, depersonalization, hallucinations, paraesthesia of the limbs, hypersensitivity to light, noise and physical contact, hyperacusis and seizures. There is evidence that, in the case of use of benzodiazepines with short duration of action, they may withdrawal symptoms become manifest between dose intervals especially at high doses.This is unlikely to occur with Frisium, as its elimination half-life is approximately 20 hours (see 5.2 "Pharmacokinetic properties").
Rebound insomnia
Upon discontinuation of treatment, a transient syndrome such as insomnia may occur, which recurs in an aggravated form following treatment with benzodiazepines. Since, after abrupt discontinuation of treatment, the risk of rebound / withdrawal phenomena is higher, it is recommended to gradually decrease the dose. The patient should be informed of the possibility of rebound phenomena in order to minimize anxiety. caused by these symptoms, which can appear when benzodiazepines are stopped.
Depression
During the use of benzodiazepines a pre-existing depressive state can be unmasked. Benzodiazepines and benzodiazepine-like compounds can cause reactions such as: restlessness, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, behavioral changes. quite severe and are more likely in children and the elderly.
In addition, other adverse reactions have been reported rarely with benzodiazepines including: increased bilirubin, jaundice, increased liver transaminases, increased alkaline phosphatase, thrombocytopenia, agranulocytosis, pancytopenia, SIAD (syndrome of inappropriate antidiuretic hormone secretion).
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
In case of intoxication, on the basis of the symptoms, the necessary measures must be taken to ensure vital functions.
As with other benzodiazepines, an overdose is not expected to be life-threatening unless concomitant other CNS depressants (including alcohol) are taken.
In the treatment of overdose of any drug, the possibility that other substances have been taken at the same time should be considered.
Following an overdose of oral benzodiazepines, vomiting should be induced (within one "hour) if the patient is conscious, or gastric lavage with respiratory protection undertaken if the patient is unconscious.
Secondary elimination of clobazam (with forced diuresis or hemodialysis) is ineffective. If no improvement is observed with stomach emptying, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in emergency therapy. Overdosage of benzodiazepines usually results in varying degrees of central nervous system depression ranging from clouding to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy.
In severe cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma, and very rarely death. "Flumazenil" can be useful as an antidote.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anxiolytics, benzodiazepines; A.T.C code: N05BA09
Clobazam is the first 1,5-benzodiazepine used in the clinic.
The results of various standard tests performed in animals show that clobazam exerts an anxiolytic action, suppresses spontaneous and induced aggression, inhibits chemical or electrically induced convulsions and eliminates photoprecipitable myoclonic seizures.
Compared to the standard 1,4-benzodiazepine (diazepam), clobazam has the same anxiolytic activity in the 2: 1 dosage ratio, but less sedative and muscle relaxant action. In fact, clobazam causes motor incoordination and manifests muscle relaxant activity at doses, depending on the tests, several times greater than those that determine the anxiolytic and anticonvulsant action.
Clinical pharmacology data, after single and repeated administration, confirm that the pharmacodynamic profile of clobazam is characterized by the possibility of maintaining, through the use of appropriate doses, the anxiolytic action without compromising psychomotor performance.
05.2 "Pharmacokinetic properties
After oral administration, absorption is rapid and at least 87% of the dose is absorbed.
After administration of a single 20 mg dose, pronounced interindividual variability in plasma concentrations (222 to 709 ng / mL) was observed after 0.25 to 4 hours post dose. Concomitant alcohol intake increases the bioavailability of clobazam by 50%.
The serum elimination half-life of clobazam is approximately 20 hours (with pronounced interindividual variability).
Clobazam is mainly metabolised in the liver. The major metabolites found in plasma are N-demethyl clobazam and 4-hydroxyclobazam. Minor amounts of 4-hydroxy-N-demethyl clobazam are also present. The N-demethyl metabolite clobazam is an active metabolite.
After administration of a 30 mg dose of clobazam, N-demethyl clobazam reaches peak plasma concentrations at 24-72 hours. Its elimination half-life is approximately 50 hours (with pronounced inter-individual variability).
Plasma protein binding is 85% - 91%.
Clobazam crosses the placental barrier and appears in breast milk. Effective concentrations can be achieved in both fetal blood and breast milk.
In elderly patients, there is a trend towards decreased clearance after oral administration; the terminal half-life is prolonged and the volume of distribution is increased. This may lead to greater drug accumulation, compared to younger patients, when administered at multiple doses. The effect of age on clearance and accumulation profile appears also valid for the active metabolite.
In patients with severe hepatic impairment, the volume of distribution of clobazam is increased and the terminal half-life is prolonged.
In patients with renal insufficiency, plasma concentrations of clobazam are reduced, possibly as a consequence of impaired drug absorption; the terminal half-life is largely independent of renal function.
05.3 Preclinical safety data
Chronic toxicity
Studies of up to 18 months duration were performed in rats. Doses up to 1000 mg / kg of body weight have been administered. At doses ranging from 12 to 1000 mg / kg there was a dose-dependent reduction in spontaneous activity and, at the higher dose, decreased weight gain, respiratory depression and hypothermia were observed.
Studies of up to 12 months duration have been performed in dogs. Sedation, somnolence, ataxia and mild tremor occurred in a dose-dependent manner at doses ranging from 2.5 to 80 mg / kg / day. Subsequently these symptoms were almost entirely absent.
Similar dose-dependent effects have been observed in monkeys in studies of up to 12 months duration at daily doses ranging from 2.5 to 20 mg / kg.
Mutagenesis
Clobazam does not possess any mutagenic or genotoxic effects.
Carcinogenesis
In a rat carcinogenicity study, a significant increase in follicular cell adenoma of the thyroid was found at the highest dose (100 mg / kg).
Clobazam, like other benzodiazepines, leads to thyroid activation in the rat. This effect was not observed in other studies conducted in other species.
Teratogenesis
Studies performed in mice, rats and thalidomide-sensitive rabbits with daily doses up to 100 mg / kg did not reveal any teratogenic effects.
Impaired fertility
In fertility studies conducted in mice at doses of 200 mg / kg / day and in rats at doses of 85 mg / kg / day, no effects on fertility and pregnancy were observed.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose, corn starch, talc, magnesium stearate.
Composition of the capsule: gelatin, titanium dioxide (E 171).
06.2 Incompatibility
They are not known.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Blister of 30 capsules.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi S.p.A. - Viale L. Bodio, 37 / B - Milan
08.0 MARKETING AUTHORIZATION NUMBER
30 hard capsules: AIC n. 023451014
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
October 1976 / February 6, 2010
10.0 DATE OF REVISION OF THE TEXT
October 2014
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