Active ingredients: Clonazepam
Rivotril 0.5 mg tablets
Rivotril 2 mg tablets
Rivotril 2.5 mg / ml oral drops solution
Indications Why is Rivotril used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Clonazepam belongs to the category of benzodiazepine derivatives with antiepileptic activity.
THERAPEUTIC INDICATIONS
Most of the epileptic clinical forms in the infant and child. Particularly:
- typical or atypical petty evil
- generalized tonic-clonic seizures, primary or secondary
- state of evil in all its clinical expressions.
Rivotril is also indicated in adult epilepsy and focal seizures.
Contraindications When Rivotril should not be used
Hypersensitivity to the active substance, to benzodiazepines or to any of the excipients.
The use of Rivotril is contraindicated in patients with clear clinical or biochemical signs of severe liver disease. It can be used in subjects with open-angle glaucoma receiving adequate therapy, but is contraindicated in acute narrow-angle glaucoma. The product is also contraindicated in myasthenia gravis.
Severe renal failure, severe respiratory failure. Do not administer in the first trimester of pregnancy.
Rivotril should not be used in patients in a coma, or in patients with known drug, drug or alcohol abuse.
Precautions for use What you need to know before taking Rivotril
Suicidal ideation and behavior have been reported in several situations in patients treated with antiepileptic drugs. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs found a slightly increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown and the available data do not exclude the possibility of an increased risk for clonazepam.
Therefore, patients presenting with signs of suicidal ideation and behavior should be monitored and if so appropriate treatment should be considered.
Patients (and caregivers) should be advised to exercise caution if such signs occur. Patients with a history of depression or suicide attempt should be closely monitored. The risk of withdrawal symptoms is increased when benzodiazepines are used with daily sedatives (cross tolerance).
If used in subjects presenting various forms of seizures, Rivotril can increase the incidence or induce the onset of generalized tonic-clonic seizures (grand mal). It may therefore be necessary to add adequate anticonvulsants or to increase the dosage of the The concomitant use of valproic acid and Rivotril can produce a state of absence.
Since Rivotril can lead to increased salivation, this should be taken into account before prescribing the drug to patients who have difficulty in controlling secretions.
For the same reason, and due to possible respiratory depression, Rivotril should be used with caution in patients with chronic respiratory diseases.
Predisposed subjects, if treated with clonazepam at high doses and for prolonged periods, may be addictive, as occurs with other drugs with hypnotic, sedative and ataraxic activity.
Since the metabolites of Rivotril are excreted via the urine, in order to avoid excessive accumulation, the drug should be administered with caution to patients with impaired renal function.
The abrupt discontinuation of Rivotril, especially in patients undergoing long-term therapy with high doses, can induce a status epilepticus: consequently the discontinuation of the drug must be carried out gradually, and during this phase the substitution administration of another may be indicated. anticonvulsant.
In infants and children, Rivotril can cause increased saliva production and bronchial secretions. Therefore, particular attention must be paid to keeping the airways open.
Rivotril should be used with caution in patients with sleep apnea, chronic pulmonary insufficiency or impaired renal or hepatic function, in the elderly, in debilitated subjects. In these cases the dose should generally be reduced. The dose of Rivotril should be promptly adjusted based on individual requirements in patients with pre-existing respiratory disease (eg chronic obstructive pulmonary disease) or liver and in patients undergoing treatment with other centrally acting drugs or convulsive agents ( antiepileptics) (see "Interactions"). Effects on the respiratory system may be aggravated by pre-existing airway obstruction or brain damage or if other drugs that depress breathing have been administered. As a rule, this effect can be avoided by individual dose adjustment.
Like all drugs in this class, Rivotril may, depending on dosage, administration and individual susceptibility, modify patient reactions (e.g. driving skills or traffic behavior). As a rule, epileptic patients are not allowed to drive. Even if adequately controlled with Rivotril, it should be remembered that any increase in dosage or change in timing of intake may modify patient reactions based on individual susceptibility (see "Special warnings").
In epileptic patients, anticonvulsant drugs including Rivotril should not be stopped suddenly as this can precipitate the epileptic disease. When, in the judgment of the clinician, the need to reduce or discontinue the dose arises, this should be done gradually. In such cases, a combination with other antiepileptic drugs is indicated.
Interactions Which drugs or foods may change the effect of Rivotril
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Pharmacokinetic interactions between drugs
The antiepileptic drugs phenytoin, phenobarbital, carbamazepine and valproate can increase the clearance of clonazepam and therefore reduce its plasma concentrations in case of combination treatments. Clonazepam does not induce the enzymes responsible for its metabolism. The addition of an additional antiepileptic drug to the patients' therapeutic regimen should include a prompt evaluation of the response to treatment due to more likely undesirable effects such as sedation and apathy. In such cases, the dose of each drug must be adjusted in order to achieve the optimum desired effect.
Concomitant treatment with phenytoin or primidone may alter the plasma concentrations of phenytoin and primidone (usually increased).
Sertraline and fluoxetine, selective serotonin reuptake inhibitors, do not alter the pharmacokinetic parameters of clonazepam when combined.
Pharmacodynamic interactions between drugs
When Rivotril is used in combination with drugs that depress the CNS, including alcohol, it can increase the sedative effect on breathing and haemodynamic parameters.
Alcohol should be avoided in patients receiving Rivotril.
For warnings related to other CNS depressant drugs, including alcohol, see the "Overdose" section.
Warnings It is important to know that:
During prolonged therapy with Rivotril it is advisable to carry out periodic blood counts and liver function tests.
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician and to avoid unexpected undesirable effects from interaction.
Porphyria
Clonazepam is considered a probable nonporphyrogenic, although there is some conflicting evidence. However, clonazepam should be administered with caution in patients with porphyria.
Abuse and addiction
The use of benzodiazepines with these products can lead to the development of physical and psychological dependence (see section 4.8). In particular, prolonged or high-dose treatment can lead to irreversible disorders such as dysarthria, impaired coordination of movements, gait disturbances. (ataxia), nystagmus and double vision (diplopia). Furthermore, the risk of antegrade amnesia that can occur with the use of benzodiazepines at therapeutic doses increases with higher doses.
The amnesic effect may be associated with behavioral abnormalities and in some forms an increase in the frequency of seizures. In some forms of epilepsy, an increase in the frequency of seizures is possible (see section 4.8) with long-term treatment.
Concomitant use of alcohol / CNS depressants
Concomitant use of Rivotril with alcohol and / or drugs with central nervous system depressant activity should be avoided. Such concomitant use could increase the clinical effects of Rivotril, including possible profound sedation and clinically relevant respiratory and / or cardiovascular depression. (see section 4.5).
Alcohol in any form can cause epileptic seizures, regardless of therapy; it is therefore essential that patients under treatment with Rivotril refrain from consuming alcoholic beverages. Combined with Rivotril, alcohol can alter the effects of the drug, compromise the results. treatment or cause unpredictable secondary reactions.
Medical history of alcohol or drug abuse
People prone to drug addiction, such as alcoholics and drug addicts, should be closely monitored when taking Rivotril, due to their predisposition to develop habit and addiction.
Rivotril should be used with extreme caution in patients with a history of alcohol and drug abuse.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Patients who may become pregnant or are of childbearing age should be given specialist advice.
The need for antiepileptic treatment should be re-evaluated when the patient plans to become pregnant.
The risk of birth defects is increased by a factor of 2 to 3 times in the offspring of mothers treated with an antiepileptic; the most frequently reported are cleft lip, cardiovascular malformations and neural tube defects.
Polytherapy with antiepileptic drugs may be associated with a higher risk of congenital malformations than monotherapy. Therefore it is important that monotherapy is practiced whenever possible.
Abrupt discontinuation of antiepileptic therapy should not be practiced due to the danger of a resumption of seizures which could have serious consequences for both mother and baby.
Do not administer in the first trimester of pregnancy; in the further period, as well as in early childhood, the drug must be administered only in case of real need under the direct supervision of the doctor.
Since the active substance in Rivotril passes into breast milk, breastfeeding should be discontinued if the product is to be taken regularly.
Effects on ability to drive and use machines
Because Rivotril causes CNS depressant effects, patients treated with this drug should refrain from occupations that require a high degree of alertness, such as operating machinery or driving cars.
Important information about some of the ingredients
Rivotril tablets contain lactose; if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Rivotril: Dosage
The dosage of Rivotril is essentially individual and depends primarily on the age of the patient.
It should be established on a case-by-case basis on the basis of clinical response and tolerance. To avoid unwanted effects at the beginning of treatment, it is essential to gradually increase the daily dose until the maintenance dose has been reached.
Indicative maintenance doses that can be increased without problems if necessary:
As far as possible, the daily dose should be divided over 24 hours in 3-4 administrations. The maintenance dose should be reached after 3-4 weeks of treatment.
To facilitate the adaptation of the dosage to individual needs and to make it easier to divide the total daily dose into 3-4 administrations, it is advisable to use the drops of Rivotril in the newborn baby (1 drop = 0.1 mg of active substance) and, in the child or adult in the initial phase of treatment, the 0.5 mg tablets.
The drops should be administered with a spoon and can be mixed with water, tea or fruit juice.
To facilitate administration, Rivotril 0.5 mg tablets can be divided into equal halves, while the 2 mg tablets can be divided into equal halves or quarters.
Elderly patients
Particular attention should be paid during treatment in elderly patients.
In the treatment of elderly patients, the posology must be carefully established by the physician who will have to evaluate a possible reduction of the dosages indicated above.
Kidney failure
The safety and efficacy of clonazepam in patients with renal insufficiency have not been studied, however, based on the pharmacokinetic criteria, no dosage adjustment is required in these patients.
Hepatic insufficiency
The safety and efficacy of clonazepam in patients with hepatic insufficiency have not been studied. There are no data on the incidence of hepatic injury on the pharmacokinetics of clonazepam.
How to use the dropper bottle
Hold the bottle vertically, with the opening facing down. If the liquid does not flow, invert the bottle several times, or shake gently.
Overdose What to do if you have taken too much Rivotril
In case of accidental ingestion / intake of an excessive dose of Rivotril, notify your doctor immediately or go to the nearest hospital.
Symptoms
Benzodiazepines commonly cause somnolence, ataxia, dysarthria and nystagmus.
An overdose of Rivotril, when taken alone, is rarely life-threatening but can result in areflexia, apnea, hypotension, cardiorespiratory depression and coma.
Coma, if it occurs, usually lasts a few hours but can last longer and be cyclical, especially in elderly patients. Respiratory depressive effects associated with benzodiazepines are more serious in patients with respiratory conditions.
Benzodiazepines enhance the effects of central nervous system depressant drugs, including alcohol.
Treatment
Monitor the patient's vital signs and define supportive measures in relation to the patient's clinical status. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.
Absorption should be prevented by an appropriate method, eg treatment with activated charcoal within 1-2 hours. If using activated charcoal, protect the respiratory tract if the patient is unconscious.
Gastric lavage should be considered if multiple drugs are ingested, but not as a routine measure.
In case of severe central nervous system depression, consider the use of flumazenil, a benzodiazepine antagonist.
This should only be administered under strictly monitored conditions. Flumazenil has a short "half-life (about one" hour), so patients given it should be monitored after its effects wear off. Flumazenil should be used with extreme caution in the presence of drugs that can lower the seizure threshold (e.g. tricyclic antidrepressants). For more information on the correct use of this medicine, you should contact your doctor.
If you have any questions about the use of Rivotril, ask your doctor or pharmacist
Side Effects What are the side effects of Rivotril
Like all medicines, Rivotril can cause side effects, although not everybody gets them.
The most frequent undesirable effects of Rivotril are referable to a "depressant action on the CNS. Experience has shown that about 50% of patients accuse drowsiness and about 30% ataxia;" in some cases these disturbances may diminish over time. Behavioral disturbances were detected in approximately 25% of patients. Other side effects are listed by system.
Immune system disorders: Allergic reactions and rare cases of anaphylaxis have been reported with benzodiazepines. Hypersensitivity reactions may occur in predisposed subjects.
Endocrine disorders: There have been isolated reports of reversible development of premature secondary sexual characteristics in children (incomplete precocious puberty).
Psychiatric disorders: impaired concentration, memory disturbances, hallucinations, agitation, confusion, disorientation have been observed. Depression may occur in patients treated with Rivotril and may also be associated with the underlying disease. Paradoxical reactions have been observed: restlessness, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams. In rare cases, decreased libido may occur.
Nervous system disorders: drowsiness, slowing of reactions, muscle hypotonia, tremor, dizziness, ataxia (see section "Special warnings"). Rare cases of headache have been observed. Very rare cases of generalized seizures have been observed. Reversible disorders such as dysarthria, impaired movement and gait coordination (ataxia) and nystagmus may occur (see section "Special warnings"). Anterograde amnesia and amnesic effects, which may be associated with behavioral changes (see section "Warnings"). special warnings "). An increase in the frequency of seizures with certain forms of epilepsy (see section" Special warnings ").
Eye disorders: Reversible visual disturbances (diplopia) may occur (see section "Special warnings"). Common: nystagmus.
Cardiac disorders: palpitations, heart failure including cardiac arrest has been reported.
Respiratory thoracic and mediastinal disorders: Respiratory depression may occur (see section "Special warnings").
Gastrointestinal disorders: the following effects have been reported in rare cases: nausea and epigastric symptoms, appetite disturbances, sialorrhea, alvus disorders, dry mouth, gastritis.
Hepatobiliary disorders: hepatomegaly, transient increase in serum transaminases and alkaline phosphatase.
Disorders of the blood and lymphatic system: anemia, leukopenia, thrombocytopenia, eosinophilia.
Skin and subcutaneous tissue disorders: The following effects have been reported in rare cases: hives, itching, rash, transient hair loss, pigmentation change.
Musculoskeletal and connective tissue disorders: muscle weakness (see section "Special warnings"). Renal and Urinary Disorders: Urinary incontinence may occur in rare cases.
Reproductive System and Breast Disorders: In rare cases, erectile dysfunction may occur.
General disorders and administration site conditions: deterioration in general physical health, hyperthermia, fatigue (tiredness, weakness) (see section "Special warnings").
Metabolism and nutrition disorders: dehydration, weight changes
Injury, poisoning and procedural complications: falls and fractures. The risk of falls and fractures is increased in patients taking concomitant sedatives (including alcoholic beverages) and in elderly patients.
Investigations: In rare cases, reduced platelet counts may occur.
Pediatric population
Endocrine disorders: isolated cases of reversible development of premature secondary sexual characteristics (incomplete precocious puberty).
respiratory, thoracic and mediastinal disorders: in infants and children, increased production of saliva or secretion (see section "Special warnings").
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable 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. Undesirable effects can also be reported directly through 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 the safety of this medicine
Expiry and Retention
Expiry: see the expiry date indicated on the package.
The expiry date refers to the product in intact packaging, correctly stored. Rivotril oral drops solution: store at a temperature not exceeding 30 ° C.
Warning: do not use the medicine after the expiry date indicated on the package.
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 THE MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN.
Composition and pharmaceutical form
Composition
Rivotril 0.5 tablets: One tablet with a fracture mark contains 0.5 mg clonazepam. Excipients: lactose, corn starch, pregelatinised potato starch, red iron oxide, yellow iron oxide, talc, magnesium stearate.
Rivotril 2 tablets: one tablet with a fracture mark contains 2 mg clonazepam. Excipients: lactose, pregelatinised starch, microcrystalline cellulose, magnesium stearate.
Rivotril drops: 1 ml (25 drops) contains 2.5 mg clonazepam. Excipients: sodium saccharin, peach flavor, glacial acetic acid, propylene glycol.
Pharmaceutical form and packaging
Rivotril 0.5 tablets: 20 tablets of 0.5 mg with fracture mark.
Rivotril 2 tablets: 20 tablets of 2 mg with fracture mark.
Rivotril drops: 10 ml of 2.5 mg / ml (1 drop = 0.1 mg)
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
RIVOTRIL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Rivotril 0.5 mg tablets. One tablet contains: 0.5 mg clonazepam.
Rivotril 2 mg tablets. One tablet contains: 2 mg clonazepam.
Rivotril 2.5 mg / ml oral drops solution. 1 ml of the drops solution contains: clonazepam 2.5 mg.
For the list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Rivotril is available in oral drops and tablets solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Most of the epileptic clinical forms in the infant and child. Particularly:
- typical or atypical petty evil
- generalized tonic-clonic seizures, primary or secondary
- state of evil in all its clinical expressions.
Rivotril is also indicated in adult epilepsy and focal seizures.
04.2 Posology and method of administration
The dosage of Rivotril is essentially individual and depends primarily on the age of the patient.
It should be established on a case-by-case basis on the basis of clinical response and tolerance.
To avoid the appearance of side effects at the beginning of the treatment, it is essential to gradually increase the daily dose until the maintenance dose has been reached.
Indicative maintenance doses that can be increased without problems if necessary:
As far as possible, the daily dose should be divided over 24 hours in 3-4 administrations.
The maintenance dose should be reached after 3-4 weeks of treatment.
To facilitate the adaptation of the dosage to individual needs and to make it easier to divide the total daily dose into 3-4 administrations, it is advisable to use the drops of Rivotril in the newborn baby (1 drop = 0.1 mg of active substance) and, in the child or adult in the initial phase of treatment, the 0.5 mg tablets.
The drops should be administered with a spoon and can be mixed with water, tea or fruit juice.
To facilitate administration, Rivotril 0.5 mg tablets can be divided into equal halves, while the 2 mg tablets can be divided into equal halves or quarters.
Elderly patients
Particular attention should be paid during treatment in elderly patients.
In the treatment of elderly patients, the posology must be carefully established by the physician who will have to evaluate a possible reduction of the dosages indicated above.
Kidney failure
The safety and efficacy of clonazepam in patients with renal insufficiency have not been studied, however, based on the pharmacokinetic criteria, no dosage adjustment is required in these patients (see section 5.2).
Hepatic insufficiency
The safety and efficacy of clonazepam in patients with hepatic insufficiency have not been studied. There are no data on the incidence of hepatic injury on the pharmacokinetics of clonazepam.
How to use the dropper bottle
Hold the bottle vertically, with the opening facing down. If the liquid does not run out, invert the bottle several times, or shake gently.
Attention: do not pour Rivotril drops into the mouth directly from the bottle.
After each opening make sure the dropper is stuck on the bottle neck.
04.3 Contraindications
Hypersensitivity to the active substance, to benzodiazepines or to any of the excipients.
The use of Rivotril is contraindicated in patients with clear clinical or biochemical signs of severe liver disease.
It can be used in people with open-angle glaucoma who are receiving adequate therapy, but is contraindicated in acute angle-closure glaucoma.
The product is also contraindicated in myasthenia gravis. Severe renal failure, severe respiratory failure. Do not administer in the first trimester of pregnancy.
Rivotril should not be used in patients in a coma, or in patients with known drug, drug or alcohol abuse.
04.4 Special warnings and appropriate precautions for use
Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs in several situations. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs found a slightly increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown and the available data do not exclude the possibility of an increased risk for clonazepam.
Therefore, patients presenting with signs of suicidal ideation and behavior should be monitored and if so appropriate treatment should be considered. Patients (and caregivers) should be advised to exercise caution if such signs occur.
Patients with a history of depression or suicide attempt should be closely monitored. The risk of withdrawal symptoms is increased when benzodiazepines are used with daily sedatives (cross tolerance).
If used in subjects presenting various forms of seizures, Rivotril can increase the incidence or induce the appearance of generalized tonic-clonic seizures (grand mal). It may therefore be necessary to add adequate anticonvulsants or to increase the dosage of the The concomitant use of valproic acid and Rivotril can produce a state of absence.
Since Rivotril can lead to increased salivation, this should be taken into account before prescribing the drug to patients who have difficulty in controlling secretions.
For the same reason, and due to possible respiratory depression, Rivotril should be used with caution in patients with chronic respiratory diseases.
Predisposed subjects, if treated with clonazepam at high doses and for prolonged periods, may be addictive, as occurs with other drugs with hypnotic, sedative and ataraxic activity.
Since the metabolites of Rivotril are excreted via the urine, in order to avoid excessive accumulation, the drug should be administered with caution to patients with impaired renal function.
The abrupt discontinuation of Rivotril, especially in patients undergoing long-term therapy with high doses, can induce a status epilepticus: consequently the discontinuation of the drug must be carried out gradually, and during this phase the substitution administration of another may be indicated. anticonvulsant.
During prolonged therapy with Rivotril it is advisable to carry out periodic blood counts and liver function tests.
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected undesirable effects from interaction.
In infants and children, Rivotril can cause increased saliva production and bronchial secretions. Therefore, particular attention must be paid to keeping the airways open.
Rivotril should be used with caution in patients with sleep apnea, chronic pulmonary insufficiency or impaired renal function, in the elderly, in debilitated subjects. In these cases the dose should generally be reduced.
The dose of Rivotril should be promptly adjusted based on individual requirements in patients with pre-existing respiratory disease (eg chronic obstructive pulmonary disease) or liver and in patients undergoing treatment with other centrally acting drugs or convulsive agents ( antiepileptics) (see section 4.5). Effects on the respiratory system may be aggravated by pre-existing airway obstruction or brain damage, or if other drugs capable of depressing breathing have been administered. As a rule, this effect can be avoided by individual dose adjustment.
Like all drugs of this class, Rivotril can, depending on the dosage, administration and individual susceptibility, modify the reactions of patients (eg driving skills or behavior in traffic). As a rule, epileptic patients are not allowed to drive. Although adequately controlled with Rivotril, it should be remembered that any increase in dosage or change in timing of dosing may modify patient reactions based on individual susceptibility (see section 4.7).
In epileptic patients, anticonvulsant drugs including Rivotril should not be stopped suddenly as they can precipitate epileptic disease. When, in the judgment of the clinician, the need to reduce or discontinue the dose arises, this should be done gradually. In such cases, a combination with other antiepileptic drugs is indicated.
Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Porphyria
Clonazepam is considered a probable nonporphyrogenic, although there is some conflicting evidence. However, clonazepam should be administered with caution in patients with porphyria.
Abuse and addiction
The use of benzodiazepines with these products can lead to the development of physical and psychological dependence (see section 4.8). In particular, prolonged or high-dose treatment can lead to irreversible disorders such as dysarthria, impaired coordination of movements, gait disturbances. (ataxia), nystagmus and double vision (diplopia). In addition, the risk of antegrade amnesia that can occur with the use of benzodiazepines at therapeutic doses increases at higher doses. The amnesiac effect may be associated with behavioral abnormalities and in certain forms an increase in the frequency of seizures. In some forms of epilepsy, an increase in the frequency of seizures is possible (see section 4.8) with long-term treatment.
Concomitant use of alcohol / CNS depressants
Concomitant use of Rivotril with alcohol and / or drugs with central nervous system depressant activity should be avoided. Such concomitant use could increase the clinical effects of Rivotril, including possible profound sedation and clinically relevant respiratory and / or cardiovascular depression. (see section 4.5).
Alcohol in any form can cause epileptic seizures, regardless of therapy; it is therefore essential that patients under treatment with Rivotril refrain from consuming alcoholic beverages. Combined with Rivotril, alcohol can alter the effects of the drug, compromise the results. treatment or cause unpredictable secondary reactions.
Medical history of alcohol or drug abuse
People prone to drug addiction, such as alcoholics and drug addicts, should be closely monitored when taking Rivotril, due to their predisposition to develop habit and addiction.
Rivotril should be used with extreme caution in patients with a history of alcohol and drug abuse.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacokinetic interactions between drugs
The antiepileptic drugs phenytoin, phenobarbital, carbamazepine and valproate can increase the clearance of clonazepam and therefore reduce its plasma concentrations in case of combination treatments. Clonazepam does not induce the enzymes responsible for its metabolism. The addition of an additional antiepileptic drug to the patients' therapeutic regimen should include a prompt evaluation of the response to treatment due to more likely undesirable effects such as sedation and apathy. In such cases, the dose of each drug must be adjusted in order to achieve the optimum desired effect.
Concomitant treatment with phenytoin or primidone may alter the plasma concentrations of phenytoin and primidone (usually increased).
Sertraline and fluoxetine, selective serotonin reuptake inhibitors, do not alter the pharmacokinetic parameters of clonazepam when combined.
Pharmacodynamic interactions between drugs
When Rivotril is used in combination with drugs that depress the CNS, including alcohol, it can increase the sedative effect on breathing and haemodynamic parameters.
Alcohol should be avoided in patients receiving Rivotril (see section 4.4).
For warnings related to other CNS depressant drugs, including alcohol, see section 4.9.
04.6 Pregnancy and lactation
Patients who may become pregnant or are of childbearing age should be given specialist advice.
The need for antiepileptic treatment should be re-evaluated when the patient plans to become pregnant.
The risk of birth defects is increased by a factor of 2 to 3 times in the offspring of mothers treated with an antiepileptic; the most frequently reported are cleft lip, cardiovascular malformations and neural tube defects (see section 5.3).
Polytherapy with antiepileptic drugs may be associated with a higher risk of congenital malformations than monotherapy. Therefore it is important that monotherapy is practiced whenever possible.
Abrupt discontinuation of antiepileptic therapy should not be practiced due to the danger of a resumption of seizures which could have serious consequences for both mother and baby.
Do not administer in the first trimester of pregnancy; in the further period, as well as in early childhood, the drug must be administered only in case of real need under the direct supervision of the doctor.
Since the active substance in Rivotril passes into breast milk, breastfeeding should be discontinued if the product is to be taken regularly.
04.7 Effects on ability to drive and use machines
Because Rivotril causes CNS depressant effects, patients treated with this drug should refrain from occupations that require a high degree of alertness, such as operating machinery or driving cars.
04.8 Undesirable effects
The most frequent undesirable effects of Rivotril are referable to a "depressant action on the CNS. Experience has shown that about 50% of patients accuse of drowsiness and about 30% of ataxia: in some cases these disorders may decrease over time. .
Behavioral disturbances were detected in approximately 25% of patients. Other side effects are listed by system.
Immune system disorders: Allergic reactions and rare cases of anaphylaxis have been reported with benzodiazepines. Hypersensitivity reactions may occur in predisposed subjects.
Endocrine disorders: There have been isolated reports of reversible development of premature secondary sexual characteristics in children (incomplete precocious puberty).
Psychiatric disorders: impaired concentration, memory disturbances, hallucinations, agitation, confusional state, disorientation have been observed. Depression may occur in patients treated with Rivotril and may also be associated with the underlying disease.
Paradoxical reactions have been observed: restlessness, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams.
In rare cases, decreased libido may occur.
Nervous system disorders: somnolence, slowing of reactions, muscle hypotonia, tremor, dizziness, ataxia (see section 4.4). Rare cases of headache have been observed.
Very rare cases of generalized seizures have been observed.
Reversible disorders such as dysarthria, impaired motor and gait coordination (ataxia) and nystagmus may occur (see section 4.4).
Anterograde amnesia and amnesic effects, which may be associated with behavioral changes (see section 4.4).
An increase in the frequency of seizures with certain forms of epilepsy (see section 4.4).
Eye disorders: Reversible disturbances of vision (diplopia) may occur (see section 4.4).
Common: nystagmus.
Cardiac pathologies: palpitations, heart failure including cardiac arrest has been reported.
Respiratory thoracic and mediastinal disorders: respiratory depression may occur (see section 4.4).
Chest congestion, rhinorrhea, breathing disturbances, upper respiratory tract hypersecretion.
Gastrointestinal disorders: The following effects have been reported in rare cases: nausea and epigastric symptoms, appetite disturbances, drooling, alvus disorders, dry mouth, gastritis.
Hepatobiliary disorders: hepatomegaly, transient increase in serum transaminases and alkaline phosphatase.
Disorders of the blood and lymphatic system: anemia, leukopenia, thrombocytopenia, eosinophilia.
Skin and subcutaneous tissue disorders: The following effects have been reported in rare cases: hives, itching, rash, transient hair loss, pigmentation change.
Musculoskeletal and connective tissue disorders: muscle weakness (see section 4.4).
Renal and urinary disorders: urinary incontinence may occur in rare cases.
Diseases of the reproductive system and breast: erectile dysfunction may occur in rare cases.
General disorders and administration site conditions: deterioration in general physical health, hyperthermia, fatigue (tiredness, weakness) (see section 4.4).
Metabolism and nutrition disorders: dehydration, weight changes.
Injury, poisoning and procedural complications: An increased risk of falls and fractures has been found in elderly patients receiving benzodiazepines.
Diagnostic tests: In rare cases, a reduction in platelet counts may occur.
Pediatric population
Endocrine disorders: isolated cases of reversible development of premature secondary sexual characteristics (incomplete precocious puberty).
respiratory, thoracic and mediastinal disorders: in infants and children, increased production of saliva or secretion (see section 4.4).
04.9 Overdose
Symptoms
Benzodiazepines commonly cause somnolence, ataxia, dysarthria and nystagmus.
An overdose of Rivotril, when taken alone, is rarely life-threatening but can result in areflexia, apnea, hypotension, cardiorespiratory depression and coma.
Coma, if it occurs, usually lasts a few hours but can last longer and be cyclical, especially in elderly patients. Respiratory depressive effects associated with benzodiazepines are more serious in patients with respiratory conditions.
Benzodiazepines enhance the effects of CNS depressant drugs, including alcohol. Symptoms of overdose or intoxication vary greatly from person to person depending on age, body weight and individual response.
Treatment
Monitor the patient's vital signs and define supportive measures in relation to the patient's clinical status. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.
Absorption should be prevented by an appropriate method, eg treatment with activated charcoal within 1-2 hours. If using activated charcoal, protect the respiratory tract if the patient is unconscious.
Gastric lavage should be considered if multiple drugs are ingested, but not as a routine measure.
In case of severe central nervous system depression, consider the use of flumazenil, a benzodiazepine antagonist. This should only be given under strictly monitored conditions. Flumazenil has a short "half-life (approximately one" hour), so patients it has been administered should be monitored after its effects have worn off. Flumazenil should be used with extreme caution in the presence of drugs that can lower the seizure threshold (eg tricyclic antidrepressants). For more information on the correct use of this medicinal product refer to the Summary of Product Characteristics for flumazenil.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiepileptic, ATC code: N03AE01.
The active ingredient of Rivotril is clonazepam, a benzodiazepine with strong antiepileptic properties.
As with any antiepileptic drug, the mechanism of action of Rivotril is not exactly known.
Experiments in animals and special electroencephalographic investigations in humans have however revealed that Rivotril determines a specific cortical or subcortical inhibition of epileptogenic foci and, more importantly, prevents the generalization of convulsive activity.
In most cases, Rivotril therefore favorably influences both focal epilepsy and primary generalized seizures.
05.2 Pharmacokinetic properties
Absorption
Clonazepam is rapidly and almost completely absorbed following oral administration of Rivotril tablets in humans, and maximum plasma levels of clonazepam are achieved within a period of usually 1-2 hours. The absorption half-life is approximately 25 minutes. Absolute bioavailability is 90%. Rivotril tablets are bioequivalent to the oral solution in the extent of absorption of clonazepam, while the rate of absorption is slightly slower with tablets.
Following once daily dosing, steady-state plasma concentrations of clonazepam are 3 times higher than after single oral administration; the predicted accumulation ratios with the two- and three-times-daily regimens are 5 and 7, respectively. After multiple oral 2 mg three times a day, steady-state plasma concentrations prior to dosing are on average 55 ng / ml. The dose-response relationship of clonazepam is linear. The target plasma concentration of clonazepam for the anticonvulsant effect is between 20 and 70 ng / ml.
After i.m. administration, maximum plasma concentrations of clonazepam are reached in approximately 3 hours, with an absolute bioavailability of 93%. Irregularities in the absorption profiles of clonazepam have occasionally been observed following IM administration.
Distribution
Clonazepam distributes very rapidly to various organs and tissues, with a preferential distribution in the brain tissue.
The half-life of distribution is approximately 0.5-1 hour. The volume of distribution is 3 L / kg. The plasma protein binding is 82-86%.
Metabolism
Clonazepam is extensively metabolised by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. There is also a "hydroxylation at the C-3 position. Cytochrome P-450 3A4 is involved in the nitro-reduction of clonazepam in pharmacologically inactive metabolites.
Metabolites are present in the urine as both free and conjugated compounds (glucuronide and sulfate)
Elimination
The mean elimination half-life is 30-40 hours. Clearance is 55 ml / min.
50-70% of the dose is excreted in the urine and 10-30% in the faeces as metabolites. Urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose.
The elimination kinetics in children are similar to that seen in adults.
Pharmacokinetics in special populations
Kidney failure
Renal insufficiency does not alter the pharmacokinetic parameters of clonazepam. Based on the pharmacokinetic criteria, no dosage adjustment is required in these patients (see section 4.2).
Hepatic insufficiency
The incidence of hepatic injury on clonazepam pharmacokinetics has not been evaluated (see section 4.2).
Senior citizens
The pharmacokinetics of clonazepam in elderly populations have not been evaluated.
Babies
The elimination half-life and clearance are of the same order of magnitude as those observed in adults.
05.3 Preclinical safety data
The acute toxicity of clonazepam is very low: in rats and mice the LD50 is higher than 4000 mg / kg.
Chronic toxicity studies also demonstrated the absence of pathology attributable to the product, in studies on dogs (3, 10 or 30 mg / kg p.o. 6 days a week for 12 months) and on rats.
Carcinogenicity
2-year carcinogenicity studies have not been conducted with clonazepam. However, in an 18-month chronic dosing study in rats, no treatment-related histopathological changes were observed up to the highest tested dose of 300 mg / kg / day.
Mutagenicity
Genotoxicity tests conducted in bacterial systems with metabolic activation in vitro or host-mediated did not indicate a genotoxic potential of clonazepam.
Impaired fertility
Studies evaluating fertility and general reproductive capacity in rats have shown a reduction in the pregnancy rate and a reduced survival of newborns with doses of 10 and 100 mg / kg / day.
Teratogenicity
Following oral administration of clonazepam during organogenesis in mice and rats, with doses up to 20 or 40 mg / kg / day, respectively, no adverse effects were observed in mothers or embryofetals.
In several studies in rabbits, following doses of clonazepam up to 20 mg / kg / day, a low, non-dose-dependent incidence of malformations of the same type (cleft palate, eyelid opening, neural tube defects and limbs) (see section 4.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Rivotril 0.5 mg tablets
lactose, corn starch, pregelatinised potato starch, red iron oxide, yellow iron oxide, talc, magnesium stearate.
Rivotril 2 mg tablets
lactose, pregelatinised starch, microcrystalline cellulose, magnesium stearate.
Rivotril 2.5 mg / ml oral drops solution
sodium saccharin, peach flavor, propylene glycol, glacial acetic acid.
06.2 Incompatibility
Not relevant
06.3 Period of validity
Rivotril tablets: 5 years.
Rivotril oral drops solution: 3 years.
06.4 Special precautions for storage
Rivotril tablets:
This medicine does not require any special storage conditions.
Rivotril oral drops solution:
Store at a temperature not exceeding 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Rivotril 0.5 mg tablets, Rivotril 2 mg tablets
plastic blister coupled with aluminum tape.
Rivotril 2.5 mg / ml oral drops solution
glass bottle with dropper.
(1 drop = 0.1 mg)
06.6 Instructions for use and handling
Rivotril 2.5 mg / ml oral drops solution
Warning: do not pour Rivotril drops into the mouth directly from the bottle.
After each opening make sure that the dropper is locked on the neck of the bottle.
07.0 MARKETING AUTHORIZATION HOLDER
Roche S.p.A. - Piazza Durante 11 - 20131 Milan
08.0 MARKETING AUTHORIZATION NUMBER
2.5 mg / ml oral drops solution bottle 10 ml AIC n ° 023159039
20 tablets 0.5 mg AIC n ° 023159054
20 tablets 2 mg AIC n ° 023159066
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal: June 2010
10.0 DATE OF REVISION OF THE TEXT
February 2012
