Active ingredients: bromazepam
Lexotan 1.5 mg hard capsules Lexotan 3 mg hard capsules Lexotan 2.5 mg / ml oral drops solution Lexotan 1.5 mg tablets Lexotan 3 mg tablets
Indications Why is Lexotan used? What is it for?
Lexotan is an anxiolytic belonging to the benzodiazepine class.
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome. Insomnia.
Benzodiazepines are only indicated when the disorder is severe, disabling, or makes the subject very uncomfortable.
Contraindications When Lexotan should not be used
Hypersensitivity to bromazepam or to any of the excipients. Myasthenia gravis. Known hypersensitivity to benzodiazepines. Severe respiratory insufficiency. Severe hepatic insufficiency (benzodiazepines are not indicated in the treatment of patients with severe hepatic insufficiency as they can cause encephalopathy). Sleep apnea syndrome.
Narrow angle glaucoma.
Acute intoxication with alcohol, hypnotic, analgesic or psychotropic drugs (neuroleptics, antidepressants, lithium).
Precautions for use What you need to know before taking Lexotan
General Precautions
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide can be precipitated in such patients). Therefore, in patients with signs and symptoms of depressive disorder or suicidal tendencies, bromazepam should be used with caution and prescription should be limited.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse (see Interactions).
Concomitant use of alcohol / CNS depressants
The concomitant use of Lexotan with alcohol and / or drugs with central nervous system depressant activity should be avoided, as it may increase the clinical effects of bromazepam, including possible profound sedation and clinically relevant respiratory and / or cardiovascular depression (see Interactions).
Serious anaphylactic / anaphylactoid reactions have been reported with the use of benzodiazepines. Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of benzodiazepines. Some patients taking benzodiazepines have have had additional symptoms such as dyspnoea, throat closure, or nausea and vomiting. Some patients have required treatment in the emergency room. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur which may be fatal.
Patients who develop angioedema after treatment with benzodiazepines should not be re-treated with the drug.
In the early stages of treatment, the patient should be monitored regularly to identify the minimum effective dose and frequency of administration and to prevent overdose during the course of treatment.
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 and benzodiazepine-like compounds 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 abuse or alcohol.
Therefore, benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
The possibility of dependence is reduced when Lexotan is used in the appropriate dose with short-term treatment.
Withdrawal symptoms
Once the physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms. These can consist of headache, diarrhea, muscle aches, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or seizures. Other symptoms are: depression, insomnia, sweating, persistent tinnitus, involuntary movements, vomiting, paraesthesia, perceptual changes, abdominal and muscle cramps, tremor, myalgia, agitation, palpitations, tachycardia, panic attacks, dizziness, hyper-reflexia, loss of short-term memory, hyperthermia.
Rebound insomnia and anxiety
A transient syndrome in which symptoms leading to benzodiazepine treatment 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.Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
Duration of treatment
The duration of treatment should be as short as possible depending on the indication (see Dose, method and time of administration) but should not exceed four weeks for insomnia and eight / twelve weeks for anxiety, including a period gradual discontinuation. Extension of therapy beyond these periods should not occur without reassessment of the clinical situation. At the beginning of the treatment it may be useful to inform the patient when the treatment will be of limited duration and to explain precisely how the dosage should be progressively decreased.
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, 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.
Amnesia
Benzodiazepines can induce antegrade amnesia. 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 uninterrupted sleep for several hours (see Side Effects).
Amnesic effects may be associated with behavioral changes (see section "Undesirable effects").
Anterograde amnesia can appear using the highest therapeutic doses (it has been documented with 6 mg): the risk is higher at higher doses.
Psychiatric and paradoxical reactions
Reactions such as restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, behavioral changes and other adverse effects related to behavior are known to occur when benzodiazepines are used. Should this occur, the use of the medicinal product should be discontinued. These reactions are more frequent in children and the elderly as well as in patients with organic brain syndrome.
For the time being, the possibility cannot be excluded that in patients in acute endogenous psychosis, especially severe depressive states, symptoms are aggravated by the use of Lexotan. Therefore, benzodiazepines are not recommended for the primary treatment of psychotic illnesses. The presence of depression must always be excluded, particularly in the initial and morning sleep disturbances, since the symptoms are also differently masked and the risks caused by the underlying disease are always present (for example suicidal tendencies).
Specific groups of patients
Pediatric Patients: Benzodiazepines should not be administered to children under the age of 18 without a "careful assessment of the actual need for treatment;" the duration of treatment should be as short as possible.
Elderly patients: 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, fatigue and therefore it is recommended to treat elderly patients with caution. The elderly should be treated with caution. take a reduced dose (see Dose, method and time of administration).
Patients with chronic respiratory insufficiency: Similarly, a lower dose is suggested for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
Patients with severe hepatic insufficiency: Benzodiazepines are not indicated in these patients as they can precipitate hepatic encephalopathy.
Patients with renal insufficiency: Lexotan should be administered with caution in patients with renal insufficiency.
The same prudential measures should be taken for patients with heart failure and low blood pressure who should be regularly monitored during Lexotan therapy (as are other benzodiazepines and other agents).
Patients with psychosis: Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Important information about some of the ingredients
Both tablets and capsules contain lactose so if your doctor has told you that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Interactions Which drugs or foods can modify the effect of Lexotan
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Pharmacodynamic interactions
The effects of benzodiazepines when administered concomitantly with alcohol or other CNS depressant drugs may be enhanced. Concomitant alcohol intake should be avoided (see Precautions for use).
The sedative effect may be enhanced when the medicinal product is concomitantly administered with alcohol or other CNS depressant substances. This adversely affects the ability to drive or use machines (Effects on ability to drive and use machines).
Bromazepam should be administered with caution in combination with other CNS depressant drugs. The central depressive effect may increase in cases of concomitant use of antipsychotics (neuroleptics), hypnotics, anxiolytics / sedatives, some antidepressant agents, opioids, narcotic analgesics, antiepileptics, anesthetics and sedative antihistamines.
Narcotic analgesics can cause an increase in euphoria leading to an increase in psychic dependence.
Particular care should be taken when bromazepam is administered with drugs that depress respiratory functions such as opioids (analgesics, antitussives, replacement treatments), particularly in elderly patients.
Pharmacokinetic interactions
Inhibitors of cytochrome P450
Compounds that inhibit certain liver enzymes (especially cytochrome P450) may increase the activity of benzodiazepines. To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation.
Pharmacokinetic interactions can occur when bromazepam is co-administered with drugs that inhibit the hepatic cytochrome P3A4 enzyme, resulting in increased plasma levels of bromazepam.
Concomitant administration of bromazepam with potent cytochrome P3A4 inhibitors (e.g. azole antifungals, protease inhibitors or some macrolides) should be done with caution considering a substantial dose reduction. In the case of narcotic analgesics, an increase in euphoria can also occur, correlated to an increase in psychic dependence.
Concomitant administration of cimetidine may prolong the elimination half-life of bromazepam.
Administration of theophylline or aminophylline may reduce the effects of benzodiazepines.
Warnings It is important to know that:
PREGNANCY AND BREASTFEEDING
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
If the product is prescribed to a woman of childbearing age, the patient must inform her doctor, both if she intends to become pregnant and if she suspects she is pregnant, in order to evaluate the suspension of the drug.
If, for serious medical reasons, the product is administered during the last period of pregnancy, or during labor at low doses, the "flaccid baby" syndrome may occur in the newborn, characterized by axial hypotonia and problems in sucking with consequent low increase These signs are reversible but can last from 1 to 3 weeks, depending on the half-life of the product. Respiratory depression or apnea and hypothermia may occur in neonates at high doses. In addition, infants born to mothers who have chronically taken benzodiazepines during late pregnancy may develop physical dependence and may be at some risk for developing postnatal withdrawal symptoms such as hyperexcitability, agitation and tremor even in the absence of "syndrome". flabby child ".
Taking these data into account, the use of bromazepam during pregnancy can be considered if the therapeutic indications and posology are strictly respected.
If treatment with bromazepam is necessary during the last trimester of pregnancy, high doses should be avoided and infants should be monitored to avoid withdrawal symptoms and / or infantile syndrome.
Pregnancy
Since bromazepam is excreted in breast milk, it is not recommended for use in breastfeeding mothers.
Effects on ability to drive vehicles and use of machinery
Lexotan impairs the ability to drive or use machines. Sedation, amnesia, impaired concentration and muscle function can adversely affect the ability to drive and use machines. The simultaneous intake of alcohol can aggravate this effect. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see Interactions).
Important Information About Some Excipients
Lexotan capsules and tablets contain lactose, in case of ascertained intolerance to sugars contact your doctor before taking the medicine.
Dosage and method of use How to use Lexotan: Dosage
Due to the variability of individual responses, the dosage should be adjusted case by case: on average 1.5-3 mg 2-3 times a day (1-2 capsules or 1-2 tablets of 1.5 mg 2-3 times a day , or 1 capsule or 1 tablet of 3 mg 2-3 times a day, or 15-30 drops 2-3 times a day).
In the treatment of elderly patients or patients with reduced hepatic function, the posology must be carefully established by the physician who will have to evaluate a possible reduction of the dosages indicated above.
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, this should not be done without reassessment of the patient's condition.
Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded.
Overdose What to do if you have taken an overdose of Lexotan
Symptoms
Benzodiazepines commonly cause somnolence, ataxia, dysarthria and nystagmus.
Bromazepam overdose is rarely life-threatening but can lead to dysarthria, areflexia, apnea, hypotension, cardiorespiratory depression and coma.
In the treatment of overdose of any drug, the possibility that other substances have been taken at the same time should be considered. Benzodiazepine overdose usually results in varying degrees of central nervous system depression ranging from somnolence 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. 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.
Treatment
Patient vital signs should be monitored and supportive measures instituted based on the patient's clinical picture. In particular, symptomatic treatment may be required for cardiorespiratory effects or central nervous system effects.
Further absorption should be prevented by using an appropriate method such as by treating (within 1-2 hours) with activated charcoal to reduce absorption. In the case of using activated charcoal in unconscious patients, protection of the airways is essential. In case of mixed ingestion, gastric lavage should be considered, but not as a routine treatment.
In emergency therapy, particular attention must be paid to respiratory and cardiovascular functions and to the central nervous system in emergency therapy.
If CNS depression is severe, consideration should be given to the administration of flumazenil, a benzodiazepine antagonist, which may be useful as an antidote.
The use of flumazenil is not indicated in patients with epilepsy treated with benzodiazepines. The antagonistic effect in these patients can trigger seizures.
Flumazenil should only be administered under closely 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 antidepressants).
For more information on the correct use of this medicine refer to the Package Leaflet for flumazenil. In case of accidental ingestion / overdose of Lexotan, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of Lexotan, ask your doctor or pharmacist.
Side Effects What are the side effects of Lexotan
Like all medicines, Lexotan can cause side effects, although not everybody gets them.
Drowsiness, dulling of emotions, decreased alertness, confusion, fatigue, headache, dizziness, decreased muscle tone, ataxia, double vision. These phenomena occur mainly at the start of therapy and usually disappear with subsequent administrations. Other adverse reactions have occasionally been reported including: gastrointestinal disturbances, changes in libido and skin reactions.
The frequency categories are as follows: Very common (≥1 / 10)
Common (≥1 / 100; <1/10)
Uncommon (≥1 / 1,000; <1/100)
Rare (≥1 / 10,000; <1 / 1,000)
Very rare (<1 / 10,000)
Not known (frequency cannot be predicted from the available data)
Not known (frequency cannot be predicted from the available data)
* These side effects phenomena mainly occur at the beginning of therapy and usually disappear with subsequent administrations.
** See paragraph Precautions for use
*** The risk of falls and fractures is increased in patients taking concomitant sedatives (including alcoholic beverages) and in patients in 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, SIADH (syndrome of inappropriate antidiuretic hormone secretion).
UNDESIRABLE EFFECTS of the BENZODIAZEPINE CLASS (BDZ)
Amnesia
Anterograde amnesia can also appear at therapeutic doses, the risk being increased at higher doses. Amnesic effects may be associated with behavioral changes (see Precautions for use).
Depression
During the use of benzodiazepines a pre-existing depressive state can be unmasked. Benzodiazepines or benzodiazepine-like compounds can cause reactions such as: restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, behavioral changes.
Such reactions can be quite severe. They are more likely in children and the elderly than in other patients.
Rebound insomnia and anxiety
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.
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.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Lexotan 1.5 mg hard capsules
Lexotan 3 mg hard capsules
Do not store above 30 ° C.
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Expiry of the pack after first opening:
oral drops solution: 16 days
Warning: do not use the medicine after the expiry date shown on the package.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
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
LEXOTAN
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lexotan 1.5 mg hard capsules
one capsule contains:
active principle: bromazepam 1.5 mg.
Excipients: lactose monohydrate.
Lexotan 3 mg hard capsules
one capsule contains:
active principle: bromazepam 3 mg.
Excipients: lactose monohydrate.
Lexotan 6 mg hard capsules
one capsule contains:
active principle: bromazepam 6 mg.
Excipients: lactose monohydrate.
Lexotan 2.5 mg / ml oral drops solution
1 ml of solution contains:
active principle: bromazepam 2.5 mg.
Lexotan 1.5 mg tablets
one tablet contains:
active principle: bromazepam 1.5 mg.
Excipients: lactose monohydrate.
Lexotan 3 mg tablets
one tablet contains:
active principle: bromazepam 3 mg.
Excipients: lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Lexotan is available in hard capsules, tablets and oral solution drops.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Lexotan
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome. Insomnia.
Lexotan 6 mg hard capsules
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome.
Benzodiazepines are only indicated when the disorder is severe, disabling, or makes the subject very uncomfortable.
04.2 Posology and method of administration
Due to the variability of individual responses, the posology must be adjusted case by case.
Lexotan: on average from 1.5 to 3 mg, 2-3 times a day (1-2 capsules or 1-2 tablets of 1.5 mg 2-3 times a day or 1 capsule or 1 tablet of 3 mg 2-3 times a day, or 15-30 drops 2-3 times a day).
Lexotan 6 mg hard capsules: on average 6-12 mg 2-3 times a day.
In the treatment of elderly patients or patients with reduced hepatic function: the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above.
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
(not applicable to Lexotan 6 mg hard capsules)
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.
Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded.
04.3 Contraindications
Bromazepam is contraindicated in patients with:
• Hypersensitivity to bromazepam or to any of the excipients.
• Known hypersensitivity to benzodiazepines.
• Myasthenia gravis.
• Severe respiratory insufficiency.
• Severe hepatic insufficiency (benzodiazepines are not indicated in the treatment of patients with severe hepatic insufficiency as they can cause encephalopathy).
• Sleep apnea syndrome.
• Narrow angle glaucoma.
• Acute intoxication with alcohol, hypnotic, analgesic or psychotropic drugs (neuroleptics, antidepressants, lithium).
04.4 Special warnings and appropriate precautions for use
General Precautions
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide can be precipitated in such patients). Therefore, in patients with signs and symptoms of depressive disorder or suicidal tendencies, bromazepam should be used with caution and prescription should be limited.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse (see section 4.5).
Concomitant use of alcohol / CNS depressants
The concomitant use of Lexotan with alcohol and / or drugs with central nervous system depressant activity should be avoided, as it may increase the clinical effects of bromazepam, including possible profound sedation and clinically relevant respiratory and / or cardiovascular depression (see paragraph 4.5).
Serious anaphylactic / anaphylactoid reactions have been reported with the use of benzodiazepines. Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of benzodiazepines. Some patients taking benzodiazepines have have had additional symptoms such as dyspnoea, throat closure, or nausea and vomiting. Some patients have required treatment in the emergency room. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur which may be fatal.
Patients who develop angioedema after treatment with benzodiazepines should not be re-treated with the drug.
In the early stages of treatment, the patient should be monitored regularly to identify the minimum effective dose and frequency of administration and to prevent overdose during the course of treatment.
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 and benzodiazepine-like compounds 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 abuse. or alcohol.
Therefore, benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
The possibility of dependence is reduced when Lexotan is used in the appropriate dose with short-term treatment.
Withdrawal symptoms
Once the physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms. These can consist of headache, diarrhea, muscle aches, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or seizures. Other symptoms are: depression, insomnia, sweating, persistent tinnitus, involuntary movements, vomiting, paraesthesia, perceptual changes, abdominal and muscle cramps, tremor, myalgia, agitation, palpitations, tachycardia, panic attacks, dizziness, hyper-reflexia, loss of short-term memory, 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 discontinuation of treatment, it is suggested to make a gradual decrease in dosage.
Duration of treatment
The duration of treatment should be as short as possible depending on the indication (see section 4.2), and 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. At the beginning of the treatment it may be useful to inform the patient that it will be of limited duration (see section 4.2) and to explain precisely how the dosage should be progressively decreased.
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, 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.
Amnesia
Benzodiazepines can induce antegrade amnesia. 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 uninterrupted sleep for several hours (see section 4.8).
Amnesic effects may be associated with behavioral changes (see section 4.8 "Undesirable effects").
Anterograde amnesia can appear using the highest therapeutic doses (it has been documented with 6 mg): the risk is higher at higher doses.
Psychiatric and paradoxical reactions
Reactions such as restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, behavioral changes and other adverse effects related to behavior are known to occur when using benzodiazepines. Should this occur, the use of the medicinal product should be discontinued. These reactions are more frequent in children and the elderly as well as in patients with organic brain syndrome.
For the time being, the possibility cannot be excluded that in patients in acute endogenous psychosis, especially severe depressive states, symptoms are aggravated by the use of Lexotan. Therefore, benzodiazepines are not recommended for the primary treatment of psychotic illnesses. The presence of depression must always be excluded, particularly in the initial and morning sleep disturbances, since the symptoms are also differently masked and the risks caused by the underlying disease are always present (for example suicidal tendencies).
Specific groups of patients
Pediatric Patients: Benzodiazepines should not be administered to patients under the age of 18 without a "careful assessment of the actual need for treatment;" the duration of treatment should be as short as possible.
Elderly patients: Benzodiazepine use may be associated with an increased risk of falls due to undesirable effects such as ataxia, muscle weakness, dizziness, somnolence, tiredness, fatigue and therefore it is recommended to treat elderly patients with caution. The elderly should be treated with caution. take a reduced dose (see 4.2).
Patients with chronic respiratory insufficiency: Similarly, a lower dose is suggested for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
Patients with severe hepatic insufficiency: Benzodiazepines are not indicated in these patients as they can precipitate hepatic encephalopathy.
Patients with renal insufficiency: Lexotan should be administered with caution in patients with renal insufficiency.
The same prudential measures should be taken for patients with heart failure and low blood pressure who should be regularly monitored during Lexotan therapy (as is recommended with other benzodiazepines and other psychopharmacological agents).
Patients with psychosis: Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Important information about some of the ingredients
Both tablets and capsules contain lactose therefore patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacodynamic interactions
The effects of benzodiazepines when administered concomitantly with alcohol or other CNS depressant drugs may be enhanced. Concomitant alcohol intake should be avoided (see section 4.4).
The sedative effect may be enhanced when the medicinal product is concomitantly administered with alcohol. This adversely affects the ability to drive or use machines (see section 4.7).
Bromazepam should be administered with caution in combination with other CNS depressant drugs. The central depressive effect may increase in cases of concomitant use of antipsychotics (neuroleptics), hypnotics, anxiolytics / sedatives, some antidepressant agents, opioids, narcotic analgesics, antiepileptics, anesthetics and sedative antihistamines.
Narcotic analgesics can cause an increase in euphoria leading to an increase in psychic dependence.
Particular care should be taken when bromazepam is administered with drugs that depress respiratory functions such as opioids (analgesics, antitussives, replacement treatments), particularly in elderly patients.
Pharmacokinetic interactions
Inhibitors of cytochrome P450
Compounds that inhibit certain liver enzymes (especially cytochrome P450) may increase the activity of benzodiazepines. To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation.
Pharmacokinetic interactions can occur when bromazepam is co-administered with drugs that inhibit the hepatic enzyme CYP3A4, resulting in increased plasma levels of bromazepam.
Concomitant administration of bromazepam with potent cytochrome P3A4 inhibitors (e.g. azole antifungals, protease inhibitors or some macrolides) should be done with caution considering a potential dose reduction. In the case of narcotic analgesics, an increase in euphoria can also occur, correlated to an increase in psychic dependence.
Concomitant administration of cimetidine may prolong the elimination half-life of bromazepam.
Administration of theophylline or aminophylline may reduce the effects of benzodiazepines.
04.6 Pregnancy and lactation
Pregnancy
The safety of use of bromazepam in pregnancy has not yet been established. A review of spontaneous reports of adverse drug events showed an incidence comparable to that which might be expected in a similar untreated population. Although no specific clinical data are available, many data from cohort studies indicate that benzodiazepine exposure in the first trimester of pregnancy is not associated with an increased risk of major malformations. However, some preliminary case-control epidemiological studies have shown an increased incidence of oral cleft risk in neonates. The data indicate that the risk of birth of a child with oral cleft after exposure to benzodiazepines by the mother is less than 2/1000 compared to an expected rate for such defects of about 1/1000 in the general population.
Treatment with benzodiazepines at high doses during the second and / or third trimester of pregnancy revealed a decrease in active fetal movements and a variability of the fetal heart rhythm.
If the product is prescribed to a woman of childbearing age, the patient must inform her doctor, both if she intends to become pregnant, and if she suspects she is pregnant, regarding the discontinuation of the drug.
If, for serious medical reasons, the product is administered during the last period of pregnancy, or during labor even at low doses, the "flaccid baby" syndrome may occur in the newborn, characterized by axial hypotonia and problems in sucking with consequent poor weight gain. These signs are reversible but can last from 1 to 3 weeks, depending on the half-life of the product. Respiratory depression or apnea and hypothermia may occur in infants at high doses. In addition, infants born to mothers who have chronically taken benzodiazepines during late pregnancy may develop physical dependence and may be at some risk of developing postnatal withdrawal symptoms such as hyperexcitability, agitation and tremor even after a few days after birth. birth and in the absence of "flaccid baby" syndrome.
Taking these data into account, the use of bromazepam during pregnancy could be considered if the therapeutic indications and posology are strictly adhered to.
If treatment with bromazepam is necessary during the last trimester of pregnancy, high doses should be avoided and infants should be monitored for withdrawal symptoms and / or "flaccid baby" syndrome.
Feeding time
Since bromazepam is excreted in breast milk, it is not recommended for use in breastfeeding mothers.
04.7 Effects on ability to drive and use machines
Sedation, amnesia, impaired concentration and muscle function can adversely affect the ability to drive and use machines. The simultaneous intake of alcohol can aggravate this effect. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see section 4.5).
04.8 Undesirable effects
The following side effects have been reported to occur following administration of Lexotan
The categories of attendance are as follows:
Very common (≥1 / 10)
Common (≥1 / 100;
Uncommon (≥1 / 1,000;
Rare (≥1 / 10,000;
Very rare (
Not known (the frequency cannot be predicted on the basis of the available data)
* These side effects mainly occur at the start of therapy and usually disappear with subsequent administrations.
** See section 4.4 Special warnings and precautions for use.
*** The risk of falls and fractures is increased in patients taking concomitant sedatives (including alcoholic beverages) and in 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, SIADH (syndrome of inappropriate antidiuretic hormone secretion).
UNDESIRABLE EFFECTS OF THE BENZODIAZEPINE CLASS (BDZ)
Amnesia
Anterograde amnesia can also appear at therapeutic dosages, the risk increases with higher doses. Amnesic effects may be associated with behavioral changes (see section 4.4).
Depression
A pre-existing depressive state can be unmasked during the use of benzodiazepines. Benzodiazepines or benzodiazepine-like compounds can cause reactions such as: restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, behavioral changes.
These reactions can be severe. They are more likely in children and the elderly than in other patients.
Rebound insomnia and anxiety
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.
Dependence
The use of benzodiazepines (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy may cause rebound or withdrawal phenomena (see section 4.4). Psychic dependence may occur. Abuse of benzodiazepines has been reported.
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
Symptoms
Benzodiazepines commonly cause somnolence, ataxia, dysarthria and nystagmus.
Bromazepam overdose rarely poses a risk to life if the drug is taken alone, but can lead to dysarthria, areflexia, apnea, hypotension, cardiorespiratory depression and coma.
In the treatment of overdose of any drug, the possibility that other substances have been taken at the same time should be considered. Benzodiazepine overdose usually results in varying degrees of central nervous system depression ranging from somnolence 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. 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 potentiate the effects of other CNS depressants including alcohol.
Treatment
The patient's vital signs should be monitored and supportive measures instituted based on the patient's clinical picture. In particular, symptomatic treatment may be required for cardiorespiratory effects or central nervous system effects.
Further absorption should be prevented by using an appropriate method such as by treating (within 1-2 hours) with activated charcoal to reduce absorption. In the case of using activated charcoal in unconscious patients, protection of the airways is essential. In case of mixed ingestion, gastric lavage should be considered, but not as a routine treatment.
In emergency therapy, particular attention must be paid to respiratory cardiovascular and central nervous system functions.
If CNS depression is severe, consideration should be given to the administration of flumazenil, a benzodiazepine antagonist, which may be useful as an antidote. Flumazenil should only be administered under closely monitored conditions.
The use of flumazenil is not indicated in patients with epilepsy treated with benzodiazepines. The antagonistic effect in these patients can trigger seizures.
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 antidepressants). For more information on the correct use of this medicinal product please refer to the Summary of Product Characteristics for flumazenil.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anxiolytic.
ATC code: N05BA08.
Bromazepam exhibits the pharmacological properties characteristic of benzodiazepine tranquilizers. In particular, in laboratory animals it has domesticating, muscle relaxant, anticonvulsant and deconditioning effects which are, in relation to those of chlordiazepoxide, respectively approximately equal to 4, 10 and 16 times higher.
Lexotan in low doses selectively reduces the states of tension or anxiety associated or not with depression, implements a prompt control of emotional imbalances (states of tension, anxiety, associated or not with depression) and consequently the normalization of visceral and generically somatic disorders which find their genesis or, in any case, a triggering or aggravating contributing cause, in a disturbance of the psycho-emotional balance of the subject.
At particularly high dosages, a sedative and muscle relaxant effect appears.
05.2 Pharmacokinetic properties
Absorption
Bromazepam is well absorbed after oral administration and peak plasma concentrations are reached within 1-2 hours of administration. The absolute (with respect to the i.v. solution) and relative (with respect to the oral solution) bioavailability of the tablets is 60% and 100% respectively.
Distribution
The plasma protein binding of bromazepam is 70%. The volume of distribution is 50 liters. Bromazepam is a benzodiazepine describable with a single compartment model.
Metabolism and elimination
Bromazepam is metabolised in the liver. From a quantitative point of view, there are two predominant metabolites: 3-hydroxybromazepam and 2- (2-amino-5-bromo-3-hydroxybenzoyl) pyridine. In the urine, compared to the administered dose, 2% of bromazepam as such is found, 27% of the glucurono-conjugate 3-hydroxybromazepam and 40% of 2- (2-amino-5-bromo-3-hydroxybenzoyl) pyridine . Elimination is mainly renal and occurs according to linear kinetics with a half-life of approximately 20.1 hours. Clearance is 40 ml / min.
Pharmacokinetics in particular groups of patients
Senior citizens
The elimination half-life may be longer in elderly patients.
05.3 Preclinical safety data
The LD50 in mice is equal to 2000 mg / kg p.o.
Carcinogenicity
Carcinogenicity studies in rats did not reveal any carcinogenic potential of bromazepam.
Mutagenicity
Bromazepam was not genotoxic in tests in vitro And in vivo.
Impaired fertility
Daily oral administration of bromazepam had no effect on the fertility and general reproductive capacity of the rats.
Teratogenicity
Increases in fetal mortality, an increase in the stillbirth rate and a reduction in neonatal survival were observed when bromazepam was administered to pregnant rats. Embryotoxicity / teratogenicity studies did not show teratogenic effects up to the dose of 125 mg / kg / day.
Following oral administration of doses up to 50 mg / kg / day to pregnant rabbits, a reduction in maternal weight gain, a reduction in fetal weight and an increase in the incidence of resorption have been observed.
Chronic toxicity
Long-term toxicity studies revealed no deviations from normal, with the exception of an increase in hepatic weight. Histopathological examination revealed centrilobular hepatocellular hypertrophy which was considered indicative of enzyme induction by bromazepam. Side effects observed after administration of high doses were sedation, ataxia, short isolated seizure manifestations, occasional increase in serum alkaline phosphatase, and borderline increase in mild to moderate SGPT (ALT).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lexotan 1.5 mg hard capsules
Lactose monohydrate, corn starch, talc, magnesium stearate, gelatin, titanium dioxide, black iron oxide (E172), red iron oxide (E172), yellow iron oxide (E172).
Lexotan 3 mg hard capsules
Lactose monohydrate, corn starch, talc, magnesium stearate, gelatin, titanium dioxide, black iron oxide (E172), red iron oxide (E172), yellow iron oxide (E172).
Lexotan 2.5 mg / ml oral drops solution
saccharin, sodium edetate, blackberry flavor, all fruit flavor, purified water, propylene glycol.
Lexotan 6 mg hard capsules
Lactose monohydrate, corn starch, talc, magnesium stearate, gelatin, titanium dioxide, black iron oxide (E172), red iron oxide (E172), yellow iron oxide (E172).
Lexotan 1.5 mg tablets
microcrystalline cellulose, lactose monohydrate, talc, magnesium stearate.
Lexotan 3 mg tablets
microcrystalline cellulose, lactose monohydrate, talc, magnesium stearate, red iron oxide (E172).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Expiry of the unopened package correctly stored:
capsules and tablets: 5 years.
oral drops solution: 3 years.
Expiry of the pack after first opening:
oral drops solution: 16 days.
The drug should not be used after the expiry date stated on the package.
06.4 Special precautions for storage
Lexotan 1.5 mg hard capsules
Lexotan 3 mg hard capsules
Lexotan 6 mg hard capsules
Do not store above 30 ° C.
Lexotan 2.5 mg / ml oral drops solution
Lexotan 1.5 mg tablets
Lexotan 3 mg tablets
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Lexotan oral drops solution comes in a glass vial enclosed in a cardboard box.
The other shapes are presented in blister packs in coupled aluminum and plastic material also enclosed in a cardboard box together with the illustrative leaflet.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Roche S.p.A. - Piazza Durante 11 - 20131 Milan
08.0 MARKETING AUTHORIZATION NUMBER
Oral drops solution 20 ml bottle AIC n ° 022905057
20 hard capsules 1.5 mg AIC n ° 022905119
20 hard capsules 3 mg AIC n ° 022905121
20 hard capsules 6 mg AIC n ° 022905133
20 tablets 3 mg AIC n ° 022905145
20 tablets 1.5 mg AIC n ° 022905158
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal: June 2010
10.0 DATE OF REVISION OF THE TEXT
June 2014
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