Active ingredients: Brotizolam
LENDORMIN 0.25 mg tablets
Why is Lendormin used? What is it for?
Lendormin contains the active substance brotizolam, which belongs to a class of medicines called benzodiazepines, which induces sedation (physical and mental relaxation) and sleep.
Lendormin is used to treat short-term insomnia (difficulty falling asleep and / or frequent or prolonged awakening at night) in adults aged 18 years and over.
Benzodiazepines are only indicated when the insomnia is severe, disabling (that is, it impairs the ability to perform normal activities) and makes the subject very uncomfortable. Contact your doctor if you do not feel better or if you feel worse.
Contraindications When Lendormin should not be used
Do not take Lendormin
- If you are allergic to brotizolam or any of the other ingredients of this medicine or other benzodiazepines
- if you suffer from muscle weakness (myasthenia gravis)
- if you suffer from severe respiratory failure (severe respiratory disease which occurs quickly and suddenly and involves an inadequate supply of oxygen and / or carbon dioxide in the blood)
- if you suffer from sleep apnea syndrome (when, during sleep at night, apnea occurs several times, i.e. the temporary suspension of breathing, which can lead to considerable and unnatural drowsiness during the day)
- if you have severe liver disease (severe liver failure) (see section "Warnings and precautions")
- if you are under 18 years of age as the tablets are only suitable for adults and no studies are available in children
- in case of rare hereditary conditions which may be incompatible with one of the components of this medicine (see also section "Lendormin contains lactose")
Precautions for use What you need to know before taking Lendormin
Talk to your doctor or pharmacist before taking Lendormin.
Warnings for specific population groups:
- If you are elderly or have reduced liver function
If you are elderly or have reduced liver function your doctor may reduce the dose of this medicine (see section 3 "How to take Lendormin"). Benzodiazepines are not indicated in patients with severe hepatic insufficiency, as these medicines can cause encephalopathy (brain disease causing confusion, disturbances in consciousness, personality disorders, memory loss, tremors and coma due to the presence of toxic substances build up in the blood due to liver malfunction) (see section "Do not take Lendormin").
- If you have chronic breathing problems (chronic respiratory failure)
If you suffer from chronic respiratory failure (respiratory disease that lasts over time, which involves an inadequate supply of oxygen and / or carbon dioxide in the blood) accompanied by an increase in carbon dioxide in the blood (hypercapnia), your doctor may reduce the dose of this medicine, as it may increase the risk of decreased breathing activity (respiratory depression) especially at night.
- If you suffer from mental disorders (psychosis)
Lendormin is not recommended for the treatment of psychosis unless in combination with other medicines.
- If you suffer from depression or anxiety associated with depression
The use of this class of medicines may make evidence of depression that is already present. Lendormin should not be used to treat depression or anxiety associated with depression unless in combination with other medicines, as it may aggravate behavior against you, such as lead to death Always follow your doctor's instructions.
- If you have had a history of drug abuse.
This medicine should not be used if you have had a history of drug abuse.
- If you have had a history of alcohol abuse
This medicine should not be used if you have had a history of alcohol abuse (see section "Lendormin with alcohol").
Tolerance
After repeated use for a few weeks, some loss of the effects of benzodiazepines may occur.
Dependence
- The use of this class of medicines can lead to the development of physical and mental dependence. This risk increases with the dose and duration of treatment and is greater if you have abused alcohol or drugs in the past, in which case you should not take Lendormin.
- After discontinuation of treatment, a transient syndrome may occur which consists in the reappearance, in an aggravated form, of the symptoms that led to the use of this medicine: this is one of the first symptoms of addiction and may be accompanied by other reactions such as changes mood, anxiety and restlessness or sleep disturbances.
- In cases where you have developed physical dependence, consult your doctor before stopping treatment with this medicine, as abrupt discontinuation of therapy will be accompanied by withdrawal symptoms of varying severity, mild complaints such as, for example, headache, muscle aches, severe psychiatric symptoms such as extreme anxiety and tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: sensation of perceiving the external world and reality in a distorted way (derealization), sensation of detachment from the external world and from oneself (depersonalization), hearing disturbance that involves an increase in sensitivity and intolerance to sounds (hyperacusis), numbness and tingling in the arms and legs, increased sensitivity to light, noise or physical contact, perception of things that do not exist in reality (hallucinations) or seizures. Please refer to the sections "Possible side effects" and "If you stop taking Lendormin". Also, if you are taking a high dose of this medicine, withdrawal symptoms may also occur in the interval between doses.
Amnesia (memory disorder)
Benzodiazepines can cause a memory disorder characterized by the inability to memorize new information (anterograde amnesia) which can occur even at recommended dosages; the risk increases with higher dosages.
Effects related to antegrade amnesia may be associated with behavioral disturbances. This condition occurs most often several hours after taking the medicine; therefore, to reduce this risk, before taking this medicine you must make sure that you can have a sufficient period of uninterrupted sleep, usually 7-8 hours (see sections "Possible side effects" and "How to take Lendormin").
Psychiatric and paradoxical reactions (behavioral disorders)
Restlessness, agitation, irritability, aggression, mental confusion (delirium), anger, nightmares, perception of things that do not exist in reality (hallucinations), mental disorders (psychosis), inappropriate behavior and others may occur during the use of benzodiazepines. adverse behavioral effects. If this occurs, you should contact your doctor to stop using the medicine (see the section "Possible side effects" and the section "If you stop taking Lendormin").
Children and adolescents
The tablets are only suitable for adults and no studies are available in children, therefore Lendormin should not be used in children and adolescents below 18 years of age.
Interactions Which drugs or foods can modify the effect of Lendormin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
The activity of Lendormin may be increased if it is prescribed together with other medicines that work by reducing the activity of the central nervous system, increasing its effects. This can happen with a variety of medications including:
- antipsychotics (neuroleptics, drugs for mental disorders)
- hypnotics (sleep medications)
- anxiolytics (anxiety medications)
- sedatives (drugs that cause physical and mental relaxation)
- antidepressants (drugs for depression)
- narcotic analgesics (drugs that reduce pain by acting on the central nervous system). In the case of narcotic analgesics, the increase in euphoria can lead to an increase in psychic dependence (feeling the strong need to take the medicine)
- antiepileptics (drugs for epilepsy)
- anesthetics (drugs that cause a temporary loss of sensation, pain, and in some cases even consciousness, associated with muscle relaxation)
- sedative antihistamines (allergy medications that also cause physical and mental relaxation of the central nervous system).
The activity of Lendormin can be changed by drugs that affect the metabolism of the liver (ie the way the liver works):
- when Lendormin is given together with medicines that stimulate the liver metabolism such as rifampicin (antibiotic), the effect of Lendormin may decrease
- when Lendormin is given together with medicines that reduce the metabolism of the liver such as ketoconazole (medicine for fungal skin infections), the effect of Lendormin may increase and become harmful.
Lendormin with alcohol
When Lendormin is used concurrently with alcohol they can increase sedation (physical and mental relaxation), fatigue and reduced concentration, therefore concomitant intake with alcohol is not recommended.
In addition, the "increased sedative effect" when the medicine is taken concomitantly with alcohol affects the ability to drive or use machines (see section "Driving and using machines").
Taking too much Lendormin together with alcohol may be life-threatening (see section "If you use more Lendormin than you should")
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Pregnancy and breastfeeding
There are insufficient data on Lendormin to evaluate the safety of the medicine during pregnancy and lactation.
Consequently, the use of Lendormin is not recommended during pregnancy and breastfeeding. If you intend to become pregnant or suspect that you are pregnant and are taking this medicine, you should contact your doctor to stop using the medicine (see section "If you stop taking Lendormin").
Although not recommended, if your doctor prescribes this medicine to you late in your pregnancy or during labor, it can have effects on the baby such as low body temperature (hypothermia), muscle tone defect sometimes associated with muscle weakness (hypotonia) and moderate decrease in respiratory activity (moderate respiratory depression), caused by the action of the medicine.
In addition, children born to mothers who took benzodiazepines (i.e. medicines of the same class as Lendormin) chronically during the latter stages of pregnancy may develop physical dependence and have some risk of developing withdrawal symptoms in the postnatal period (see section 4 "Possible Side Effects").
Since benzodiazepines are excreted in breast milk, the use of this medicine is not recommended for mothers who are breastfeeding.
Fertility
No fertility data are available for this medicinal product. Studies with brotizolam, the active ingredient in Lendormin, have not shown any adverse effects on fertility.
Driving and using machines
No studies on the effect of the medicine on the ability to drive and use machines have been performed.
However, undesirable effects such as sedation (physical and mental relaxation), memory disturbance (amnesia), reduced mental and physical abilities may occur during treatment (see section "Possible undesirable effects").
Mental and physical impairment can increase the risk of falls and road accidents.
The concomitant use of alcohol and / or drugs that reduce the activity of the central nervous system can increase this impairment.
In the case of insufficient sleep duration, the likelihood of decreased alertness is increased. Therefore caution is recommended when driving vehicles and using machines.
If you experience any of the above, you should avoid potentially hazardous activities such as driving or operating machinery.
Lendormin contains lactose
If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Lendormin: Posology
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Adults aged 18 and over
How many
Unless otherwise prescribed by your doctor, the following dosages are recommended:
Adults: The recommended dose is 0.25 mg (1 tablet) in the evening before going to bed
Elderly: the recommended dose is 0.125 mg (half tablet) -0.25 mg (1 tablet) in the evening before going to bed
The tablets can be divided into equal halves.
Treatment should be started at the lowest recommended dose.
The dose of 0.25 mg (1 tablet) should not be exceeded due to the "increased risk of" developing undesirable effects on the central nervous system (see section 4 "Possible undesirable effects").
If your doctor prescribes a high dose, withdrawal symptoms may occur in the interval between doses (see section 4 "Possible side effects").
As the risk of withdrawal or rebound symptoms is greater if treatment is stopped abruptly, your doctor will gradually reduce your dose before stopping it permanently (see section "If you stop taking Lendormin").
Like
The medicine should be taken with a small amount of liquid just before going to bed. After taking this medicine, you should allow 6-7 hours to rest or sleep.
If you have impaired liver function
If you have impaired liver function, the dose should be decreased as prescribed by the doctor.
If you have reduced kidney function
Available data demonstrate that dose adjustment is not necessary in case of impaired kidney function. Take this medicine as prescribed by your doctor.
Duration of treatment
Treatment should be as short as possible. The duration of treatment varies from a few days to a maximum of 2 weeks. Your doctor will adjust the dose tapering on an individual basis.
Therefore, at the beginning of the treatment, your doctor will inform you that this will be of limited duration and will explain to you exactly how you will have to gradually decrease the dosage.
In certain cases, the doctor after a general re-evaluation of your condition may decide to extend the therapy beyond the maximum treatment period (i.e. beyond 2 weeks).
Use in children and adolescents
The tablets are only suitable for adults and no studies are available in children, therefore Lendormin should not be used in children and adolescents below 18 years of age.
Overdose What to do if you have taken too much Lendormin
In case of accidental ingestion / intake of an excessive dose of Lendormin, notify your doctor immediately or go to the nearest hospital.
Symptoms
In the event of accidental ingestion / ingestion of an excessive dose of Lendormin usually a reduction in central nervous system activity to varying degrees may occur. In mild cases, symptoms include momentary loss of sensory and intellectual abilities associated with sense. disorientation (drowsiness), mental confusion and lethargy (deep sleep with reduced response to normal stimuli); in severe cases, symptoms may include progressive loss of muscle coordination (ataxia), defect in muscle tone sometimes associated with muscle weakness ( hypotonia), low blood pressure (hypotension), decreased respiratory activity (respiratory depression), rarely coma and very rarely death.
As with other benzodiazepines, "accidental ingestion / ingestion of an overdose should not be life-threatening unless taken at the same time as other substances that reduce central nervous system activities, including" alcohol (see section " Lendormin with alcohol ").
Treatment
If you accidentally ingest / take an overdose of oral benzodiazepines, your doctor will make you vomit if you are conscious (within 1 hour of taking the overdose).
If he has lost consciousness, he will undergo a gastric lavage (which will be carried out in the hospital by specialized personnel).
If emptying the stomach (either through vomiting or gastric lavage) does not lead to any benefit, your doctor will give you activated charcoal, a substance that is used to reduce absorption. Your heart and respiratory functions will be carefully monitored in the hospital. in the intensive care unit.
If necessary, the doctor could use flumazenil (a substance capable of blocking the sedative effect of benzodiazepines, ie physical and mental relaxation in the central nervous system) as an antidote.
If you forget to take Lendormin
Do not use a double dose to make up for a forgotten dose.
If you stop taking Lendormin
- If you have developed a physical dependence on this medicine (see section "Warnings and precautions") consult your doctor before stopping treatment, as abruptly stopping treatment may cause:
- withdrawal symptoms (such as headache, body aches, extreme anxiety and tension, restlessness, confusion or irritability)
- rebound symptoms (when symptoms present at the start of treatment are more severe and may cause other reactions including mood changes, anxiety and restlessness)
Therefore, since the risk of withdrawal or rebound symptoms is greater if treatment is stopped abruptly, the doctor will reduce the dosage gradually.
- Behavioral disturbances may occur during the use of benzodiazepines: restlessness, agitation, irritability, aggression, mental confusion (delirium), anger (rage), nightmares, perception of things that do not exist in reality (hallucinations), mental disorder (psychosis), inappropriate behavior and other undesirable effects of the behavior (see section "Possible side effects"). If this occurs, you should contact your doctor immediately to stop using the medicine.
- If you intend to become pregnant or suspect that you are pregnant, and you are taking this medicine, you should contact your doctor to stop using the medicine (see section "Pregnancy, breast-feeding and fertility"). If you have any questions about its use. of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Lendormin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Most of the side effects observed so far are related to the way the medicine works. These effects mostly occur at the start of therapy and usually decrease during treatment.
The risk of dependence increases with the duration of therapy with this medicine, which should not exceed two weeks.
Addiction symptoms can be:
- rebound effect (a condition that can occur if you have developed a physical dependence on the drug and in which the symptoms present at the beginning of treatment are manifested in a more severe form in the event of abrupt interruption of therapy)
- mood changes
- anxiety
- restlessness
Common (may affect up to 1 in 10 patients)
- drowsiness
- headache (headache)
- stomach and intestinal disorders (gastrointestinal disorders)
Uncommon (may affect up to 1 in 100 patients)
- nightmares, drug addiction, depression, mood alteration, anxiety, emotional disturbances, behavioral disturbances, agitation, altered sexual desire (libido disorder)
- dizziness, physical and mental relaxation (sedation), progressive loss of muscle coordination (ataxia), memory disorder characterized by the inability to memorize new information (anterograde amnesia)
- dementia, mental disorders, reduced mental and physical abilities; these undesirable effects are characteristic of benzodiazepines
- double vision (diplopia), dry mouth, liver disorder, yellowing of the skin and whites of the eyes (jaundice), skin reactions, muscle weakness
- withdrawal syndrome (a condition that can occur if you have developed a physical dependence on the medicine and abruptly stop treatment). Symptoms are for example: headache, body aches, extreme anxiety and tension, restlessness, confusion or irritability (see section "If you stop taking Lendormin")
- rebound effects (a condition that can occur if you have developed a physical dependence on the medicine and in which the symptoms present at the start of treatment become more severe in the event of abrupt discontinuation of therapy). other reactions including mood changes, anxiety and restlessness (see section "If you stop taking Lendormin")
- unexpected mental and behavioral disturbances (paradoxical reactions), irritability, feeling fatigued - abnormal tests to evaluate liver function
Rare (may affect up to 1 in 1,000 patients)
- Confusional state, restlessness, reduced levels of consciousness
Other possible side effects for which the frequency is unknown
Trauma
Road accidents, falls; these side effects are characteristic of benzodiazepines.
Dependence
Use (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy can cause withdrawal or rebound phenomena (see sections "Warnings and precautions" and "If you stop taking Lendormin"). psychic dependence Cases of benzodiazepine abuse have been reported.
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. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Store below 25 ° C.
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
What Lendormin contains
- the active ingredient is: brotizolam 0.25 mg.
- the other ingredients are: lactose (see section "What you need to know before you take Lendormin"), maize starch, sodium starch glycolate, microgranular cellulose, magnesium stearate.
What Lendormin looks like and contents of the pack
Lendormin 0.25 mg tablets are packed in opaque blister packs of 30 tablets.
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
LENDORMIN 0.25 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 tablet contains: active ingredient: brotizolam 0.25 mg
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Tablet
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Short-term treatment of insomnia.
Benzodiazepines are indicated only when insomnia is severe, disabling and subjects the subject to severe discomfort.
04.2 Posology and method of administration
Unless otherwise prescribed by your doctor, the following dosages are recommended:
Adults: 0.25 mg
Elderly: 0.125 mg - 0.25 mg
The medicine should be taken with a small amount of liquid just before going to bed.
After taking brotizolam, the patient should be sure to have a period of 6-7 hours to rest or sleep.
Treatment should be started at the lowest recommended dose.
The recommended dose of 0.25 mg should not be exceeded due to the increased risk of developing CNS side effects.
In patients with impaired hepatic function, the dose should be decreased.
Available data demonstrate that dose adjustment is not necessary in case of impaired renal function.
Treatment should be as short as possible. The duration of treatment varies from a few days to a maximum of two weeks. Gradual dose reduction should be adapted on an individual basis.
In certain cases, extension beyond the maximum treatment period may be necessary; this should not be done without reassessment of the patient's condition.
04.3 Contraindications
Brotizolam is contraindicated in patients with myasthenia gravis, severe respiratory failure, sleep apnea syndrome and severe hepatic insufficiency (see section 4.4).
Brotizolam is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients or to other benzodiazepines.
The pharmaceutical forms available are only suitable for adults and no studies have been performed in children.
Therefore, Lendormin should not be given to children and adolescents up to 18 years of age.
The use of the medicinal product is contraindicated in case of rare hereditary conditions which may be incompatible with any of the excipients (see section 4.4).
04.4 Special warnings and appropriate precautions for use
Tolerance
After repeated use for a few weeks, some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may occur.
Dependence
Physical and psychological dependence can develop. The risk of addiction increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse, in whom brotizolam should not be used.
When brotizolam is used concomitantly with alcohol, sedation, fatigue and decreased concentration may be accentuated (see section 4.5).
In cases where physical dependence has developed, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms. These withdrawal symptoms include for example headache, muscle aches, anxiety and extreme tension, restlessness, confusion or irritability.
In severe cases the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise or physical contact, hallucinations or seizures.
One of the first symptoms of addiction development is the occurrence of a rebound phenomenon in which the symptoms that led to treatment with benzodiazepines recur in an aggravated form after discontinuation of the drug. This effect may be accompanied by other reactions including mood swings, anxiety and restlessness.
Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, it is recommended to gradually decrease the dosage.
Duration of treatment
The duration of treatment should be as short as possible (see section 4.2.) But should not exceed two weeks. Gradual dose reduction should be tailored on an individual basis.
It may be useful to inform the patient at the beginning of the treatment that this will be of limited duration and to explain exactly how the dosage should be progressively decreased.
Furthermore, it is important that the patient is aware of the possibility of rebound phenomena occurring, thus minimizing the anxiety caused by these symptoms should they arise during the drug withdrawal phase.
There are indications that when benzodiazepines with a short duration of action are used, withdrawal symptoms may occur in the interval between doses, especially if the dosage is high.
Amnesia
Benzodiazepines can induce anterograde amnesia which can occur even at therapeutic dosages and the risk increases with higher dosages. Effects related to antegrade amnesia may be associated with behavioral abnormalities. This condition occurs most often several hours after taking the medicine; therefore, to reduce this risk, patients should ensure that they can have a sufficient period of uninterrupted sleep, usually 7-8 hours (see section 4.8).
Depression
The use of benzodiazepines can unmask a pre-existing depression.
Psychiatric and paradoxical reactions
During the use of benzodiazepines the following may occur: restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, inappropriate behavior and adverse behavioral effects. Should this occur, the use of the medicinal product should be discontinued.
Such reactions are more frequent in children and the elderly.
Specific groups of patients
A reduced dose should be considered for the elderly and patients with impaired hepatic function (see section 4.2).
The same precaution applies to patients with chronic respiratory insufficiency with hypercapnia, due to the risk of respiratory depression especially during the night.
Brotizolam alone is not recommended for the treatment of psychosis.
Brotizolam should not be used alone for the treatment of depression or anxiety associated with depression as they may precipitate suicidal behaviors in such patients.
Brotizolam should not be used in patients with a history of alcohol or drug abuse.
Benzodiazepines are not indicated in patients with severe hepatic impairment, as these medicinal products can precipitate an "encephalopathy" (see section 4.3).
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
When brotizolam is prescribed in conjunction with other CNS depressants, potentiation of central nervous effects may occur.
Such potential interactions must be considered with a variety of agents including antipsychotics (neuroleptics), hypnotics, anxiolytics, sedatives, antidepressants, narcotic analgesics, anti-epileptics, anesthetics, and sedative antihistamines.
In the case of narcotic analgesics, the enhancement of euphoria can lead to an increase in psychic dependence.
When brotizolam is used in combination with alcohol, they can increase sedation, fatigue and decrease in concentration.
In vitro interaction studies suggest a significant contribution by CYP 3A4 on the hepatic metabolism of brotizolam.
Potential pharmacokinetic interactions with other medicinal products and the consequent alteration of the activity of brotizolam should therefore be taken into account when brotizolam is co-administered with inducers (potential lack of efficacy of brotizolam) or inhibitors (e.g. rifampicin or ketoconazole, respectively) (potential increased toxicity of brotizolam) of CYP 3A4.
The simultaneous intake of alcohol is not recommended.
The sedative effect may increase when the medicine is taken concomitantly with alcohol. This affects the ability to drive or use machines.
04.6 Pregnancy and lactation
There are insufficient data on brotizolam to evaluate the safety of the medicine during pregnancy and lactation.
Consequently, the use of brotizolam is not recommended during pregnancy and lactation.
If the medicine is prescribed to a woman of childbearing potential, she should be advised to contact her doctor to discontinue the medicine if she intends to become pregnant or suspects that she is pregnant.
Although not recommended if brotizolam is administered in late pregnancy or during labor, effects such as hypothermia, hypotonia and moderate respiratory depression (Floppy Infant Syndrome) caused by the drug's pharmacological action can be expected on the newborn. , children born to mothers who took benzodiazepines chronically during the later stages of pregnancy may develop physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period. Since benzodiazepines are excreted in breast milk, use of brotizolam is not recommended for mothers who are breastfeeding.
No clinical data on fertility are available for brotizolam. Preclinical studies performed with brotizolam have shown no adverse effects on fertility.
04.7 Effects on ability to drive and use machines
No studies on the effect of the medicine on the ability to drive and use machines have been performed.
However, patients should be warned that undesirable effects such as sedation, amnesia, reduced psycho-motor skills may occur during treatment.
Psycho-motor impairment can increase the risk of falls and road accidents. Concomitant intake of alcohol and / or CNS depressant drugs may potentiate this impairment. In the case of insufficient sleep duration, the likelihood of decreased alertness is increased.
Therefore, caution should be advised when driving and operating machinery. If the patient experiences any of these effects, potentially hazardous activities such as driving or operating machinery should be avoided.
04.8 Undesirable effects
Most of the undesirable effects observed so far are related to the pharmacological action of the medicine. These effects are predominantly present at the start of therapy and usually subside with continued treatment. The risk of addiction (eg rebound effect, mood changes, anxiety and restlessness) increases with the duration of brotizolam therapy, which should not exceed two weeks.
To determine the frequency of undesirable effects, data from studies in which a total of 2,603 subjects, healthy adult volunteers and patients, were treated with brotizolam for a period ranging from 1 day to 26 weeks were pooled.
The frequencies listed below refer to 1,259 subjects, healthy volunteers and patients treated with brotizolam at the recommended dosage of 0.25 mg.
Frequencies according to the MedDRA classification:
Very common ≥ 1/10
Common ≥ 1/100
Uncommon ≥ 1 / 1,000
Rare ≥ 1 / 10,000
Very rare
Not known frequency cannot be estimated from the available data.
Psychiatric disorders
Uncommon: nightmares, drug addiction, depression, mood alteration, anxiety, emotional disturbances, abnormal behavior, agitation, libido disturbance.
Rare: confusional state, restlessness.
Nervous system disorders
Common: somnolence, headache.
Uncommon: dizziness, sedation, ataxia, anterograde amnesia, dementia * #, mental impairment * #, reduced psycho-motor skills * #.
Rare: reduced levels of consciousness.
Eye disorders
Uncommon: diplopia.
Gastrointestinal disorders
Common: gastrointestinal disturbances.
Uncommon: dry mouth.
Hepatobiliary disorders
Uncommon: liver disorders, jaundice.
Skin and subcutaneous tissue disorders
Uncommon: skin reactions.
Musculoskeletal and connective tissue disorders
Uncommon: muscle weakness.
General disorders and administration site conditions
Uncommon: withdrawal syndrome, paradoxical reactions, "rebound effects". , irritability, feeling of fatigue.
Diagnostic tests
Uncommon: liver function test abnormalities.
Injury, poisoning and procedural complications
Road accidents * #, falls * #.
*) These undesirable effects were not observed in clinical studies among 1,259 subjects exposed to brotizolam at a dose of 0.25 mg.
#) Benzodiazepine class effect.
Dependence
Use (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy can cause withdrawal or rebound phenomena (see section 4.4). Psychic dependence may occur. Cases of benzodiazepine abuse have been reported.
04.9 Overdose
As with other benzodiazepines, overdose is not expected to pose a fatal hazard unless they have been taken at the same time as other CNS depressants (including alcohol). more substances. In the event of an overdose of benzodiazepines for oral use, induce vomiting (within 1 hour) if the patient is conscious or perform a gastric lavage, with respiratory protection, if the patient is unconscious. stomach emptying should not lead to any benefit, administer activated charcoal to reduce absorption. Cardiovascular and respiratory functions must be carefully monitored in the intensive care unit.
Overdose with benzodiazepines usually results in varying degrees of CNS depression, ranging from "drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy; in severe cases, symptoms may include ataxia, hypotonia. , hypotension, respiratory depression, rarely coma and very rarely death Flumazenil can be used as an antidote.
Before use, the relevant Summary of Product Characteristics should be consulted.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: hypnotics and sedatives, benzodiazepine derivatives, ATC code N05CD09.
Brotizolam is an etrazepine which binds specifically and with high affinity to the benzodiazepine receptors of the central nervous system.
It reduces the time it takes to fall asleep and the number of awakenings decrease, the duration of sleep increases.
05.2 Pharmacokinetic properties
Absorption
Brotizolam administered orally is rapidly absorbed from the gastrointestinal tract. Following a single 0.25 mg oral dose, a mean maximum plasma concentration of 5.5 ± 0.7 ng / mL was observed in 45 ± 12 min.
Absorption occurs with an evident first pass process with an absorption half-life on average of 14.9 ± 8.5 min.
Absolute bioavailability after oral administration is approximately 70%.
Distribution
Brotizolam is 89-95% bound to plasma proteins, and has an apparent distribution half-life of 7 to 26 min.
The areas subtended by the plasma concentration over time (AUC) curves show values between 31.0 ± 5.7 ng h / ml and 56.6 ± 21.3 ng h / ml. Brotizolam is well distributed in the human body, with an average volume
apparent distribution of about 0.66 l / kg.
In animals, brotizolam crosses the placental barrier and is also excreted in breast milk.
Metabolism
Brotizolam is metabolised via oxidative reactions in the liver by CYP 3A4; the preferred metabolic pathway is hydroxylation at the different reaction sites of the brotizolam molecule, ie the methyl group and the diazepine ring.
All hydroxylated metabolites are almost completely conjugated to glucuronic acid and / or sulfuric acid.
The hydroxylated metabolites are less active than the parent compound, and are not believed to contribute to clinical effects.
Elimination
About two-thirds of orally administered brotizolam is eliminated by the kidney, the remainder in the faeces. Less than 1% of the administered dose is recovered unchanged in the urine. The major metabolites of brotizolam α-hydroxybrotizolam and 6-hydroxybrotizolam can be detected in the urine at concentrations of 27% and 7%, respectively.
Other highly polar metabolites may also be detected in the urine, possibly with more than one hydroxy group, as well as a less polar substance than brotizolam.
The mean elimination half-life of brotizolam from plasma is short and ranges from 3 to 8 hours in healthy subjects.
Brotizolam was classified as a short-acting benzodiazepine. The apparent mean oral clearance values of brotizolam obtained after an oral dose of 0.25 mg ranged from 128.36 to 188.37 mL / min. The observed differences can be attributed to the methods of determination used, namely RIA (Radio Immuno Assay), GLC (Gas-Liquid Chromatography).
The daily intake of 0.25 mg of brotizolam did not lead to accumulation or changes in the pharmacokinetics of brotizolam compared to single administration.
Pharmacokinetic properties in special population groups:
Senior citizens
Following oral administration of 0.25 mg, the mean time to peak plasma concentration in elderly patients (mean age 82 years) is slightly longer than that observed in younger subjects (mean age 23 years), i.e. 1.7 hours against 1.1 hours. The mean peak concentration in elderly patients after the same oral dose is approximately 5.6 ng / ml, and does not show any difference with that calculated in studies in young healthy subjects. The oral elimination half-life is significantly higher than that observed in young volunteers (9.1 hours versus 5.0 hours, p
Kidney failure
The pharmacokinetic properties of brotizolam remain substantially unchanged in patients with varying degrees of renal insufficiency (blood creatinine clearance was estimated at 8.15 hours, 6.90 hours and 7.61 hours in patients with mild, moderate and severe renal insufficiency, respectively. .
Hepatic insufficiency
The time to peak absorption and peak concentration of brotizolam in patients with liver cirrhosis are similar to those seen in healthy subjects while the half-life is lengthened. Protein binding and clearance of free brotizolam are lower than those observed. in healthy subjects, while the mean elimination half-life is 12.8 hours (9.4 - 25 hours).
Alcohol
Concomitant alcohol consumption results in a significant decrease in brotizolam clearance (1.85 ml / min / kg vs 2.19 ml / min / kg), an increase in peak plasma concentrations (5.3 ng / ml vs 4, 3 ng / mL) and a prolonged final elimination half-life (5.2 hours versus 4.4 hours).
05.3 Preclinical safety data
Brotizolam has a very low acute toxicity: oral LD50 values are> 10 g / kg in mice and rats and> 2 g / kg in rabbits and dogs. Clinical manifestations include ataxia and sedation in all species studied.
In repeated oral dose toxicity studies in rats (with gavage or food additive) for up to 13 weeks, the No Observed Adverse Effect Level (NOAEL) was 0.3 mg / kg / day and higher. No deaths occurred. In addition to the sedative effect, rats treated with 100 mg / kg / day and with higher doses showed aggression. Tolerance to the drug developed. At the end of the treatment period, rats treated with 400 mg / kg / day and with higher doses showed hepatomegaly and increased serum cholesterol. Withdrawal signs occurred upon discontinuation of treatment. All effects resulting from the treatment were reversible.
Rats treated with 400 mg / kg / day, equivalent to approximately 12,000 times the MRHD (Maximum Recommended Human Dose) on a mg / m2 basis, showed increased mortality due to poor general conditions, as well as histopathological findings of phospholipidosis in the lung. , pyelonephritis and testicular atrophy.
Monkeys (Rhesus type) tolerated 1 mg / kg / day for 12 months (NOAEL). At medium doses (10 or 7 mg / kg / day for 3 or 12 months), ataxia, decreased activity and somnolence were observed. The increase in appetite led to weight gain and consequent side effects.
At high doses (100 or 50 mg / kg / day), muscle spasms with hyperreflexia have been observed. Signs of withdrawal were observed after discontinuation of treatment. In the 3-month study, all symptoms were reversible. Brotizolam was neither embryotoxic nor teratogenic at oral doses up to 30 mg / kg / day (rat) and 9 mg / kg / day (rabbit).
In rats, embryotoxic effects were observed at maternal toxic doses of 250 mg / kg / day and above (equivalent to approximately 8,000 times the MRDH on a mg / m2 basis).
Fertility is not impaired at doses up to 10 mg / kg / day.
In a peri- and postnatal development study conducted in rats, the NOAEL was 0.05 mg / kg / day.
At doses of 2.5 mg / kg / day (equivalent to 80 times the MRDH on a mg / m2 basis) and at higher doses that caused sedation and more reduced body weight gain in females, pup viability during lactation an increase in offspring mortality was observed at 10 mg / kg / day and at higher doses.
The results of the mutagenicity studies performed (Ames test, bone marrow micronucleus test in mice, cytogenetic tests in Chinese hamster bone marrow and "dominant lethal test" in mice) were negative.
Brotizolam did not show any tumorigenic potential in carcinogenicity studies in mice treated with doses up to 200 mg / kg. In the rat study, the NOAEL was 10 mg / kg / day. At 200 mg / kg / day, hyperplastic and neoplastic changes were found in the thyroid gland, in the thymus and in the uterus, but are considered species-specific, stress-related or incidental and therefore not relevant to the use of the drug in humans. .
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose, corn starch, sodium glycolate starch, microgranular cellulose, magnesium stearate.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store at a temperature not exceeding 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Opaque Al / PVC - PVDC blister.
Box of 30 tablets.
06.6 Instructions for use and handling
To release a tablet it is necessary to press on the blister from the plastic part.
07.0 MARKETING AUTHORIZATION HOLDER
Boehringer Ingelheim Italia S.p.A.
Via Lorenzini, 8
20139 Milan
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n .: 026343018
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
29.09.1988/01.06.2010
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 23 March 2012
