Active ingredients: Brotizolam
BROTIZOLAM ABC 0.25 mg tablets
Why is Brotizolam used - Generic drug? What is it for?
BROTIZOLAM ABC contains the active substance brotizolam which belongs to a group of medicines called benzodiazepines.
This medicine is indicated for the short-term treatment of insomnia, in cases where the disorder is severe, disabling and makes the person very uncomfortable.
Contraindications When Brotizolam should not be used - Generic drug
Do not take BROTIZOLAM ABC
- if you are allergic to brotizolam, other similar medicines (benzodiazepines) or any of the other ingredients of this medicine;
- if you suffer from myasthenia gravis, a disease which causes muscle weakness and tiredness;
- if you have severe breathing problems (severe respiratory failure);
- if you have severe liver problems (severe liver failure);
- if you have trouble breathing during sleep (sleep apnea);
- if you are pregnant (see section "Pregnancy and breastfeeding");
- if you are breast-feeding (see section "Pregnancy and breast-feeding")
- if the patient is a child or adolescent under the age of 18.
Precautions for use What you need to know before taking Brotizolam - Generic drug
Talk to your doctor or pharmacist before taking BROTIZOLAM ABC:
- if you are elderly and / or suffer from liver problems (impaired liver function). In this case the doctor may decide to reduce the dose (see section 3 Use in the elderly);
- if you have breathing problems (chronic respiratory failure) or an excess of carbon dioxide in your blood due to lung problems (hypercapnia), as you may have severe problems breathing especially at night (respiratory depression);
- if you suffer from mental disorders (psychosis) or from depression and anxiety; in this case, contact your doctor as BROTIZOLAM ABC must be taken in combination with other medicines; in particular if you suffer from depression and anxiety and take only this medicine, you may exhibit suicidal behaviors.
- if you have previously abused alcohol or drugs
During treatment with this medicine:
- a decrease in efficacy (tolerance) may occur, if this happens contact your doctor;
- you may feel the need to continue taking the medicine (physical and mental dependence). The risk increases with dose and duration of treatment and is greater if you have abused drugs or alcohol in the past (see section 4 "Possible side effects"). If you have been abusing drugs or alcohol in the past, you should not take BROTIZOLAM ABC. Take special care if you are addicted. In this case, you should not abruptly stop treatment with this medicine, as withdrawal symptoms may occur (see section 3 "If you stop taking BROTIZOLAM ABC");
- you may have memory lapses (anterograde amnesia), especially if you take this medicine in high doses. This effect occurs several hours after taking the medicine, to reduce this risk, ensure uninterrupted sleep for 7-8 hours after taking BROTIZOLAM ABC. - if you are depressed you may experience symptoms; - you may experience behavioral disturbances ( psychiatric and paradoxical reactions) such as restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis and other behavioral disturbances. If you experience these disturbances, please contact your doctor as treatment must be discontinued (see section 4 " Possible side effects "). These reactions are more frequent in children and the elderly.
- After stopping treatment, symptoms called rebound phenomena may occur, that is, you may experience, more intensely, the symptoms that led you to take this medicine (see section "If you stop taking BROTIZOLAM ABC") .
- The duration of treatment should be as short as possible and should not exceed 2 weeks. Treatment with this medicine will be stopped by gradually reducing the dose to minimize the appearance of withdrawal symptoms (see section 3 "If you stop taking BROTIZOLAM ABC"). However, you can still experience these symptoms, especially between taking one dose and the next and if your dose is high.
Children and adolescents
BROTIZOLAM ABC should not be used in children and adolescents under the age of 18.
Interactions Which drugs or foods can modify the effect of Brotizolam - Generic drug
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Take special care and tell your doctor if you are taking the following medicines:
- antipsychotics (neuroleptics), medicines used to treat mental disorders;
- antidepressants, medicines used to treat depression;
- hypnotics and sedatives, medicines used to treat sleep problems;
- anxiolytics, medicines used to treat anxiety;
- narcotic analgesics, medicines used to treat moderate to severe pain and which can cause an increased feeling of well-being (euphoria) when taken with BROTIZOLAM ABC. This may increase your desire to continue taking these medicines (psychological dependence);
- antiepileptics, medicines used to treat epilepsy;
- anesthetics, medicines used during surgery to induce anesthesia;
- antihistamines with a sedative effect, medicines used to treat allergies and which can make you sleepy;
- rifampicin, used to treat infections caused by bacteria;
- ketoconazole, used to treat infections caused by fungi.
BROTIZOLAM ABC with alcohol
Avoid drinking alcohol while taking this medicine as it may experience lightheadedness (increased sedation), fatigue and difficulty concentrating (see section Driving and using machines).
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 taking this medicine.
Pregnancy
Do not take BROTIZOLAM ABC during pregnancy.
If your doctor thinks that you must necessarily take BROTIZOLAM ABC in the late stages of pregnancy or during childbirth, he should be aware that your baby may experience low body temperature (hypothermia), muscle weakness (hypotonia) and difficulty in breathing at birth. ("Floppy Infant Syndrome" or hypotonia of the infant). Also, if BROTIZOLAM ABC has been taken regularly during the later stages of pregnancy, your baby may experience physical dependence or withdrawal symptoms.
Feeding time
Do not take this medicine if you are breast-feeding, as brotizolam passes into breast milk.
Driving and using machines
This medicine can cause side effects such as sleepiness (sedation), memory lapses (amnesia), reduced ability to coordinate movements. These effects may affect the ability to drive and use machines. In addition, these side effects are enhanced if you have not rested enough, if you take alcohol or other medicines used to treat mental disorders (CNS depressants) at the same time.
BROTIZOLAM ABC contains lactose
This medicine contains lactose, a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, consult your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Brotizolam - Generic drug: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Adults
The recommended dose is 0.25 mg (1 tablet), unless otherwise prescribed by your doctor.
Senior citizens
The recommended dose ranges from 0.125 mg (half tablet) to 0.25 mg (whole tablet).
If you have liver problems your doctor will reduce the dose.
Start treatment with BROTIZOLAM ABC with the minimum recommended dose. The maximum recommended dose is 0.25 mg, do not exceed this dose.
Treatment with this medicine should be as short as possible and should be a maximum of two weeks. In certain cases, the doctor may decide to extend the treatment, after evaluating your health condition.
Your doctor will gradually reduce the dose based on your health condition.
Take this medicine with some water in the evening before going to bed and make sure you have at least 6-7 hours to rest or sleep.
If you forget to take BROTIZOLAM ABC
Do not take a double dose to make up for a forgotten dose.
If you stop taking BROTIZOLAM ABC
Do not stop taking BROTIZOLAM ABC suddenly. Your doctor will decide when to stop treatment.
Since the risk of withdrawal symptoms is greater if treatment is stopped abruptly, your doctor will advise you to gradually reduce the dose before stopping treatment altogether.
Withdrawal symptoms can include:
- headache (headache);
- pain in the muscles;
- anxiety, tension, restlessness, confusion, irritability.
In severe cases of withdrawal, the following can occur:
- feeling that things are not real (derealization);
- feeling of detachment from the surrounding environment (depersonalization);
- intolerance to sounds (hyperacusis);
- numbness and tingling in the hands and feet;
- sensitivity to light, noise and physical contact;
- hallucinations (seeing and hearing things that are not there);
- Seizures.
After the interruption of treatment, symptoms called rebound phenomena may occur, that is, you can manifest, in a more intense way, the symptoms that led you to take this medicine and you may experience other symptoms such as mood changes, anxiety and restlessness .
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken an overdose of Brotizolam - Generic drug
An overdose of this medicine can be very dangerous or fatal if you take alcohol or medicines that affect the central nervous system at the same time (CNS depressant medicines, see section "Other medicines and BROTIZOLAM ABC").
Symptoms of overdose are:
- state of confusion and decreased orientation or reason (clouding), mental confusion, severe tiredness (lethargy);
- in severe cases the symptoms may be: severe difficulty in movement (ataxia), decreased strength in the muscles (hypotonia), low blood pressure (hypotension), difficulty in breathing (respiratory depression), rarely coma and very rarely death.
In case of accidental ingestion / intake of an overdose of BROTIZOLAM ABC, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Brotizolam - Generic drug
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Possible side effects occur mainly at the start of treatment and generally disappear gradually. The risk of withdrawal symptoms (eg rebound phenomena, mood changes, anxiety and restlessness) increases with the duration of treatment, which should not exceed the two weeks. The following side effects may occur:
Common (may affect up to 1 in 10 people):
- drowsiness, headache (headache);
- stomach and bowel problems (gastrointestinal disorders).
Uncommon (may affect up to 1 in 100 people):
- nightmares, drug addiction, depression, mood swings, anxiety, emotional disturbances, abnormal behavior, agitation, disturbances in sexual desire (libido);
- dizziness, sedation, difficulty in coordinating movements (ataxia), memory lapses (anterograde amnesia), dementia, mental alteration, reduction of coordination skills (reduction of psycho-motor skills);
- double vision (diplopia);
- dry mouth;
- liver problems (liver disorders, jaundice);
- skin disorders (skin reactions);
- muscle weakness;
- withdrawal syndrome, rebound phenomena, paradoxical reactions, irritability, feeling of fatigue;
- changes in the results of some liver function tests.
Rare (may affect up to 1 in 1000 people):
- confusion, restlessness;
- reduced levels of consciousness.
Frequency not known (frequency cannot be estimated from the available data):
- reduction of concentration and the degree of attention that can cause road accidents and falls;
- physical dependence, psychological dependence; Following discontinuation of treatment (see sections Warnings and precautions and If you stop taking BROTIZOLAM ABC) withdrawal effects or other effects called rebound phenomena may occur.
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 www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package after "EXP".
The expiry date refers to the last day of that month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What BROTIZOLAM ABC contains
- The active ingredient is brotizolam. Each tablet contains 0.25 mg of brotizolam.
- The other ingredients are: lactose monohydrate, microcrystalline cellulose, maize starch, sodium starch glycolate, magnesium stearate, gelatin.
Description of what BROTIZOLAM ABC looks like and contents of the pack
Pack of 30 divisible 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
OLABROM 0.25 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 tablet contains:
Active ingredient: brotizolam 0.25 mg.
Excipients with known effects: lactose.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Divisible 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
Senior citizens: 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 ensure that he has a period of 6-7 hours to rest or sleep.
Treatment should be started at the lowest recommended dose.
The maximum 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 tailored on an individual basis.
In certain cases, extension beyond the maximum treatment period may be necessary; this should not occur without reassessment of the patient's condition.
04.3 Contraindications
Brotizolam is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients or to other benzodiazepines.
Brotizolam is contraindicated in patients with myasthenia gravis, severe respiratory failure, sleep apnea syndrome and severe hepatic insufficiency (see section 4.4).
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).
Brotizolam is contraindicated during pregnancy and lactation (see section 4.6).
OLABROM is for use in adults only, no studies have been performed on the administration of this medicine in children. Therefore, OLABROM should not be given to children and adolescents up to 18 years of age.
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 :
The use of benzodiazepines can lead to the development of physical and psychological dependence on these drugs. The risk of dependence increases with dose and duration of treatment; it is 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 and physical contact, hallucinations or seizures.
After discontinuation of treatment, a rebound phenomenon may occur, consisting in the aggravated reappearance of the symptoms that led to treatment with a benzodiazepine. This effect may be accompanied by other reactions including mood changes, 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) and should not exceed two weeks. Gradual dose reduction should be tailored on an individual basis.
It may be helpful to inform the patient at the start of 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. Most often this condition occurs 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 :
Restlessness, agitation, irritability, aggression, delirium, anger, nightmares, hallucinations, psychosis, inappropriate behavior and adverse behavioral effects may occur during benzodiazepine use.
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).
A lower dose is also recommended for patients with chronic respiratory insufficiency with hypercapnia, due to the risk of respiratory depression especially during the night.
Benzodiazepines are not indicated in patients with severe hepatic impairment, as these medicinal products can precipitate an "encephalopathy" (see section 4.3).
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.
Important information about some of the excipients
OLABROM contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
OLABROM contains 110,000 mg of lactose per tablet.
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, there may also be an "accentuation of the sense of euphoria, which 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.
The simultaneous intake of alcohol should be avoided.
The sedative effect may be enhanced if the medicine is taken concomitantly with alcohol. This adversely affects the ability to drive or use machines.
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 administered with inducers, such as rifampicin, (potential lack of efficacy of brotizolam) or inhibitors, such as ketoconazole (potential increase of brotizolam toxicity) of CYP 3A4.
04.6 Pregnancy and breastfeeding
There are insufficient data on brotizolam to assess its safe use 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 stop treatment if she intends to become pregnant or suspects that she is pregnant.
If, although not recommended, due to absolute medical necessities, brotizolam is administered in the advanced stage of pregnancy or during childbirth, effects on the newborn can be expected such as: hypothermia, hypotonia and moderate respiratory depression ("Floppy Infant Syndrome" or hypotonia of the infant. ), caused by the pharmacological action of the medicine.
Additionally, babies 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, brotizolam should not be given to breastfeeding mothers.
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 vehicles and operating machines. 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 2,603 subjects, including adult healthy 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 convention:
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: Vertigo, sedation, ataxia, anterograde amnesia, dementia * #, mental impairment * #, reduced psycho-motor skills * #.
Rare: Decreased levels of consciousness.
Eye disorders
Uncommon: Diplopia.
Gastrointestinal disorders
Common: Gastrointestinal disturbances.
Uncommon: Dry mouth.
Hepatobiliary disorders
Uncommon: Hepatic 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: Abnormal liver function tests.
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, an overdose should not be life threatening unless they have been taken at the same time as other CNS depressants (including alcohol). When treating overdose of any medicinal product, it should be borne in mind that more substances may have been taken. 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 in a state of Unconsciousness. If stomach emptying is not beneficial, give activated charcoal to reduce absorption. Cardiovascular and respiratory functions must be closely 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 consult the relevant Summary of Product Characteristics.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: hypnotics and sedatives, benzodiazepine derivatives.
ATC code N05CD09.
Brotizolam is a thienotriazolodiazepine (etrazepine).
Brotizolam 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 decreases, increases the duration of sleep.
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 apparent mean volume of distribution of approximately 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 via 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 1 - hydroxyibrotizolam 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 differences observed 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 conducted in healthy young 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 is similar to that observed 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 atrophy of the testicles.
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 monohydrate, microcrystalline cellulose, corn starch, sodium starch glycolate, magnesium stearate, gelatin.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
24 months
06.4 Special precautions for storage
No special storage precautions
06.5 Nature of the immediate packaging and contents of the package
Box of 30 divisible 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
Epifarma S.r.l. - Via San Rocco, 6 - 85033 Episcopia (PZ)
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n .: 040805018
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
14/02/2013
10.0 DATE OF REVISION OF THE TEXT
"AIFA determination of" 14/02/2013
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