Active ingredients: Bromazepam
COMPENDIUM® 1.5 mg hard capsules
COMPENDIUM® 3 mg hard capsules
COMPENDIUM® 2.5 mg / ml oral drops, solution
Why is Compendium used? What is it for?
Pharmacotherapeutic category
ANSIOLYTICS: BENZODIAZEPINE DERIVATIVES
Therapeutic indications
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 Compendium should not be used
Bromazepam should not be given to patients with known hypersensitivity to benzodiazepines, severe respiratory insufficiency, severe hepatic insufficiency (benzodiazepines are not indicated in patients with severe hepatic insufficiency as they can cause encephalopathy), myasthenia gravis or sleep apnea syndrome.
Known hypersensitivity to bromazepam, to any of the excipients
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 Compendium
General Precautions
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide can be precipitated in such patients). Therefore, bromazepam should be used with caution and prescription should be limited in patients with signs and symptoms. symptoms of a depressive disorder or suicidal tendencies.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse. (see section Interactions) In the early stages of treatment the patient should be monitored regularly in order to minimize dosage and / or frequency of administration and to prevent overdose due to accumulation.
Duration of treatment
The duration of treatment should be as short as possible (see section Posology, method and time of administration), but should not exceed four weeks for insomnia and eight to twelve weeks for anxiety, including a gradual withdrawal period. . Extension of therapy beyond these periods should not occur without re-evaluation of the clinical situation.
It may be useful to inform the patient when the treatment has started that it 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 if they occur when the medicine is stopped.
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 sudden change to a benzodiazepine with a short duration of action is not recommended, as withdrawal symptoms may occur.
Tolerance
Some loss of efficacy of benzodiazepines may develop after repeated use for a few weeks
Dependence
The use of benzodiazepines can lead to the development of physical and mental dependence on these drugs. The risk of addiction increases with dose and duration of treatment; it is even greater in patients with a history of alcohol and drug abuse. 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 Compendium is used in the appropriate dose with short-term treatment. 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, hyperreflexia, memory loss a short term, 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 and "greater after abrupt cessation of treatment, a gradual reduction in dosage is recommended.
Amnesia
Benzodiazepines can induce antegrade amnesia. This occurs more 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. Amnesic effects may be associated with behavioral changes (see effects section. 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, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes and other behavioral disturbances are known to occur when benzodiazepines are used. Should this occur, use of the medicinal product should be discontinued.
Such 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 the Compendium. Therefore, benzodiazepines are not recommended for the primary treatment of psychotic illnesses.
The presence of depression must always be excluded in particular 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).
Concomitant use of alcohol / CNS depressants
Concomitant use of Compendium with alcohol and / or drugs with central nervous system depressant activity should be avoided. Concomitant use may enhance the clinical effects of Compendium including possible profound sedation and clinically relevant respiratory and / or cardiovascular depression. (see section 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.
Specific groups of patients
Benzodiazepines should not be given to children without "careful consideration of" the actual need for treatment; the duration of treatment should be as short as possible.
Elderly people should take a reduced dose (see section Posology, method and time of administration). 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.
A lower dose is suggested for patients with chronic respiratory failure due to the risk of respiratory depression. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they can precipitate hepatic encephalopathy. Compendium should be administered with caution to 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 Compendium therapy (as recommended with other benzodiazepines and other psychopharmacological agents).
Patients with psychosis: Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Interactions Which drugs or foods may change the effect of Compendium
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Pharmacodynamic interactions
Benzodiazepines produce an additive effect when taken in conjunction with alcohol or other CNS depressants. The concomitant intake of alcohol should be avoided (see paragraph on precautions for use).
This adversely affects the ability to drive or use machines. Bromazepam should be used with caution in combination with CNS depressant drugs. The central depressant effect may be enhanced by concomitant use of antipsychotics (neuroleptics), hypnotics, anxiolytics / sedatives, some antidepressants, opioids, antiepileptics, anesthetics and sedative H1 antihistamines.
Particular attention should be paid to drugs that depress the respiratory function, such as opioids (analgesics, cough suppressants, replacement treatments), particularly in the elderly.
Pharmacokinetic interactions Pharmacokinetic interactions may occur when bromazepam is co-administered with drugs that inhibit the hepatic enzyme CYP3A4, increasing the plasma levels of Bromazepam. To a lesser extent, this also applies to benzodiazepines which are metabolised only by conjugation.
Co-administration of bromazepam with strong CYP3A4 inhibitors (e.g. azole antifungals, protease inhibitors or some macrolides) should be done with caution, considering a substantial dose reduction. Narcotic analgesics can cause an increase in euphoria leading 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
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 they are not available for bromazepam specific clinical data, a large amount of data based on cohort studies indicate that benzodiazepine exposure during the first trimester is not associated with an increased risk of major malformations. However, some early epidemiological case-control studies have shown an increased risk of oral cleft. The data indicate that the risk of birth of a child with an oral cleft after maternal exposure to benzodiazepines is less than 2/1000 compared to an expected rate for such defects of about 1/1000 in the general population. 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.
When treatment is to be administered for medical reasons during the latter part of pregnancy, even at low doses, symptoms of "flaccid baby" syndrome such as axial hypotonia and sucking problems leading to reduced weight gain may be observed. These signs are reversible, but can last from 1 to 3 weeks, depending on the half-life of the product. At high doses, respiratory depression or apnea and hypothermia may appear in the infant. In addition, neonatal withdrawal symptoms with hyperexcitability, agitation and tremor can be observed a few days after birth, although "flaccid baby" syndrome is not observed.
Additionally, infants born to mothers who have taken benzodiazepines chronically during late pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. Taking these data into account, the use of bromazepam during pregnancy can be considered if the therapeutic indications and posology are strictly observed. If treatment with Bromazepam is necessary during the latter part of pregnancy, high doses should be avoided and should be avoided. be monitored in neonates for withdrawal symptoms and / or "flaccid baby" syndrome.
If the product is prescribed to a woman of childbearing age, she should contact her doctor, both if she intends to become pregnant and if she suspects that she is pregnant, regarding discontinuation of the medicine.
Feeding time
Since Bromazepam is excreted in breast milk, breastfeeding is not recommended during treatment.
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 interactions section). This effect is enhanced if the patient drank alcohol.
Important information about some of the ingredients
The capsules contain lactose therefore patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Dosage and method of use How to use Compendium: Dosage
Average dose in outpatient practice: 1.5 - 3 mg, two or three times a day (1-2 hard capsules of 1.5 mg, 2-3 times a day; or 1 hard capsule of 3 mg, 2-3 times a day per day; or 15-30 oral drops, 2-3 times a day).
In severe cases, especially in hospitalized patients: 6-12 mg, two or three times a day.
The above doses are purely indicative; they will have to be tailored to individual needs.
In outpatient practice, the lowest recommended dose should be started, which can, if necessary, be gradually increased. 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 aforementioned dosages.
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 Compendium
Symptoms
Benzodiazepines commonly cause somnolence, ataxia, dysarthria and nystagmus. An overdose of bromazepam rarely poses a risk to life when taken alone, but can lead to slurred speech, 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 enhance the effects of other central nervous system depressants, including alcohol.
Treatment
Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical status. In particular, patients may require symptomatic treatment for cardiorespiratory or central nervous system effects.
Following an overdose of oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage with respiratory protection undertaken if the patient is unconscious.
Further absorption should be prevented by using an appropriate method, for example, treatment with activated charcoal within 1-2 hours. If activated charcoal is used, airway protection is imperative for unconscious patients. In case of mixed ingestion, gastric lavage can be considered, but not as a routine measure.
In emergency therapy, special attention should be paid to respiratory and cardiovascular functions
If CNS depression is severe, consider the use of flumazenil, a benzodiazepine antagonist. This should only be given under closely monitored conditions. The use of flumazenil is not indicated in patients with epilepsy being 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.
In case of accidental ingestion / intake of an overdose of Compendium, notify your doctor immediately or go to the nearest hospital
Side Effects What are the side effects of Compendium
Like all medicines, Compendium can cause side effects, although not everybody gets them.
Drowsiness, dulling of emotions, decreased alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, double vision. These phenomena occur mainly at the beginning of therapy and usually disappear with subsequent administrations.
The following undesirable effects have been reported during treatment with bromazepam with the following frequencies: very common (≥1 / 10); common (≥1 / 100, a
* These side effects mainly occur at the start of therapy and usually disappear with subsequent administrations
** See section 4.4
*** The risk of falls and fractures is increased in patients treated with 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).
Benzodiazepine class (BDZ) undesirable effects
Amnesia
Anterograde amnesia can also occur at therapeutic dosages, the risk increases at higher dosages. Amnesic effects may be associated with behavioral changes (see section 4.4)
Depression
A pre-existing depressive state may be unmasked during the use of benzodiazepines. Benzodiazepines or benzodiazepine-like compounds can cause reactions such as: restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes.
Such reactions can be quite severe. They are more likely in children and the elderly.
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 the sudden suspension of treatment, the risk of rebound phenomena from withdrawal is higher, it is recommended to gradually decrease the dose. The patient must be informed of the possibility of rebound phenomena, in order to minimize the anxiety caused. from such symptoms, which may appear when benzodiazepines are discontinued.
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".
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact and correctly stored packaging.
Hard capsules: Store at a temperature not exceeding 30 ° C.
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.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
Composition and pharmaceutical form
Composition
COMPENDIUM 1.5 mg hard capsules
1 hard capsule contains:
active ingredient: bromazepam 1.5 mg;
excipients: anhydrous lactose, corn starch, talc, magnesium stearate, titanium dioxide (E171), yellow iron oxide (E172), gelatin.
COMPENDIUM 3 mg hard capsules
1 hard capsule contains:
active ingredient: bromazepam 3 mg;
excipients: anhydrous lactose, corn starch, talc, magnesium stearate, titanium dioxide (E171), indigo carmine (E132), gelatin.
COMPENDIUM 2.5 mg / ml oral drops, solution
1 ml of solution contains:
active ingredient: bromazepam 2.5 mg;
excipients: sodium saccharin, edetate disodium, currant flavoring, raspberry flavoring, purified water, propylene glycol
Pharmaceutical form and content
Box of 30 hard capsules of 1.5 mg
Box of 30 hard capsules of 3 mg
Carton of 1 bottle oral drops, solution of 2.5 mg / ml
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
COMPENDIUM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
COMPENDIUM 1.5 mg hard capsules
One hard capsule contains:
Active ingredient: Bromazepam 1.5 mg
Excipients: anhydrous lactose
For the full list of excipients see section 6.1
COMPENDIUM 3 mg hard capsules
One hard capsule contains:
Active ingredient: Bromazepam mg 3
Excipients: anhydrous lactose
For the full list of excipients see section 6.1
COMPENDIUM 2.5 mg / ml oral drops, solution
1 ml of solution contains:
Active ingredient: Bromazepam 2.5 mg
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Hard capsules, oral drops, solution
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
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.
04.2 Posology and method of administration
Due to the variability of individual responses, the posology must be adjusted case by case.
Dose: on average 1.5-3 mg, two or three times a day (1-2 1.5 mg hard capsules, 2-3 times a day; or 1 3 mg hard capsule, 2-3 times a day day; or 15-30 oral 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 aforementioned dosages.
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.
04.3 Contraindications
Bromazepam should not be given to patients with known hypersensitivity to benzodiazepines, severe respiratory insufficiency, severe hepatic insufficiency (benzodiazepines are not indicated in patients with severe hepatic insufficiency as they can cause encephalopathy), myasthenia gravis or sleep apnea syndrome.
Known hypersensitivity to bromazepam, to any of the excipients.
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 related anxiety
depression (suicide can be precipitated in such patients). Therefore, bromazepam should be used with caution and prescribing should be limited in patients with signs and symptoms of a depressive disorder or suicidal tendencies.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse. (see section 4.5)
In the early stages of treatment the patient should be monitored regularly in order to minimize dosage and / or frequency of administration and to prevent overdose due to accumulation.
Duration of treatment
The duration of treatment should be as short as possible (see section 4.2), but should not exceed four weeks for insomnia and eight to twelve weeks for anxiety, including a gradual withdrawal period. Extension of therapy beyond these periods should not occur without re-evaluation of the clinical situation.
It may be helpful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage should be progressively decreased.
Furthermore, it is important that the patient is informed of the possibility of rebound phenomena, thus minimizing the 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 a sudden change to a benzodiazepine with a short duration of action is not recommended because withdrawal symptoms may occur.
Tolerance
Some loss of efficacy of benzodiazepines may develop after repeated use for a few weeks
Dependence
The use of benzodiazepines can lead to the development of physical and psychological dependence on these drugs.
The risk of addiction increases with dose and duration of treatment; it is even greater in patients with a history of alcohol and drug abuse.
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 Compendium is used in the appropriate dose with short-term treatment.
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, hyperreflexia, memory loss a short term, 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 and "greater after abrupt cessation of treatment, a gradual reduction in dosage is recommended.
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.
Amnesic effects may be associated with behavioral changes (see section 4.8). Anterograde amnesia may occur 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, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes and other behavioral disturbances are known to occur when benzodiazepines are used. Should this occur, use of the medicinal product should be discontinued.
Such 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 the Compendium. Therefore, benzodiazepines are not recommended for the primary treatment of psychotic illnesses.
The presence of depression must always be excluded in particular 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).
Concomitant use of alcohol / CNS depressants
Concomitant use of Compendium with alcohol and / or drugs with central nervous system depressant activity should be avoided. Concomitant use may enhance the clinical effects of Compendium including possible profound sedation and clinically relevant respiratory and / or cardiovascular depression. (see section 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.
Specific groups of patients
Benzodiazepines should not be given to children without "careful consideration of" the actual need for treatment; the duration of treatment should be as short as possible.
Elderly people should take a reduced dose (see section 4.2).
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.
A lower dose is suggested for patients with chronic respiratory failure due to the risk of respiratory depression.
Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they can precipitate hepatic encephalopathy.
Compendium should be administered with caution to 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 Compendium therapy (as 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
The 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
Benzodiazepines produce an additive effect when taken in conjunction with alcohol or other CNS depressants. Concomitant alcohol intake should be avoided (see section 4.4).
This adversely affects the ability to drive or use machines.
Bromazepam should be used with caution in combination with CNS depressant drugs. The central depressant effect may be enhanced by concomitant use of antipsychotics (neuroleptics), hypnotics, anxiolytics / sedatives, some antidepressants, opioids, antiepileptics, anesthetics and sedative H1 antihistamines.
Particular attention should be paid to drugs that depress the respiratory function, such as opioids (analgesics, cough suppressants, replacement treatments), particularly in the elderly.
Pharmacokinetic interactions
Pharmacokinetic interactions may occur when bromazepam is co-administered with drugs that inhibit the hepatic enzyme CYP3A4, increasing the plasma levels of Bromazepam. To a lesser extent, this also applies to benzodiazepines which are metabolised only by conjugation.
Co-administration of bromazepam with strong CYP3A4 inhibitors (e.g. azole antifungals, protease inhibitors or some macrolides) should be done with caution, considering a substantial dose reduction. Narcotic analgesics can cause an increase in euphoria leading 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 for bromazepam, a large amount of data based on cohort studies indicate that benzodiazepine exposure during the first trimester is not associated with an increased risk of major malformations.However, some early epidemiological case-control studies have shown an increased risk of oral cleft. The data indicated that the risk of having a baby with an oral cleft after maternal exposure to benzodiazepines 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.
When treatment has to be administered for medical reasons during the latter part of pregnancy, even at low doses, symptoms of "flaccid baby" syndrome such as axial hypotonia and sucking problems leading to reduced weight gain may be observed. signs are reversible, but can last from 1 to 3 weeks, depending on the half-life of the product.
At high doses, respiratory depression or apnea and hypothermia may appear in the infant.
In addition, neonatal withdrawal symptoms with hyperexcitability, agitation and tremor may be observed a few days after birth, although "flaccid baby" syndrome is not observed.
Additionally, infants born to mothers who have taken benzodiazepines chronically during late pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.
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 latter part of pregnancy, high doses should be avoided and withdrawal symptoms and / or 'flaccid baby' syndrome should be monitored in neonates.
If the product is prescribed to a woman of childbearing age, she should contact her doctor, both if she intends to become pregnant and if she suspects that she is pregnant, regarding discontinuation of the medicine.
Feeding time
Since Bromazepam is excreted in breast milk, breastfeeding is not recommended during treatment.
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). This effect is enhanced if the patient drank alcohol.
04.8 Undesirable effects
Drowsiness, dulling of emotions, decreased alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, double vision. These phenomena occur mainly at the beginning of therapy and usually disappear with subsequent administrations.
The following undesirable effects have been reported during treatment with bromazepam with the following frequencies: very common (≥1 / 10); common (≥1 / 100, a
* These side effects mainly occur at the start of therapy and usually disappear with subsequent administrations
** See section 4.4
*** The risk of falls and fractures is increased in patients treated with 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).
Benzodiazepine class (BDZ) undesirable effects
Amnesia
Anterograde amnesia can also occur at therapeutic dosages, the risk increases at higher dosages. Amnesic effects may be associated with behavioral changes (see section 4.4)
Depression
A pre-existing depressive state may be unmasked during the use of benzodiazepines. Benzodiazepines or benzodiazepine-like compounds can cause reactions such as: restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes.
Such reactions can be quite severe. They are more likely in children and the elderly.
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 the sudden suspension of treatment, the risk of rebound phenomena from withdrawal is higher, it is recommended to gradually decrease the dose. The patient must be informed of the possibility of rebound phenomena, in order to minimize the anxiety caused. from such symptoms, which may appear when benzodiazepines are discontinued.
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. An overdose of bromazepam rarely poses a risk to life when taken alone, but can lead to slurred speech, 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 enhance the effects of other central nervous system depressants, including alcohol.
Treatment
Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical status. In particular, patients may require symptomatic treatment for cardiorespiratory or central nervous system effects.
Following an overdose of oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage with respiratory protection undertaken if the patient is unconscious.
Further absorption should be prevented by using an appropriate method, for example, treatment with activated charcoal within 1-2 hours. If activated charcoal is used, airway protection is imperative for unconscious patients. In case of mixed ingestion, gastric lavage can be considered, but not as a routine measure.
In emergency therapy, special attention should be paid to respiratory and cardiovascular functions.
If CNS depression is severe, consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should only be given 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 (Anexate®).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
ATC code: N05BA08
The active ingredient of COMPENDIUM is Bromazepam.
Bromazepam is a benzodiazepine characterized by an incisive action on the nervous structures that oversee the emotional, relational and neurovegetative life.
In dogs, even at a dose of 50 mg / kg / os, bromazepam does not cause alterations in blood pressure, breathing and ECG.
Bromazepam, at concentrations equal to or greater than therapeutic human blood concentrations, does not significantly affect the tone and phasism of the smooth muscle of the isolated intestine.
Bromazepam showed the following pharmacological activities:
- antiaggressive activity (the action is comparable to that of diazepam administered at doses 3 times higher);
- deconditioning effect in mice conditioned to the avoidance reflex (this action is "superimposable to that of diazepam administered at doses 20 times higher); the reversibility of this deconditioning effect is" ready and complete upon suspension of treatment;
- anticonvulsant activity (the "action" is comparable to that of diazepam administered at doses 3 times higher);
- activity enhancing the hypnonarcotic action of luminal;
- muscle relaxant activity, comparable to that of diazepam.
Ultimately, bromazepam has a spectrum of pharmacological action similar to other benzodiazepines; it has proved to have a quantitatively superior activity to that of diazepam.
05.2 "Pharmacokinetic properties
Bromazepam is well absorbed after administration and the plasma peak, equal to about 100 ng / ml, is reached one hour after the administration of 6 mg. In the liver it is metabolized to 4 compounds, only one of which, 3 -hydroxybromazepam, is endowed with pharmacological activity.
Metabolic transformation occurs in the liver through the microsomal system and the rate of elimination is lower in elderly than in young subjects.
The predominantly renal elimination (70%) occurs according to linear kinetics, with a half-life time of approximately 20.1 hours, both for bromazepam and 3-hydroxybromazepam. The binding to plasma proteins is equal to 70 %.
05.3 Preclinical safety data
For acute administration:
LD50 (Swiss mouse, per os) 1874 mg / Kg;
LD50 (Swiss mouse, for i.p.) 469 mg / Kg;
LD50 (Wistar rat, per os) 2039 mg / kg;
LD50 (Wistar rat, for i.p.) 380 mg / kg.
For prolonged administration:
Teratogenesis
The product administered to pregnant rats from the 2nd to the 19th day of pregnancy and to pregnant rabbits from the 4th to the 29th day of gestation, at doses of 5 and 15 mg / kg / day per os, did not cause teratogenic or embryotoxic effects. .
Carcinogenic activity
The negativity to the histological examination of tumoral alterations, as shown by the toxicity studies for repeated administration (182 days), as well as the structural relationship of bromazepam with benzodiazepines absolutely free of this danger, allow us to consider bromazepam devoid of any carcinogenic action .
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
COMPENDIUM 1.5 mg hard capsules:
Anhydrous lactose; cornstarch; talc; magnesium stearate; titanium dioxide (E171); yellow iron oxide (E172); jelly.
COMPENDIUM 3 mg hard capsules:
Anhydrous lactose; cornstarch; talc; magnesium stearate; titanium dioxide (E171); indigo carmine (E132); jelly.
COMPENDIUM 2.5 mg / ml oral drops, solution:
Sodium saccharin; edetate disodium; currant flavoring; raspberry flavoring; purified water; propylene glycol.
06.2 Incompatibility
There are no known incompatibilities with the use of the product.
06.3 Period of validity
5 years for 1.5 mg and 3 mg hard capsules
3 years for oral drops, solution 2.5 mg / ml
06.4 Special precautions for storage
Hard capsules, oral drops, solution
Hard capsules: Store at a temperature not exceeding 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Hard capsules
Carton containing 30 hard capsules in non-transparent milk white PVC blisters, sealed on a semi-rigid aluminum support.
30 hard capsules of 1.5 mg
30 hard capsules of 3 mg
Oral drops, solution
Carton containing a bottle dosed at 20 ml of oral drops with child safety closure. 20 ml 2.5 mg / ml
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
POLIFARMA S.p.A. - Viale dell "Arte, 69 - 00144 ROME.
08.0 MARKETING AUTHORIZATION NUMBER
COMPENDIUM 1.5 mg hard capsules - AIC: 023844020
COMPENDIUM 3 mg hard capsules - AIC: 023844018
COMPENDIUM 2.5 mg / ml oral drops, solution - AIC: 023844044
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
COMPENDIUM 1.5 mg hard capsules: June 2010 (Renewal)
COMPENDIUM 3 mg hard capsules: June 2010 (Renewal)
COMPENDIUM 2.5 mg / ml oral drops, solution: June 2010 (renewal)
10.0 DATE OF REVISION OF THE TEXT
October 2014
