Active ingredients: Lorazepam
Tavor 1mg tablets
Tavor 2.5 mg tablets
Tavor package inserts are available for pack sizes: - Tavor 1mg tablets, Tavor 2.5mg tablets
- Tavor 1 mg buccal tablets, Tavor 2.5 mg buccal tablets
- Tavor 2 mg / ml Oral drops, solution
- Tavor 4 mg / ml solution for injection
Why is Tavor used? What is it for?
Pharmacotherapeutic group
Anxiolytic; benzodiazepine derivative
Therapeutic indications
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome. Insomnia. Benzodiazepines are indicated only when the disorder is severe, disabling and subjects the subject to severe distress.
Contraindications When Tavor should not be used
Myasthenia gravis; hypersensitivity to the active substance (lorazepam), to benzodiazepines or to any of the excipients; severe respiratory failure; severe liver failure; sleep apnea syndrome; narrow angle glaucoma.
Do not administer during pregnancy.
Precautions for use What you need to know before you take Tavor
Specific groups of patients
The efficacy and safety of use in children under 12 years of age has not been established. 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.
For the highly variable reactivity to psychotropic drugs, elderly or debilitated patients and those with organic brain changes (especially atherosclerotic) must be treated with low doses (see posology) or not be treated at all. Elderly or debilitated patients may be more susceptible to the effects of Tavor, therefore such patients should be monitored frequently and their dosage carefully adjusted according to the patient's response. Due to the risk of respiratory depression, the same prudential measures should be taken for patients with heart failure, low blood pressure, impaired respiratory function, chronic respiratory failure, COPD (chronic pulmonary obstruction), sleep apnea syndrome. Such patients should be monitored regularly during Tavor therapy (as recommended with other benzodiazepines and other psychopharmacological agents).
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients); in such patients the administration of large amounts of Tavor should be avoided.
Pre-existing depression may emerge or worsen during benzodiazepine use, including Tavor.
The use of benzodiazepines can unmask suicidal tendencies in depressed patients and they should not be administered without adequate antidepressant therapy.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse.
Tavor should be used with caution in patients with severe hepatic insufficiency and / or encephalopathy as, like all benzodiazepines, it can precipitate hepatic encephalopathy.
During prolonged treatment or in the treatment of patients with renal or hepatic insufficiency it is advisable to carry out frequent checks of the blood picture and renal and / or hepatic function. In patients with renal or hepatic insufficiency the dosage should be carefully adjusted according to the patient's response.
Interactions Which drugs or foods can modify the effect of Tavor
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician in order to avoid unexpected undesirable effects from interaction.
Concomitant intake with alcohol should be avoided. The sedative effect may be enhanced when the medicinal product is taken in conjunction with alcohol. This adversely affects the ability to drive or use machines.
Association with central nervous system (CNS) depressants: the central depressive effect may be enhanced in cases of concomitant use with alcohol, barbiturates, antipsychotics (neuroleptics), hypnotics / sedatives, anxiolytics, antidepressants, narcotic analgesics, antiepileptics, anesthetics and Sedative antihistamines In the case of narcotic analgesics, increased euphoria may occur, leading to an increase in psychic dependence.
The concomitant use of clozapine and Tavor can produce marked sedation, excessive salivation, ataxia.
Co-administration of Tavor with valproate may result in increased plasma concentrations and reduced elimination of Tavor.
Tavor dosage should be reduced by 50% when co-administered with valproate.
Co-administration of Tavor with probenecid may result in a more rapid onset or prolongation of the effect of Tavor due to a longer half-life or decreased total elimination. Tavor dosage should be reduced by 50% when co-administered with probenecid Administration of theophylline or aminophylline may reduce the effects of benzodiazepines, including Tavor.
Compounds that inhibit certain liver enzymes (especially cytochrome P450) may increase the activity of benzodiazepines. To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation.
The cytochrome P-450 system has not been shown to be involved in the metabolism of Tavor and, unlike many benzodiazepines, pharmacokinetic interactions involving the P-450 system have not been observed with Tavor.
Cases of excessive stupor, significant reduction in respiratory rate and, in one case, hypotension have been reported when Tavor was administered concomitantly with loxapine.
No interferences in laboratory tests have been reported or identified with the use of lorazepam.
Warnings It is important to know that:
The use of benzodiazepines, including Tavor, can lead to life-threatening respiratory depression.
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.
Periodic monitoring of the need for continued Tavor therapy is advised. As with other benzodiazepines, treatment of anxiety symptoms should be short-lived. Furthermore, in conditions in which anxiety and tensions associated with contingent phenomena of daily life occur, it is not normally necessary to resort to the use of anxiolytics.
The use in subjects predisposed to dependence such as, for example, alcoholics and drug addicts, should be avoided entirely, if possible due to the predisposition of such patients to habit and dependence.
Tavor is not intended for the treatment of primary depressive disorders or in the primary treatment of psychosis.
Tolerance
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines can lead to the development of physical and mental dependence on these drugs. The risk of dependence increases with dose and duration of treatment; it is greater in patients with a history of drug, drug, alcohol or drug abuse. personality disorders.
The possibility of dependence is reduced when Tavor is used in the appropriate dose with short-term treatment. In general, benzodiazepines should only be prescribed for short periods (2-4 weeks). Long-term continuous use is not recommended.
Withdrawal symptoms (eg rebound insomnia) may occur following discontinuation of the recommended dosage after only one week of therapy. Abrupt discontinuation of treatment should be avoided and an extended period of therapy should be followed by a gradual dose reduction program.
Once the physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headache, muscle aches, extreme anxiety, tension, restlessness, confusion, irritability, rebound phenomena, dysphoria, dizziness, nausea, diarrhea, loss of appetite. 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 / delirium, seizures or convulsions. Seizures / seizures may occur more commonly in patients with pre-existing seizure disorders or who use other drugs that lower the seizure threshold such as antidepressants.
Other symptoms are: depression, insomnia, sweating, persistent tinnitus, involuntary movements, vomiting, paraesthesia, perceptual changes, abdominal and muscle cramps, tremor, myalgia, agitation, palpitations, tachycardia, panic attacks, dizziness, hyper-reflexia, loss of short-term memory, hyperthermia.
Rebound insomnia and anxiety: A transient syndrome in which symptoms leading to benzodiazepine treatment recur in an aggravated form may occur on discontinuation of treatment. It may be accompanied by other reactions, including mood changes, anxiety, restlessness or disturbances sleep.
Withdrawal symptoms, especially the more serious ones, are more common in those patients who have received excessive doses for a long period of time, but they can also occur after discontinuation of benzodiazepines taken continuously at therapeutic doses, especially if the withdrawal occurs in a manner abrupt.
Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
Always consult your doctor before increasing or decreasing the dose of medication or before stopping it.
There is evidence of developing tolerance to the sedative effects of benzodiazepines. Tavor may have potential for abuse especially in patients with a history of drug and / or alcohol abuse.
Duration of treatment
The duration of treatment should be as short as possible (see "Dose, method and time of administration") depending on the indication, but should not exceed four weeks for insomnia and eight to twelve weeks in the case of anxiety, including a gradual withdrawal period. Extension of therapy beyond these periods should not occur without reassessment 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.
Amnesia
Benzodiazepines can induce anterograde amnesia or memory impairment. This occurs more often several hours after ingestion of the drug and, therefore, to reduce the risk it must be ensured that patients can have an uninterrupted sleep of 7-8 hours (see section "Undesirable effects").
Psychiatric and paradoxical reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes, anxiety states, hostility, excitement, sleep disturbances / insomnia, have occasionally been reported with the use of benzodiazepines. sexual arousal, sedation, fatigue, drowsiness, ataxia, confusion, depression, unmasking of depression, dizziness, changes in libido, impotence, decreased orgasm. Should this occur, use of the drug should be discontinued. Such reactions are more frequent in children and the elderly.
Fertility, pregnancy and breastfeeding
Tavor should not be used during pregnancy. Taking benzodiazepines during pregnancy can cause fetal harm. An increased risk of congenital malformations associated with the use of anxiolytic agents (chlordiazepoxide, diazepam, meprobamate) during the first trimester of pregnancy has been suggested in several studies; therefore, always avoid the administration of benzodiazepines during the first trimester of pregnancy.
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.
If, for serious medical reasons, the product is administered during the last period of pregnancy, or during labor at high doses, effects on the newborn may occur such as hypothermia, hypotonia and moderate respiratory depression due to the pharmacological action of the drug.
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.
Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers unless the expected benefit to the woman outweighs the potential risk to the newborn.
Sedation and inability to take breast milk have occurred during lactation in infants whose mothers were taking benzodiazepines. Infants born to such mothers should be observed for pharmacological effects (including sedation and irritability).
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. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see "Interactions" section).
As with all patients receiving CNS-acting drugs, patients should be advised not to operate hazardous machinery and not to drive until they are certain they are not drowsy or light headed by Tavor.
The medicine contains lactose and is therefore not suitable for people with lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome.
Dosage and method of use How to use Tavor: Dosage
Tavor is administered orally. For best results the dose, frequency of administration and duration of therapy should be individually adjusted according to the patient's response. The lowest effective dose should be prescribed for the shortest time possible.
Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
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.
In general practice, most patients respond to a dosage of 2-3 tablets of 1 mg per day. For particularly severe cases and in psychiatry the dosage can be increased up to 3 or 4 tablets of 2.5 mg per day. It is recommended to take the highest dose in the evening, before going to bed.
In elderly or debilitated patients, an initial dosage of 1-2 mg per day in divided doses is recommended, to be adjusted according to need and tolerability.
In patients with renal or hepatic insufficiency the dosage should be carefully adjusted according to the patient's response. Lower dosages may be sufficient for such patients.
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, it may be necessary to extend beyond the maximum treatment period; if so, it should not take place without reassessment of the patient's condition.
For sleep disorders, 1-2 1 mg tablets given at bedtime should be sufficient.
If the complaints are persistent it is recommended to use 2.5 mg tablets.
In elderly or debilitated patients, an initial dosage of 1-2 mg per day in divided doses is recommended, to be adjusted according to need and tolerability.
In patients with renal or hepatic insufficiency the dosage should be carefully adjusted according to the patient's response. Lower dosages may be sufficient for such patients.
As a pre-surgical therapy, a dosage of 2-4 mg of Tavor the evening before and / or 1-2 hours before surgery is recommended.
Treatment should be started with the lowest recommended dose.
The maximum dose should not be exceeded.
Overdose What to do if you have taken too much Tavor
In case of accidental ingestion / intake of an excessive dose of TAVOR, notify your doctor immediately or go to the nearest hospital.
As with other benzodiazepines, overdose is not expected to be life-threatening unless concomitant other CNS depressants (including alcohol) are taken. In postmarketing experience, overdose with Tavor has predominantly occurred in combination with alcohol and / or other drugs. In the treatment of overdosage of any drug, the possibility that other substances have been taken at the same time should be considered.
Following an overdose of benzodiazepines for oral use, vomiting should be induced (within one "hour) if the patient is conscious or gastric lavage undertaken, immediately after ingestion, with respiratory protection if the patient is deprived. of acquaintance or in patients presenting with symptoms. These operations should be followed by general resuscitation practices, monitoring of vital signs and close observation of the patient. Where there is a risk of aspiration, induction of vomiting is not recommended.
Tavor is poorly dialyzable. The glucuronide, the inactive metabolite of Tavor, can be highly dialyzable.
If no improvement is observed with stomach emptying, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in emergency therapy.
Overdosage of benzodiazepines usually results in varying degrees of central nervous system depression ranging from clouding to coma. In mild cases, symptoms include drowsiness, dysarthria, mental confusion, and lethargy. In more severe cases, such as those that can occur following massive suicidal intake, or when other drugs or alcohol have been concomitantly ingested, symptoms may include ataxia, hypotonia, hypotension, hypnosis, paradoxical reactions, CNS depression, depression cardiovascular, respiratory depression, 1st-3rd degree coma and death. "Flumazenil" can be useful as an antidote. Physicians should be aware of the risk of seizures in association with flumazenil treatment, particularly in those who have been taking benzodiazepines for a long time and in case of overdose of cyclic antidepressants.
If you have any questions about the use of TAVOR, ask your doctor or pharmacist.
Side Effects What are the side effects of Tavor
As with all medicines, TAVOR can cause side effects, although not everybody gets them.
Side effects, if they occur, are normally seen at the start of treatment and generally decrease in intensity or disappear as therapy progresses, or by reducing the dosage. The most frequently observed side effects include drowsiness during the day, dulling of emotions, decreased alertness, confusion, fatigue, muscle weakness, ataxia, sense of instability.
Less frequently have been observed: extrapyramidal symptoms, tremor and dizziness, dysarthria / difficulty in speech articulation, visual disturbances (including diplopia and blurred vision), disorientation, depression, nausea, appetite changes, headache, seizures / seizures , amnesia, disinhibition, euphoria, coma, suicidal ideation / suicide attempts, impaired attention / concentration, balance disturbances, sleep disturbances, changes in libido, agitation, dermatological symptoms including very severe reactions, allergic skin reactions, alopecia, ocular function disorders, various gastrointestinal disorders, constipation, increased bilirubin, jaundice, increased liver transaminases, increased alkaline phosphatase, thrombocytopenia, agranulocytosis, pancytopenia, hypersensitivity reactions, anaphylactic / anaphylactoid reactions, angioedema, SIADH (syndrome of inappropriate secretion ne of antidiuretic hormone), hyponatremia, hypothermia, hypotension, lowering of blood pressure, respiratory depression, apnea, worsening of sleep apnea (the extent of respiratory depression for benzodiazepine use is dose-dependent; more severe depression occurs with higher dosages), worsening of obstructive pulmonary disease and autonomic manifestations. The incidence of sedation and sense of instability increases with age.
The effects of benzodiazepines on the CNS are dose-dependent. High dosages result in more severe CNS depression.
In case of relative overdose, ataxia, dysarthria, hypotension, urinary retention, libido impairment may rarely be observed.
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 "Special warnings").
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. they can be quite severe and are more likely in children and the elderly.
Dependence
The use of benzodiazepines (even at therapeutic doses) may lead to the development of physical dependence; discontinuation of therapy may result in rebound or withdrawal phenomena (see section "Special warnings"). Psychic dependence may occur. Abuse of drug has been reported. benzodiazepines.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date indicated on the package. The expiry date refers to the last day of the month.
Warning: do not use the medicine after the expiry date indicated on the package.
Do not store above 25 ° C.
The expiry date indicated refers to the product in intact packaging, correctly stored.
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 this medicine out of the reach and sight of children.
Composition and pharmaceutical form
Composition
TAVOR 1 mg tablets:
Each tablet contains: active ingredient: Lorazepam 1 mg Excipients: lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate, hypromellose E15, macrogol 6000, titanium dioxide, talc.
TAVOR 2.5 mg tablets:
Each tablet contains: active ingredient: Lorazepam 2.5 mg Excipients: lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate, hypromellose E15, macrogol 6000, titanium dioxide, talc.
Pharmaceutical form and content
Blister containing 20 tablets of 1 mg. Blister containing 20 tablets of 2.5 mg
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TAVOR - ORAL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
TAVOR 1 mg GOLD SOLUBLE TABLETS
Each buccal tablet contains:
Active ingredient: lorazepam 1 mg
TAVOR 2.5 mg GOLD SOLUBLE TABLETS
Each buccal tablet contains:
Active ingredient: lorazepam 2.5 mg.
TAVOR 1 mg TABLETS
Each tablet contains:
Active ingredient: lorazepam 1.0 mg
TAVOR 2.5 mg TABLETS
Each tablet contains:
Active ingredient: lorazepam 2.5 mg.
TAVOR 2 mg / ml oral drops, solution
10 ml of solution contain:
Active ingredient: lorazepam 20 mg
20 drops = 1 mg of lorazepam
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Buccal tablets.
Tablets.
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 indicated only when the disorder is severe, disabling and subjects the subject to severe distress.
04.2 Posology and method of administration
Tavor is administered orally.
For best results the dose, frequency of administration and duration of therapy should be individually adjusted according to the patient's response. The lowest effective dose should be prescribed for the shortest time possible.
The buccal tablets can be taken without water, as they dissolve quickly on the tongue without needing to be swallowed.
Each buccal tablet has a notch for possible subdivision.
Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
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.
In general practice, most patients respond to a dosage of 2-3 tablets / 1 mg buccal tablets per day or 20 drops 2-3 times a day. For particularly severe cases and in psychiatry the dosage can be increased up to 3 or 4 buccal tablets / tablets of 2.5 mg per day or 50 drops 3-4 times a day. It is recommended to take the highest dose in the evening, before going to bed.
In elderly or debilitated patients, an initial dosage of 1-2 mg per day in divided doses is recommended, to be adjusted according to need and tolerability.
In patients with renal or hepatic insufficiency the dosage should be carefully adjusted according to the patient's response. Lower dosages may be sufficient for such patients.
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, it should not take place without reassessment of the patient's condition.
For sleep disorders, 1-2 tablets / 1 mg buccal tablets or 20-40 drops, given at bedtime, should be sufficient. If the complaints are persistent it is recommended to use 2.5 mg buccal tablets / tablets.
In elderly or debilitated patients, an initial dosage of 1-2 mg per day in divided doses is recommended, to be adjusted according to need and tolerability.
In patients with renal or hepatic insufficiency the dosage should be carefully adjusted according to the patient's response. In hepatic insufficiency, lower dosages may be sufficient for such patients.
As presurgical therapy, a dosage of 2-4 mg of Tavor the evening before and / or 1-2 hours before surgery is recommended.
Treatment should be started with the lowest recommended dose.
The maximum dose should not be exceeded.
04.3 Contraindications
Myasthenia gravis; hypersensitivity to the active substance (lorazepam), to benzodiazepines or to any of the excipients; severe respiratory failure; severe liver failure; sleep apnea syndrome; narrow angle glaucoma.
Do not administer during pregnancy.
04.4 Special warnings and appropriate precautions for use
The use of benzodiazepines, including Tavor, can lead to life-threatening respiratory depression.
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.
Periodic monitoring of the need for continued Tavor therapy is advised. As with other benzodiazepines, treatment of anxiety symptoms should be short-lived. Furthermore, in conditions in which anxiety and tensions associated with contingent phenomena of daily life occur, it is not normally necessary to resort to the use of anxiolytics.
The use in subjects predisposed to dependence such as, for example, alcoholics and drug addicts, should be avoided entirely, if possible due to the predisposition of such patients to habit and dependence.
Tavor is not intended for the treatment of primary depressive disorders or in the primary treatment of psychosis.
Tavor oral drops contain ethyl alcohol. For those who carry out sporting activities, the use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Tolerance
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines can lead to the development of physical and mental dependence on these drugs. The risk of dependence increases with dose and duration of treatment; it is greater in patients with a history of drug, drug, alcohol or drug abuse. personality disorders. The possibility of dependence is reduced when Tavor is used in the appropriate dose with short-term treatment. In general, benzodiazepines should only be prescribed for short periods (2-4 weeks). Continuous long-term use does not It is recommended.
Withdrawal symptoms (eg rebound insomnia) may occur following discontinuation of the recommended dosage after only one week of therapy. Abrupt discontinuation of treatment should be avoided and an extended period of therapy should be followed by a gradual dose reduction program.
Once the physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headache, muscle aches, extreme anxiety, tension, restlessness, confusion, irritability, rebound phenomena, dysphoria, dizziness, nausea, diarrhea, loss of appetite. 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 / delirium, seizures or convulsions. Seizures / seizures may occur more commonly in patients with pre-existing seizure disorders or who use other drugs that lower the seizure threshold such as antidepressants.
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 disturbances sleep.
Withdrawal symptoms, especially the more serious ones, are more common in those patients who have received excessive doses for a long period of time, but they can also occur after discontinuation of benzodiazepines taken continuously at therapeutic doses, especially if the withdrawal occurs in a manner abrupt.
Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
The patient should be advised to consult their physician both before increasing or decreasing the dose of the drug, and before stopping it.
There is evidence of developing tolerance to the sedative effects of benzodiazepines.
Tavor may have potential for abuse especially in patients with a history of drug and / or alcohol abuse.
Duration of treatment
The duration of treatment should be as short as possible (see section 4.2) depending on the indication, 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.
Amnesia
Benzodiazepines can induce anterograde amnesia or memory impairment. This occurs most often several hours after ingestion of the drug and, therefore, to reduce the risk, it must be ensured that patients can have an uninterrupted sleep of 7-8 hours (see section 4.8).
Psychiatric and paradoxical reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes, anxiety states, hostility, excitement, sleep disturbances / insomnia, have occasionally been reported with the use of benzodiazepines. sexual arousal, sedation, fatigue, drowsiness, ataxia, confusion, depression, unmasking of depression, dizziness, changes in libido, impotence, decreased orgasm. Should this occur, use of the drug should be discontinued. Such reactions are more frequent in children and the elderly.
Specific groups of patients
The efficacy and safety of use in children under 12 years of age has not been established.
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.
Due to the highly variable reactivity to psychotropic drugs, elderly or debilitated patients and those with organic brain changes (especially atherosclerotic) should be treated with low doses (see section 4.2) or not be treated at all. Elderly or debilitated patients may be more susceptible to the effects of Tavor, therefore such patients should be monitored frequently and their dosage carefully adjusted according to the patient's response. Due to the risk of respiratory depression, the same prudential measures should be taken for patients with heart failure, low blood pressure, impaired respiratory function, chronic respiratory failure, COPD (chronic pulmonary obstruction), sleep apnea syndrome. Such patients should be monitored regularly during Tavor therapy (as recommended with other benzodiazepines and other psychopharmacological agents).
Benzodiazepines are not recommended for the primary treatment of psychotic illness. Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients); in such patients the administration of large amounts of Tavor should be avoided.
Pre-existing depression may emerge or worsen during the use of benzodiazepines, including Tavor. The use of benzodiazepines can unmask suicidal tendencies in depressed patients and should not be administered without adequate antidepressant therapy.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse.
Tavor should be used with caution in patients with severe hepatic insufficiency and / or encephalopathy as, like all benzodiazepines, it can precipitate hepatic encephalopathy.
During prolonged treatment or in the treatment of patients with renal or hepatic insufficiency it is advisable to carry out frequent checks of the blood picture and renal and / or hepatic function.
In patients with renal or hepatic insufficiency the dosage should be carefully adjusted according to the patient's response.
In patients, in whom gastrointestinal or cardiovascular disturbances coexist with anxiety, it should be noted that Tavor has not shown significant benefit in the treatment of the gastrointestinal or cardiovascular component.
Dilation of the esophagus was observed in rats treated with lorazepam for more than one year with a dosage of 6 mg / kg / day.The dose at which this effect did not occur was 1.25 mg / kg / day (approximately 6 times the maximum therapeutic dose in humans, which is 10 mg / day).
The effect was reversible only if the treatment was stopped within 2 months of the first observation of the phenomenon. The clinical significance of this is not known. However, the use of Tavor for prolonged periods and in geriatric patients requires precaution and frequent monitoring should be performed. symptoms related to upper gastrointestinal disorders.
The tablets contain lactose therefore not suitable for subjects with lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome.
04.5 Interactions with other medicinal products and other forms of interaction
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician in order to avoid unexpected undesirable effects from interaction.
Concomitant intake with alcohol should be avoided. The sedative effect may be enhanced when the medicinal product is taken in conjunction with alcohol. This adversely affects the ability to drive or use machines.
Association with central nervous system (CNS) depressants: the central depressive effect may be enhanced in cases of concomitant use with alcohol, barbiturates, antipsychotics (neuroleptics), hypnotics / sedatives, anxiolytics, antidepressants, narcotic analgesics, antiepileptics, anesthetics and Sedative antihistamines In the case of narcotic analgesics, increased euphoria may occur, leading to an increase in psychic dependence.
The concomitant use of clozapine and Tavor can produce marked sedation, excessive salivation, ataxia.
Co-administration of Tavor with valproate may result in increased plasma concentrations and reduced elimination of Tavor.
Tavor dosage should be reduced by 50% when co-administered with valproate.
Co-administration of Tavor with probenecid may result in a more rapid onset or prolongation of the effect of Tavor due to a longer half-life or decreased total elimination. Tavor dosage should be reduced by 50% when co-administered with the probenecid.
Administration of theophylline or aminophylline may reduce the effects of benzodiazepines, including Tavor.
Compounds that inhibit certain liver enzymes (especially cytochrome P450) may increase the activity of benzodiazepines. To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation.
The cytochrome P-450 system has not been shown to be involved in the metabolism of Tavor and, unlike many benzodiazepines, pharmacokinetic interactions involving the P-450 system have not been observed with Tavor.
Cases of excessive stupor, significant reduction in respiratory rate and, in one case, hypotension have been reported when Tavor was administered concomitantly with loxapine.
No interferences in laboratory tests have been reported or identified with the use of lorazepam.
04.6 Pregnancy and lactation
Tavor should not be used during pregnancy. Taking benzodiazepines during pregnancy can cause fetal harm. An increased risk of congenital malformations associated with the use of anxiolytic agents (chlordiazepoxide, diazepam, meprobamate) during the first trimester of pregnancy has been suggested in several studies; therefore, always avoid the administration of benzodiazepines during the first trimester of pregnancy.
If the product is prescribed to a woman of childbearing potential, 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.
In humans, blood levels obtained from the umbilical cord indicate that Tavor and its glucuronide pass through the placenta. If, for serious medical reasons, the product is administered during the last period of pregnancy, or during labor at high doses. , effects on the newborn may occur. Symptoms such as hypoactivity, hypotonia, moderate respiratory depression, hypothermia, apnea, nutritional problems and metabolic responses altered by decreased resistance to cold have been observed in newborns whose mothers used benzodiazepines during late pregnancy or during delivery.
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.
It appears that Tavor conjugation occurs slowly in neonates as its glucuronide is detectable in the urine for more than 7 days. Tavor glucuronidation can competitively inhibit bilirubin conjugation, leading to hyperbilirubinemia in the neonate.
Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers unless the expected benefit to the woman outweighs the potential risk to the newborn.
Sedation and inability to take breast milk have occurred during lactation in infants whose mothers were taking benzodiazepines. Infants born to such mothers should be observed for pharmacological effects (including sedation and irritability).
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. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see section 4.5).
As with all patients receiving CNS-acting drugs, patients should be advised not to operate hazardous machinery and not to drive until they are certain they are not drowsy or light headed by Tavor.
04.8 Undesirable effects
Side effects, if they occur, are normally seen at the start of treatment and generally decrease in intensity or disappear as therapy progresses, or the dosage is reduced.
The most frequently observed side effects include daytime sleepiness, dulling of emotions, decreased alertness, confusion, fatigue, muscle weakness, ataxia, dullness.
Less frequently have been observed: extrapyramidal symptoms, tremors and dizziness, dysarthria / speech difficulties, visual disturbances (including diplopia and blurred vision), disorientation, depression, nausea, appetite changes, headache, seizures / seizures , amnesia, disinhibition, euphoria, coma, suicidal ideation / suicide attempts, impaired attention / concentration, balance disturbances, sleep disturbances, changes in libido, agitation, dermatological symptoms including very severe reactions, allergic skin reactions, alopecia, ocular function disorders, various gastrointestinal disorders, constipation, increased bilirubin, jaundice, increased liver transaminases, increased alkaline phosphatase, thrombocytopenia, agranulocytosis, pancytopenia, hypersensitivity reactions, anaphylactic / anaphylactoid reactions, angioedema, SIADH (syndrome of inappropriate secretions one of the antidiuretic hormone), hyponatremia, hypothermia, hypotension, lowering of blood pressure, respiratory depression, apnea, worsening of sleep apnea (the extent of respiratory depression from benzodiazepine use is dose-dependent; more severe depression occurs with higher dosages), worsening of obstructive pulmonary disease and autonomic manifestations. The incidence of sedation and sense of instability increases with age.
The effects of benzodiazepines on the CNS are dose-dependent. High dosages result in more severe CNS depression.
In case of relative overdose, ataxia, dysarthria, hypotension, urinary retention, libido impairment may rarely be observed.
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.
Dependence
The use of benzodiazepines (even at therapeutic doses) may lead to the development of physical dependence; discontinuation of therapy may result in rebound or withdrawal phenomena (see special warnings and precautions). Psychic dependence may occur. Abuse has been reported. of benzodiazepines.
04.9 Overdose
As with other benzodiazepines, an overdose is not expected to be life-threatening unless concomitant other CNS depressants (including alcohol) are taken.
In postmarketing experience, overdose with Tavor has predominantly occurred in combination with alcohol and / or other drugs.
In the treatment of overdose of any drug, the possibility that other substances have been taken at the same time should be considered.
Following an overdose of benzodiazepines for oral use, vomiting should be induced (within one "hour) if the patient is conscious or gastric lavage undertaken, immediately after ingestion, with respiratory protection if the patient is deprived. of acquaintance or in patients presenting with symptoms. These operations should be followed by general resuscitation practices, monitoring of vital signs and close observation of the patient. Where there is a risk of aspiration, induction of vomiting is not recommended.
Tavor is poorly dialyzable. The glucuronide, the inactive metabolite of Tavor, can be highly dialyzable.
If no improvement is observed with stomach emptying, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in emergency therapy.
Overdosage of benzodiazepines usually results in varying degrees of central nervous system depression ranging from clouding to coma. In mild cases, symptoms include drowsiness, dysarthria, mental confusion, and lethargy. In more severe cases, such as those that can occur following massive suicidal intake, or when other drugs or alcohol have been concomitantly ingested, symptoms may include ataxia, hypotonia, hypotension, hypnosis, paradoxical reactions, CNS depression, depression cardiovascular, respiratory depression, 1st-3rd degree coma and death. "Flumazenil" can be useful as an antidote. Physicians should be aware of the risk of seizures in association with flumazenil treatment, particularly in those who have been using benzodiazepines for a long time and in case of overdose of cyclic antidepressants.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anxiolytics, benzodiazepine derivatives
ATC code: N05BA06
Lorazepam (Tavor), anti-anxiety agent, is a 1,4-benzodiazepine having the following chemical name: 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine -2-one.
Lorazepam is an almost white powder, almost insoluble in water and slightly soluble in alcohol and chloroform. The molecular weight is 321.2. Like all benzodiazepines, Tavor carries out anxiolytic, hypnotic and tranquilizing actions in proportion to the administered dose.
The exact mechanism of action of benzodiazepines has not yet been elucidated; however, benzodiazepines appear to act through various mechanisms. Presumably benzodiazepines exert their effects through binding to specific receptors at different sites within the central nervous system, or by potentiating the effects of synaptic or presynaptic inhibition, mediated by γ-aminobutyric acid, or by directly influencing the mechanisms that generate the potential d "action.
Tavor is therapeutically active in extremely low dosages. Its action is characterized by a well-balanced protection against the effects of psychic stress and by a decrease in emotional reactions to such stresses; its anxiolytic effect is particularly marked.
With the decrease or suppression of emotional factors, Tavor removes the causes of illnesses of emotional and psychoreactive origin.
In the field of psychotherapy, psychic exploration is benefited by the improvement of contact between the doctor and the patient. The resulting effect is a valid complement to psychotherapy.
Thanks to its beneficial effect on mood and thanks to the protection against psychic stress, Tavor can appropriately complete the antidepressant therapy and therefore be administered in combination with it as well as with other common psychotropic drugs whose effect it reinforces, completes it and in part. accelerates it.
With a single dose in the evening, Tavor facilitates sleep and the resulting sleep is quite comparable to normal sleep.
05.2 Pharmacokinetic properties
Tavor, given orally, is rapidly absorbed. Maximum plasma concentrations are achieved within approximately 2-3 hours of administration. The half-life of unconjugated Tavor in human plasma is approximately 12-16 hours. At clinically significant concentrations, Tavor binds approximately 90% to plasma proteins. Conjugation with glucuronic acid to form the inactive Tavor glucuronide is the major process of metabolic transformation. 70-75% of the dose is excreted as glucuronide in the urine. In animals, Tavor glucuronides have no demonstrable activity on the central nervous system and no active metabolites appear to be produced.
Plasma levels of Tavor are proportional to the administered dose. There is no evidence of excessive accumulation of Tavor when administered for up to 6 months, nor is there any indication of induction of drug-metabolizing enzymes under these conditions. Tavor is not a substrate for N-dealkylating enzymes of the cytochromic P-450 system, nor is it significantly hydrolyzed.
Comparative studies in young and elderly subjects have shown that the pharmacokinetics of Tavor remain unchanged with advancing age. In patients with hepatic diseases (hepatitis, alcoholic cirrhosis) no changes in absorption, distribution, metabolism and excretion have been reported. As with other benzodiazepines, the pharmacokinetics of lorazepam may be altered in renal insufficiency.
05.3 Preclinical safety data
Toxicology
Tavor showed a very low acute toxicity with LD50 equal to (for oral administration): mouse> 3000 mg / kg; rat> 5000 mg / kg; dog> 2000 mg / kg.
Numerous subacute and chronic toxicity tests have been conducted in rats and dogs. Doses have been used which, with respect to body weight, are thousands of times higher than those fixed as daily therapy in man.
Tavor has been shown to have very low toxicity. Histopathological, ophthalmological and haematological examinations, urine and serum analysis, basal metabolism tests, have shown that extremely high dosages do not cause significant biological changes.
Teratogenesis
Numerous trials conducted on rabbits, rats and mice exclude teratogenic effects of lorazepam.
Carcinogenesis, mutagenesis
No evidence of carcinogenic potential emerged in rats or mice during an 18-month study with orally administered Tavor. An "investigation" of Tavor's mutagenic activity on Drosophila melanogaster indicated that this drug is mutagenicly inactive.
Fertility Studies
A pre-implantation study in rats performed with oral Tavor at a dose of 20 mg / kg showed no reduction in fertility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
TAVOR 1 mg Buccal Tablets and TAVOR 2.5 mg Buccal Tablets
Excipients: gelatin; mannitol
TAVOR 1 mg Tablets and TAVOR 2.5 mg Tablets
Excipients: lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate, hypromellose, macrogol 6000, titanium dioxide, talc.
TAVOR 2 mg / ml oral drops, solution
Excipients: mannitol, 95 ° ethyl alcohol, deionized water
06.2 Incompatibility
To date, no incompatibility is known.
06.3 Period of validity
With intact packaging:
Tablets: 2 years
Buccal tablets and drops: 3 years.
The oral drops after reconstitution: 30 days; store in a refrigerator (2 ° C - 8 ° C).
06.4 Special precautions for storage
None in particular except those common to all drugs.
1.0 mg and 2.5 mg tablets: Do not store above 25 ° C.
Drops: for storage conditions of the reconstituted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
TAVOR 1 mg Buccal tablets: Blister pack containing 20 buccal tablets
TAVOR 2.5 mg Buccal tablets: Blister pack containing 20 buccal tablets
TAVOR 1 mg Tablets: Blister packs (in PVC and aluminum) 20 tablets
TAVOR 2.5 mg Tablets: Blister packs (in PVC and aluminum) 20 tablets
TAVOR 2 mg / ml oral drops, solution: 20 ml glass bottle
06.6 Instructions for use and handling
See what reported in section 4.2.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l., Via Isonzo, 71 - 04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
Tavor 1.0 mg buccal tablets: AIC n. 022531103
Tavor 2.5 mg buccal tablets: AIC n. 022531127
Tavor 1.0 mg tablets: AIC n. 022531053
Tavor 2.5 mg tablets: AIC n. 022531077
Tavor 2 mg / ml oral drops, solution: AIC n. 022531091
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Buccal tablets: 05/07/1990 - 31/05/2010
Tablets: 04/29/1972 - 05/31/2010
Oral drops, solution: 01/08/1980 - 31/05/2010
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 26/02/2013
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