Active ingredients: Alprazolam
FRONTAL 0.25 mg tablets
FRONTAL 0.50 mg tablets
FRONTAL 1 mg tablets
FRONTAL 0.75 mg / ml oral drops, solution
Indications Why is Frontal used? What is it for?
PHARMACO-THERAPEUTIC CATEGORY
Anxiolytic - benzodiazepine derivative.
THERAPEUTIC INDICATIONS
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome. Panic attacks with or without agoraphobia. Benzodiazepines are indicated only when the disorder is severe, disabling and subjects the subject to severe distress.
Contraindications When Frontal should not be used
FRONTAL is contraindicated in patients with known hypersensitivity to benzodiazepines, alprazolam or to any of the excipients and in patients with acute narrow-angle glaucoma. The product can be used in patients with open-angle glaucoma receiving appropriate therapy. benzodiazepines are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, sleep apnea syndrome, severe hepatic insufficiency. Do not administer in the first trimester of pregnancy and during lactation.
Precautions for use What you need to know before taking Frontal
Duration of treatment
The duration of treatment should be as short as possible (see Dose, method and time of administration) and in the case of anxiety it should not exceed 8 - 12 weeks, including a gradual withdrawal period. The extension of therapy beyond this period it should not take place 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. It is also important that the patient is informed of the possibility of rebound phenomena, thus minimizing anxiety about these symptoms should they occur when the drug is discontinued.
There is evidence that in the case of benzodiazepines with a short duration of action, withdrawal symptoms may become manifest within the dose interval between doses, particularly for high doses. When using benzodiazepines with a long duration of action it is important to warn the patient that abrupt change to a benzodiazepine with a short duration of action is inadvisable, as withdrawal symptoms may occur.
Discontinuation of treatment
As with any other benzodiazepine, the dosage of FRONTAL should be gradually reduced as stopping abruptly or too quickly can lead to withdrawal symptoms. Withdrawal symptoms can include mild dysphoria and insomnia or present as major syndromes with cramps. abdominal muscles, vomiting, sweating, tremors and convulsions. In addition, withdrawal crises may occur following a rapid decrease or abrupt discontinuation of therapy with alprazolam (see Dose, method and time of administration - Discontinuation of therapy). These symptoms, especially the most severe, are generally more common in those patients who have been treated with excessive doses for prolonged periods of time. However, withdrawal symptoms have also been reported following abrupt discontinuation of therapeutic doses of benzodiazepines. abrupt should be avoided and a reduction prescribed g radius of the dosage (see Dose, method and time of administration). During discontinuation of the drug in patients with panic disorder, symptoms related to the reappearance of panic attacks that mimic those typical of withdrawal can sometimes be observed.
Amnesia
Benzodiazepines can induce antegrade amnesia. This most often happens several hours after ingestion of the drug.
Psychiatric and paradoxical reactions
When benzodiazepines are used it is known that reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes can occur. Should this occur, the use of the medicinal product should be discontinued. These reactions are more frequent in children and the elderly.
Specific groups of patients
Benzodiazepines should not be given to children without careful evaluation of the actual need for treatment; the duration of treatment should be as short as possible. In elderly and / or debilitated patients it is recommended to always use the lowest dose to avoid the risk of residual sedation or ataxia. Elderly people should take a reduced dose (see Dose, method and time of administration). Likewise, a lower dose is suggested for patients with chronic respiratory insufficiency due to the risk of respiratory depression. The usual ones are recommended. precautions in the treatment of patients with impaired renal function and mild or moderate hepatic insufficiency, while in patients with severe hepatic insufficiency, benzodiazepines are not indicated as they can precipitate encephalopathy. Benzodiazepines are not recommended for the primary treatment of psychotic illness. Benzodiazepines should not be used alone to treat severe depression or anxiety associated with depression (suicide can be precipitated in such patients). Combination with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected effects. from interaction. As with other psychotropic drugs, alprazolam in severely depressed or suicidal patients should be administered with appropriate precautions and prescribed in appropriate packaging. A concomitant depressive disorder (primary or secondary) with increased cases of suicide in untreated patients. Therefore the same precaution should be taken both when using the higher doses of FRONTAL for the treatment of patients with panic disorder and when using any psychotropic drug in the treatment of depressed or depressed patients. those in whom suicidal ideation or attempt is suspected. Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse. must be kept under close medical supervision, due to the prey exposure of these subjects to addiction and dependence.
Cases of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.
Interactions Which drugs or foods can modify the effect of Frontal
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
For the same reason, patients must be warned of the dangers associated with the simultaneous intake of alcohol or other drugs having a depressant action on the CNS. 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. Particular attention, especially in elderly patients, should be used with respiratory depressant drugs such as opioids (analgesics, cough suppressants, replacement treatments). Alprazolam should be used with caution in combination with other CNS depressants.
Association with CNS depressants: the central depressive effect may be enhanced in the case of concomitant use with anti-psychotics (neuroleptics), hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics and antihistamines-H1 sedatives. of narcotic analgesics may result in increased euphoria leading to an increase in psychic dependence. Pharmacokinetic interactions can occur when alprazolam is co-administered with drugs that interfere with its metabolism.
Molecules that inhibit certain liver enzymes (especially cytochrome P4503A4) can increase the plasma concentration of alprazolam and enhance its activity. Azole antifungal agents - ketoconazole and itraconazole are potent inhibitors of CYP3A and have been shown in vivo to increase alprazolam concentrations 3.98-fold and 2.70-fold, respectively. Concomitant administration of alprazolam with these two drugs is not recommended. Other azole-type antifungal agents should be considered potent inhibitors of CYP3A and their co-administration with alprazolam is not recommended.Co-administration of alprazolam with potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), protease inhibitors or certain macrolides (erythromycin, clarithromycin, telithromycin) should be substantial dose reduction. Clinical and in vitro studies with alprazolam and clinical studies with metabolised drugs such as alprazolam show a possible interaction at varying degrees of alprazolam with a number of drugs. Based on the degree of interaction and the type of data available, the following recommendations should be considered:
- The concomitant administration of FRONTAL with ketoconazole, itraconazole or other antifungals of the azole group is not recommended.
- Caution and caution in decreasing the dose is recommended when FRONTAL is concomitantly administered with nefazodone, fluvoxamine and cimetidine.
- Caution is advised when FRONTAL is co-administered with fluoxetine, propoxyphene, oral contraceptives, diltiazem or macrolide antibiotics such as erythromycin and troleandomycin.
- Interactions between HIV protease inhibitors (eg ritonavir) and alprazolam are complex and time dependent. Low dose ritonavir causes a reduction in alprazolam clearance, prolongs its elimination half-life, and increases clinical effects. of prolonged exposure to ritonavir, induction of CYP3A compensates for this inhibition. This interaction will require a dose adjustment or "discontinuation of FRONTAL treatment.
- Increases in digoxin concentration have been reported with administration of alprazolam, particularly in the elderly (> 65 years of age). Therefore patients receiving alprazolam and digoxin should be monitored for signs and symptoms related to digoxin toxicity.
To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation. Steady-state plasma concentrations of imipramine and desipramine increase by 31% and 20%, respectively, following concomitant administration of FRONTAL in doses up to 4 mg / day. Kinetic interactions between benzodiazepines and other drugs have been described. For example, the clearance of alprazolam and some other benzodiazepines may be decreased by concomitant administration of cimetidine or macrolide antibiotics. The clinical significance of these effects has not been established.
Warnings It is important to know that:
Tolerance
Some loss of the hypnotic effect of benzodiazepines may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines, including alprazolam, can lead to the development of physical and mental dependence on these drugs. As with all benzodiazepines, the risk of addiction increases with dose and duration of treatment; it is greater in patients with a history of drug or alcohol abuse. Dependence can occur at therapeutic doses and / or in patients with no individual risk factors. The risk of dependence increases with the concomitant use of several benzodiazepines regardless of the anxiolytic or hypnotic indication. Cases of abuse have also been reported. Once physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms. These can consist of headache, body 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.
Rebound insomnia or 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 changes in mood, anxiety, restlessness or sleep disturbances. of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
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). Given the CNS depressant effect of alprazolam, patients taking the drug should be warned that it may be dangerous for them to engage in activities that require full mental attention, such as working on hazardous machinery or driving cars, until it is possible to exclude an impairment of attention and reflexes following the intake of the drug.
Use in case of pregnancy and lactation
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
Data on teratogenicity and effects on postnatal development and behavior following benzodiazepine treatment are inconsistent. There is evidence from some early studies with other benzodiazepine class compounds showing that in utero exposure may be associated with malformations. Subsequent studies with benzodiazepine class drugs have provided no clear evidence of any type of defect. 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 approximately 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. Infants exposed to benzodiazepines during the late third trimester of pregnancy have been reported or during labor they show "floppy infant" syndrome or neonatal withdrawal symptoms. When treatment is to be administered for medical reasons during the latter part of pregnancy, even at low doses, floppy infant 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 average half-life of the product. High doses during the last period of pregnancy or during labor can cause effects in the newborn such as respiratory depression or apnea and hypothermia, due to the pharmacological action of the drug. If alprazolam treatment is necessary during the latter part of pregnancy, high doses should be avoided and withdrawal symptoms and / or floppy infant syndrome should be monitored in the neonate. In addition, neonatal withdrawal symptoms such as hyperexcitability, agitation and tremor may be observed a few days after birth, although "floppy infant" syndrome is not observed. The appearance of withdrawal symptoms after birth depends on the half-life of the product. Due to potential risks of congenital malformations, already observed with other benzodiazepines, do not administer the drug in the first trimester of pregnancy. If the product is prescribed to a woman of childbearing potential, she should contact her doctor, whether she intends to become pregnant or suspects that she is pregnant. , regarding discontinuation of the medicinal product If FRONTAL is administered during pregnancy or if the patient discovers that it is pregnant during treatment with FRONTAL, the patient should be informed of the potential danger to the fetus. Taking these data into account, the use of alprazolam during pregnancy can only be considered if the therapeutic indications and posology are strictly respected.
Feeding time
Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers.
Important information about some of the ingredients of Frontal
FRONTAL tablets contain lactose; in case of ascertained intolerance to sugars contact your doctor before taking this medicine.
FRONTAL 0.75 mg / ml oral drops, solution: this medicine contains ethanol (alcohol).
For those who play sports (only for drops)
The use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Dosage and method of use How to use Frontal: Dosage
The optimal dosage of FRONTAL should be individualized according to the severity of symptoms and the patient's subjective response. The dosage indications given should cover the needs of most patients. If a higher dosage is necessary, the doses should be gradually increased to avoid the risk of side effects. In these cases it is advisable to increase the evening dose earlier than the day dose, except in patients suffering from agoraphobia and / or panic disorder. In this case, see the dedicated paragraph. In general, patients never treated with psychotropic drugs require lower doses than those previously treated with anxiolytics or sedatives, antidepressants, hypnotics or chronic alcoholic patients. It is recommended to always use the lowest dose to avoid the risk of residual sedation or ataxia. In case of side effects already with the initial administration it is recommended to decrease the dosage.
The maximum dose should not be exceeded. The evening dose of the drug should be taken just before going to bed. Treatment should be as short as possible. Patients should be re-evaluated regularly and the need for continued treatment should be carefully considered, particularly if the patient is symptom-free.
Anxiety
The starting dose ranges from 0.25 to 0.50 mg 3 times a day. This dosage will be increased according to the patient's needs up to a maximum of 4 mg per day in divided doses for a duration not exceeding 8 - 12 weeks including a gradual withdrawal period. In certain cases, extension beyond the maximum treatment period may be necessary; in this case, this should not occur without re-evaluation of the patient's condition. In elderly patients, in patients with severe liver disease and / or impaired renal function or in the presence of of debilitating organic diseases it is recommended to start with 0.25 mg 2-3 times a day and increase if necessary, only if tolerated. The treatment can also be carried out using the pack in drops: 10 drops correspond to 0.25 mg of alprazolam, 20 drops to 0.50 mg The recommended doses are the same as for the tablets The concentration of the formulation in drops is 0.75 mg / ml.
Agoraphobia and panic disorder
In patients with agoraphobia associated with panic attacks or with panic disorder with or without phobic avoidance, the starting dose is 0.5-1 mg, given at bedtime, for one to two days. The dose should therefore be adjusted according to the individual patient's response. Dosage increases should not exceed 1 mg every three to four days. Dosage increases can be made first at noon, then in the morning and finally in the afternoon / evening until a dosing schedule 3 or 4 times a day is achieved for a duration of no more than 8 months. In an international multicenter study involving a large number of patients, the mean daily dose was 5.7 mg / day; only in some rare cases it was necessary to reach 10 mg / day.
Discontinuation of therapy
As a good clinical rule, administration should be withdrawn slowly.
It is suggested to reduce the daily dosage by no more than 0.5 mg every three days. Some patients may require an even more gradual reduction (see "Special warnings" and "Precautions for" use ").
Children and adolescents
The safety and efficacy of alprazolam have not been established in children and adolescents below 18 years, therefore the use of alprazolam is not recommended.
OPENING DROPS BOTTLE
Press on the plastic cap and at the same time unscrew
UNSCREW BY PRESSING
To close, screw the cap back on completely.
Overdose What to do if you have taken too much Frontal
Symptoms of overdose with FRONTAL are manifested as an increase in its pharmacological activity and mainly include ataxia and somnolence, dysarthria, motor incoordination, coma and respiratory depression. Treatment in cases of overdose is primarily to support respiratory and cardiovascular functions. The efficacy of dialysis has not been determined. As with other benzodiazepines, an overdose is not expected to be life-threatening unless there is concomitant intake of other CNS depressants or ethanol (alcohol). 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 initiated flushing gastric with respiratory protection if the patient is unconscious. 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. Benzodiazepine overdose usually presents with varying degrees of central nervous system depression ranging from "drowsiness to coma. In mild cases, symptoms include: drowsiness, mental confusion, and lethargy. In severe cases, symptoms may include: ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death Flumazenil may be useful as an antidote Flumazenil additionally may be used in the management of respiratory and cardiovascular function associated with overdose.
Animal experiments indicate that after a massive intravenous dose of FRONTAL (over 195 mg / kg; more than 975 times the maximum daily human dose) cardiovascular collapse may occur. The animals were treated with mechanical ventilation and intravenous infusion of Noradrenaline Other animal experiments have shown that hemodialysis and forced diuresis are of little use in the treatment of overdose.
In case of accidental ingestion / intake of an excessive dose of FRONTAL, notify your doctor immediately or go to the nearest hospital. If you have any questions about the use of FRONTAL, ask your doctor or pharmacist.
Side Effects What are the side effects of Frontal
Any side effects of FRONTAL are usually seen at the start of treatment and usually resolve with continued therapy or by reducing doses.
Patients who participated in controlled clinical trials have reported the following undesirable effects associated with FRONTAL therapy.
The following undesirable effects have been observed and reported during treatment with alprazolam with the following frequencies: very common (≥ 1/10), common (≥ 1/100,
As a result of post-marketing experience, the following additional side effects have been reported:
Use (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy can cause withdrawal or withdrawal phenomena. Psychic dependence may occur. Abuse of benzodiazepines has been reported (see section 4.4 "Special warnings and "use" precautions).
In many of the spontaneous reports for adverse behavioral effects, patients were treated concomitantly with other CNS medications and / or had pre-existing mental health problems. Patients with borderline personality problems, with a past history of aggressive or violent behavior, or who abuse alcohol or other substances, may be at risk for such events. Reactions of irritability, hostility and invasive thoughts have been reported following discontinuation of FRONTAL treatment in patients with PTSD.
Amnesia
Although no reports have been received for FRONTAL to date, benzodiazepines can cause anterograde amnesia. This can also occur at therapeutic dosages and the risk increases at higher dosages. Amnesic effects may be associated with behavioral changes (see section 4.4 "Special warnings and precautions for use").
Depression
A pre-existing depressive state may be unmasked during the use of benzodiazepines.
Psychiatric and paradoxical reactions
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) can lead to the development of physical dependence: discontinuation of therapy may cause rebound or withdrawal phenomena. Psychic dependence may occur. Abuse of benzodiazepines has been reported (see section 4.4 "Warnings special and precautions for use ").
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at “www.agenziafarmaco.gov.it/it/responsabili.” By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Expiry: see the expiry date indicated on the package.
WARNING: Do not use the medicine after the expiry date indicated on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored. Protect from light.
Keep the bottle and blisters in the cardboard box.
FRONTAL 0.75 mg / ml oral drops, solution
Shelf-life after first opening the bottle: 90 days.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
Composition and pharmaceutical form
COMPOSITION
FRONTAL 0.25 mg tablets
Each tablet contains:
Active ingredient: alprazolam 0.25 mg.
Excipients: lactose monohydrate; microcrystalline cellulose; dioctyl sodium sulfosuccinate; sodium benzoate; colloidal silica; cornstarch; magnesium stearate.
FRONTAL 0.5 mg tablets
Each tablet contains:
Active ingredient: alprazolam 0.50 mg.
Excipients: lactose monohydrate; microcrystalline cellulose; dioctyl sodium sulfosuccinate; sodium benzoate; colloidal silica; cornstarch; magnesium stearate; E110; hydrated aluminum oxide.
FRONTAL 1 mg tablets
Each tablet contains:
Active ingredient: alprazolam 1 mg.
Excipients: lactose monohydrate; microcrystalline cellulose; dioctyl sodium sulfosuccinate; sodium benzoate; colloidal silica; cornstarch; magnesium stearate; E132; hydrated aluminum oxide.
FRONTAL 0.75 mg / ml oral drops, solution
1 ml contains:
Active ingredient: alprazolam 0.75 mg. (10 drops contain 0.25 mg of alprazolam)
Excipients: alcohol; propylene glycol; sodium saccharinate; grapefruit flavor; purified water.
Pharmaceutical form and content
Tablets: box of 20 tablets of 0.25 mg. Box of 20 tablets of 0.50 mg. Box of 20 tablets of 1 mg.
Oral drops, solution: 20 ml bottle.
Oral use
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
FRONTAL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
FRONTAL 0.25 mg tablets
One tablet contains:
Active principle: alprazolam 0.25 mg
FRONTAL 0.50 mg tablets
One tablet contains:
Active principle: alprazolam 0.50 mg
FRONTAL 1 mg tablets
One tablet contains:
Active principle: alprazolam 1 mg
FRONTAL 0.75 mg / ml oral drops, solution
1 ml contains:
Active principle: alprazolam 0.75 mg
10 drops contain 0.25 mg of alprazolam
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Oral tablets and drops, solution.
ORAL USE.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Anxiety, tension and other somatic or psychiatric manifestations associated with anxiety syndrome.
Panic attacks with or without agoraphobia.
Benzodiazepines are indicated only when the disorder is severe, disabling and subjects the subject to severe distress.
04.2 Posology and method of administration
The optimal dosage of FRONTAL should be individualized according to the severity of symptoms and the patient's subjective response.
The dosage indications given should cover the needs of most patients. If a higher dosage is necessary, the doses should be gradually increased to avoid the risk of side effects. In these cases it is advisable to increase the evening dose earlier than the day one, except in patients suffering from agoraphobia and / or panic disorder. In this case, see the dedicated paragraph.
In general, patients never treated with psychotropic drugs require lower doses than those previously treated with anxiolytics or sedatives, antidepressants, hypnotics or chronic alcoholic patients.
It is recommended to always use the lowest dose to avoid the risk of residual sedation or ataxia.
In case of side effects already with the initial administration it is recommended to decrease the dosage.
Treatment should be as short as possible.
Patients should be re-evaluated regularly and the need for continued treatment should be carefully considered, particularly if the patient is symptom-free.
The maximum dose should not be exceeded.
The evening dose of the drug should be taken just before going to bed.
Anxiety
The starting dose ranges from 0.25 to 0.50 mg 3 times a day. This dosage will be increased according to the patient's needs up to a maximum of 4 mg per day in divided doses for a duration not exceeding 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 elderly patients, in patients with severe liver disease and / or impaired renal function or in the presence of debilitating organic diseases it is recommended to start with 0.25 mg 2-3 times a day and to increase if necessary, only if tolerated. The treatment can also be carried out using the package in drops: 10 drops correspond to 0.25 mg of alprazolam, 20 drops to 0.50 mg. The recommended doses are the same as for the tablets. The concentration of the formulation in drops is 0.75 mg / ml.
Agoraphobia and panic disorder
In patients with agoraphobia associated with panic attacks or with panic disorder with or without phobic avoidance, the starting dose is 0.5-1 mg, given at bedtime, for one to two days. The dose should therefore be adjusted according to the individual patient's response. Dosage increases should not exceed 1 mg every three to four days. Dosage increases can be made first at noon, then in the morning and finally in the afternoon / evening until a dosing schedule 3 or 4 times a day is achieved for a duration of no more than 8 months.
In an international multicenter study involving a large number of patients, the mean daily dose was 5.7 mg / day; only in some rare cases it was necessary to reach 10 mg / day.
Discontinuation of therapy
As a good clinical rule, administration should be withdrawn slowly.
It is suggested to reduce the daily dosage by no more than 0.5 mg every three days. Some patients may require an even more gradual reduction (see section 4.4 "Special warnings and precautions for use").
Pediatric use
The safety and efficacy of alprazolam have not been established in children and adolescents below 18 years, therefore the use of alprazolam is not recommended.
04.3 Contraindications
FRONTAL is contraindicated in patients with known hypersensitivity to benzodiazepines, alprazolam or to any of the excipients and in patients with acute narrow-angle glaucoma. The product can be used in patients with open-angle glaucoma receiving appropriate therapy. benzodiazepines are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, sleep apnea syndrome, severe hepatic insufficiency. Do not administer to children, in the first trimester of pregnancy and during lactation.
04.4 Special warnings and appropriate precautions for use
Tolerance
Some loss of the hypnotic effect of benzodiazepines may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines, including alprazolam, can lead to the development of physical and mental dependence on these drugs. As with all benzodiazepines, the risk of addiction increases with dose and duration of treatment; it is greater in patients with a history of drug or alcohol abuse.
Dependence can occur at therapeutic doses and / or in patients with no individual risk factors. The risk of dependence increases with the concomitant use of several benzodiazepines regardless of the anxiolytic or hypnotic indication. Cases of abuse have also been reported.
Once physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms.
These can consist of headache, body 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.
Rebound insomnia or 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 changes in mood, anxiety, restlessness or sleep disturbances. of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
Duration of treatment
The duration of treatment should be as short as possible (see section 4.2 "Posology and method of administration") and in the case of anxiety it should not exceed 8 - 12 weeks, including a gradual withdrawal period. this period 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.
It is also important that the patient is informed of the possibility of rebound phenomena, thus minimizing anxiety about these symptoms should they occur when the drug is discontinued.
There is evidence that in the case of benzodiazepines with a short duration of action, withdrawal symptoms may become manifest within the dosing interval between doses, particularly for high doses.
When using benzodiazepines with a long duration of action it is important to warn the patient that abrupt change to a benzodiazepine with a short duration of action is not recommended, as withdrawal symptoms may occur.
Discontinuation of treatment
As with any other benzodiazepine, the dosage of FRONTAL should be gradually reduced as stopping abruptly or too quickly can lead to withdrawal symptoms.
Withdrawal symptoms may include mild dysphoria and insomnia or present as major syndromes with muscle and abdominal cramps, vomiting, sweating, tremors and convulsions.
In addition, withdrawal crises may occur following a rapid decrease or abrupt discontinuation of alprazolam therapy (see section 4.2 Posology and method of administration - Discontinuation of therapy).
These symptoms, especially the more severe ones, are generally more common in those patients who have been treated with excessive doses for prolonged periods of time. However, withdrawal symptoms have also been reported following abrupt discontinuation of therapeutic doses of benzodiazepines. Therefore abrupt discontinuation should be avoided and a gradual reduction in dosage should be prescribed (see Posology).
During discontinuation of the drug in patients with panic disorder, symptoms related to the reappearance of panic attacks that mimic those typical of withdrawal can sometimes be observed.
Amnesia
Benzodiazepines can induce antegrade amnesia. This occurs most often several hours after ingestion of the drug (see section 4.8 "Undesirable effects").
Psychiatric and paradoxical reactions
When benzodiazepines are used it is known that reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes can occur. Should this occur, the use of the medicinal product should be discontinued. These reactions are more frequent in children and the elderly.
Specific groups of patients
Benzodiazepines should not be given to children without careful evaluation of the actual need for treatment; the duration of treatment should be as short as possible. In elderly and / or debilitated patients it is recommended to always use the lowest dose to avoid the risk of residual sedation or ataxia. Elderly people should take a reduced dose (see section 4.2 "Posology and method of administration"). Similarly, a lower dose is suggested for patients with chronic respiratory failure due to the risk of respiratory depression.
The usual precautions are recommended in the treatment of patients with impaired renal function and mild or moderate hepatic insufficiency, while in patients with severe hepatic insufficiency, benzodiazepines are not indicated as they can precipitate encephalopathy. Benzodiazepines are not recommended for primary treatment. of psychotic illness Benzodiazepines should not be used alone to treat severe depression or anxiety associated with depression (suicide can be precipitated in such patients).
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected effects from interaction.
As with other psychotropic drugs, alprazolam in severely depressed or suicidal patients should be administered with due precautions and prescribed in appropriate packaging.
A concomitant depressive disorder (primary or secondary) is associated with panic attack disorder with increased cases of suicide in untreated patients. Therefore, the utmost precaution should be taken both when using the higher doses of FRONTAL for the treatment of patients with panic disorder and when using any psychotropic drug in the treatment of depressed patients or those in whom ideation or ideation is suspected. suicide attempt.
Benzodiazepines should be used with extreme caution in patients with a history of drug or alcohol abuse (see section 4.5 Interactions with other medicinal products and other forms of interaction).
Patients who habitually abuse alcohol and / or drugs, when being treated with benzodiazepines must be kept under strict medical supervision, due to the predisposition of these subjects to addiction and dependence.
Cases of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.
FRONTAL tablets:
Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose / galactose malabsorption should not take Frontal tablets.
The safety and efficacy of alprazolam have not been established in children and adolescents below 18 years, therefore the use of alprazolam is not recommended.
FRONTAL 0.75 mg / ml oral drops, solution
This medicine contains ethanol (alcohol).
04.5 Interactions with other medicinal products and other forms of interaction
Benzodiazepines produce additional CNS depressant effects when administered concomitantly with alcohol or other CNS depressant drugs.
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.
Particular attention, especially in elderly patients, should be used with respiratory depressant drugs such as opioids (analgesics, cough suppressants, replacement treatments).
FRONTAL should be used with caution in combination with other CNS depressants. Association with CNS depressants: the central depressive effect may be enhanced in the case of concomitant use with anti-psychotics (neuroleptics), hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics, and antihistamines-H1 sedatives.
In the case of narcotic analgesics, an increase in euphoria can occur, leading to an increase in psychic dependence.
Molecules that inhibit certain liver enzymes (especially cytochrome P4503A4) can increase the plasma concentration of alprazolam and enhance its activity.
To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation.
Co-administration of alprazolam with potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), protease inhibitors or certain macrolides (erythromycin, clarithromycin, telithromycin) should be substantial dose reduction.
Clinical and in vitro studies with alprazolam show variability of interactions and the possibility of interactions between alprazolam and different drugs. Depending on the degree of interaction and the type of data available, the following recommendations should be considered:
- The concomitant administration of FRONTAL with ketoprofen, itraconazole or other antifungals of the azole group is not recommended.
- Caution and caution in decreasing the dose is recommended when FRONTAL is concomitantly administered with nefazodone, fluvoxamine and cimetidine.
- Caution is advised when FRONTAL is co-administered with fluoxetine, propoxyphene, oral contraceptives, diltiazem or macrolide antibiotics such as erythromycin and troleandomycin.
- Interactions between HIV protease inhibitors (eg ritonavir) and alprazolam are complex and time dependent. Low dose ritonavir causes a reduction in alprazolam clearance, prolongs its elimination half-life and increases clinical effects. following prolonged exposure to ritonavir, induction of CYP3A compensates for this inhibition.
This interaction will require a dose adjustment or "discontinuation of FRONTAL treatment.
Steady-state plasma concentrations of imipramine and desipramine increase by 31% and 20%, respectively, following concomitant administration of FRONTAL in doses up to 4 mg / day.
Kinetic interactions between benzodiazepines and other drugs have been described. For example, the clearance of alprazolam and some other benzodiazepines may be decreased by concomitant administration of cimetidine or macrolide antibiotics.
The clinical significance of these effects has not been defined.
04.6 Pregnancy and lactation
Pregnancy
Data on teratogenicity and effects on postnatal development and behavior following benzodiazepine treatment are inconsistent.
There is evidence from some early studies with other compounds of the benzodiazepine class showing that in utero exposure may be associated with malformations.
Subsequent studies with drugs of the benzodiazepine class, on the other hand, have not provided any clear evidence of any type of defect.
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 is to be administered for medical reasons during the latter part of pregnancy, even at low doses, symptoms of "floppy infant" 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. High doses, during the last period of pregnancy or during labor, can cause effects in the newborn such as respiratory depression or apnea and hypothermia, due to the pharmacological action of the drug. If alprazolam treatment is necessary during the latter part of pregnancy, high doses should be avoided, and withdrawal symptoms and / or floppy infant syndrome should be monitored in the neonate. In addition, neonatal withdrawal symptoms such as hyperexcitability, agitation and tremor may be observed a few days after birth, although floppy infant syndrome is not observed The appearance of withdrawal symptoms after birth depends on the half-life of the product.
If FRONTAL is administered during pregnancy or if the patient discovers that she is pregnant during treatment with FRONTAL, the patient should be informed of the potential danger to the fetus.
Taking these data into account, the use of alprazolam during pregnancy can only be considered if the therapeutic indications and posology are strictly observed.
Feeding time
Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers.
The content of ethanol present in Frontal drops must be taken into account in case of administration to pregnant and breastfeeding women.
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 "Interactions with other medicinal products and other forms of interaction").
Given the CNS depressant effect of alprazolam, patients taking the drug should be warned that it may be dangerous for them to engage in activities that require full mental attention, such as working on hazardous machinery or driving cars, until it is possible to exclude an impairment of attention and reflexes following the intake of the drug.
04.8 Undesirable effects
Any side effects of FRONTAL are usually seen at the start of treatment and usually resolve with continued therapy or by reducing doses.
Patients who participated in controlled clinical trials have reported the following undesirable effects associated with FRONTAL therapy.
The following undesirable effects have been observed and reported during treatment with alprazolam with the following frequencies: very common (≥ 1/10), common (≥ 1/100,
As a result of post-marketing experience, the following additional side effects have been reported:
Use (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of therapy can cause withdrawal or withdrawal phenomena. Psychic dependence may occur. Abuse of benzodiazepines has been reported (see section 4.4 "Special warnings and "use" precautions).
In many of the spontaneous reports for adverse behavioral effects, patients were treated concomitantly with other CNS medications and / or had pre-existing mental health problems. Patients with borderline personality problems, with a past history of aggressive or violent behavior, or who abuse alcohol or other substances, may be at risk for such events. Reactions of irritability, hostility and invasive thoughts have been reported following discontinuation of FRONTAL treatment in patients with PTSD.
Amnesia
Although no reports have been received for FRONTAL to date, benzodiazepines can cause anterograde amnesia. This can also occur at therapeutic dosages and the risk increases at higher dosages. Amnesic effects may be associated with behavioral changes (see section 4.4 "Special warnings and precautions for use").
Depression
A pre-existing depressive state may be unmasked during the use of benzodiazepines.
Psychiatric and paradoxical reactions
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) can lead to the development of physical dependence: discontinuation of therapy may cause rebound or withdrawal phenomena. Psychic dependence may occur. Abuse of benzodiazepines has been reported (see section 4.4 "Warnings special and precautions for use ").
04.9 Overdose
Symptoms of overdose with FRONTAL manifest as increased pharmacological activity and mainly include ataxia and somnolence, dysarthria, coma and respiratory depression.
Treatment in cases of overdose is primarily to support respiratory and cardiovascular functions. The efficacy of dialysis has not been determined.
As with other benzodiazepines, an overdose should not be life-threatening unless concomitant other CNS depressants (including alcohol) are taken. In the treatment of overdose of any drug, the possibility should be considered. that other substances have been taken at the same time.
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.
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. Benzodiazepine overdose usually presents with varying degrees of central nervous system depression ranging from "drowsiness to coma. In mild cases, symptoms include: drowsiness, mental confusion, and lethargy. In severe cases, symptoms may include: ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.
"Flumazenil" can be useful as an antidote.
Animal experiments indicate that cardiovascular collapse may occur after a massive intravenous dose of FRONTAL (over 195 mg / kg; more than 975 times the maximum daily dose in humans).
The animals were treated with mechanical ventilation and intravenous infusion of norepinephrine. Other animal experiments have shown that hemodialysis and forced diuresis are of little use in the treatment of overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: benzodiazepine-derived anxiolytics, ATC code: N05BA12
FRONTAL contains alprazolam, a triazole-benzodiazepine, as the active substance.
Alprazolam binds to the GABAergic site of benzodiazepines by synergizing the activity of GABA, an inhibitory neurotransmitter, thus causing a reduction in neuronal excitation. This characteristic gives the molecule anxiolytic - hypnotic - sedative properties.
Clinical studies in healthy volunteers have shown that single doses up to 4 mg produce effects which can be considered extensions of its pharmacological activity.
No significant effects on the cardiovascular nervous system or respiratory system were observed.
05.2 "Pharmacokinetic properties
After oral administration, alprazolam is rapidly absorbed. Maximum plasma concentrations are achieved 1 to 2 hours after drug administration.
Plasma levels are dose proportional; in the arc of doses between 0.5 and 3 mg, plasma peaks from 8 to 37 ng / ml are observed.
The mean half-life of alprazolam in healthy adults is 11.2 hours (range: 6.3-26.9 hours).
The main metabolites are alpha-hydroxialprazolam and a benzophenone.
The biological activity of hydroxy-alprazolam is about half that of alprazolam. Benzophenone is inactive. The plasma levels of these metabolites are extremely low, however their half-lives are of the same order of magnitude as that of alprazolam.
Alprazolam and its metabolites are mainly excreted in the urine.
FRONTAL does not affect prothrombin time or plasma warfarin levels in volunteers to whom warfarin was administered orally.
In vitro, about 80% of alprazolam is bound to serum proteins.
After administration of 14C alprazolam to pregnant female mice, the radioactivity was uniformly distributed in the fetuses in concentrations of 14C approximately equal to those present in the mother's blood and skeletal muscle.
Differences in benzodiazepine kinetics and metabolism have been observed in various pathological conditions, including alcoholism and liver and kidney function abnormalities, as well as in the geriatric patient.
In healthy elderly subjects, the mean half-life of alprazolam is 16.3 hours (range: 9-26.9 hours). In healthy women, concomitant oral contraceptives prolong the half-life of alprazolam (mean half-life: 12.4 hours). Concomitant intake of cimetidine also prolongs the mean half-life of alprazolam (16.6 hours).
In patients with alcoholic liver disease, the half-life of alprazolam ranges from 5.8 to 65.3 hours, with a mean of 19.7 hours. In obese subjects, the half-life range of the drug varies from 9.9 to 40.4 hours, on average 21.8 hours.
In view of the similarity of alprazolam to other benzodiazepines, it is hypothesized that the drug crosses the placenta and is excreted in breast milk.
05.3 Preclinical safety data
Mutagenesis, Carcinogenesis, Impaired fertility and effects on the eyes
According to the Ames in vitro test, alprazolam is not mutagenic. Alprazolam does not induce chromosomal aberrations in in vivo micronucleus tests in rats up to the maximum tested dose of 100 mg / kg, which is 500 times the daily dose maximum recommended in humans of 10 mg / day.
No evidence of carcinogenic potential was found in 2-year studies with alprazolam conducted in rats at doses up to 30 mg / kg / day (150 times the maximum dose of 10 mg / kg / day) and in dose-treated mice. up to 10 mg / kg / day (50 times the human dose of 10 mg / day). Alprazolam showed no mutagenic effects in the rat micronucleus test with doses up to 100 mg / kg, which corresponds to 500 times the dose used in humans equal to 10 mg / day.
Alprazolam did not cause impairment of fertility in rats at doses up to 5 mg / kg / day, which is 25 times the human dose of 10 mg / day.
When rats were treated with alprazolam at a dose of 3 mg, 10 mg and 30 mg / kg / day (15 to 150 times the human dose of 10 mg / day) orally for 2 years, in in females there was a trend towards a dose-related increase in the number of cataracts, while in males there was a trend for a dose-related increase in the vascularity of the cornea. These lesions were not seen until 11 months after the start of treatment. .
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
FRONTAL 0.25 mg tablets
One tablet contains:
lactose monohydrate, microcrystalline cellulose, dioctyl sodium sulfosuccinate, sodium benzoate, colloidal silica, corn starch, magnesium stearate.
FRONTAL 0.5 mg tablets
One tablet contains:
lactose monohydrate, microcrystalline cellulose, dioctyl sodium sulfosuccinate, sodium benzoate, colloidal silica, corn starch, magnesium stearate, E110, aluminum oxide hydrate.
FRONTAL 1 mg tablets
One tablet contains:
lactose monohydrate, microcrystalline cellulose, dioctyl sodium sulfosuccinate, sodium benzoate, colloidal silica, corn starch, magnesium stearate, E132, aluminum oxide hydrate.
FRONTAL 0.75 mg / ml oral drops, solution
100 ml contain:
alcohol, propylene glycol, sodium saccharinate, grapefruit flavor, purified water.
06.2 Incompatibility
No data are known in this regard.
06.3 Period of validity
Tablets: 5 years.
Drops: 3 years. Shelf-life after first opening the bottle: 90 days.
06.4 Special precautions for storage
Protect from light.
Keep the bottle and blisters in the cardboard box.
06.5 Nature of the immediate packaging and contents of the package
Opaque PVC + Aluminum blister.
Box of: 20 tablets of 0.25 mg - 0.5 mg - 1 mg.
Amber glass bottle with polythene dropper cap.
Bottle of 20 ml, 0.75 mg / ml oral drops, solution.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with current legislation.
07.0 MARKETING AUTHORIZATION HOLDER
Abbott S.r.l.
S.R. 148 Pontina km 52 snc
04011 Campoverde di Aprilia (LT)
08.0 MARKETING AUTHORIZATION NUMBER
20 tablets of 0.25 mg, AIC n. 028644019
20 tablets of 0.5 mg, AIC n. 028644021
20 tablets of 1 mg, AIC n. 028644033
Bottle of 20 ml, 0.75 mg / ml oral drops, solution, AIC n. 028644084
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
20/04/1993
Renewal: 20/04/2008
10.0 DATE OF REVISION OF THE TEXT
July 2012
