Xanax - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Alprazolam

XANAX extended release tablets 0.5mg, 1mg, 2mg, 3mg

Why is Xanax used? What is it for?

XANAX belongs to the category of Benzodiazepine derivatives. XANAX prolonged-release tablets are indicated for the treatment of panic disorder with or without agoraphobia. Benzodiazepines are only indicated when the disorder is severe, disabling, or makes the subject very uncomfortable.

Contraindications When Xanax should not be used

XANAX prolonged-release tablets are contraindicated in patients with a known hypersensitivity to benzodiazepines, alprazolam or 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.

It is also contraindicated in patients with:

  • Severe respiratory failure.
  • Severe hepatic insufficiency.
  • Myasthenia gravis.
  • Sleep apnea syndrome.

XANAX prolonged-release tablets are contraindicated in the first trimester of pregnancy and during lactation.

Precautions for use What you need to know before taking Xanax

Duration of treatment

The duration of treatment should be as short as possible. 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 upon discontinuation of the drug. When using benzodiazepines with a long duration of action it is important to warn the patient that it is not recommended. sudden change to a benzodiazepine with a short duration of action, as withdrawal symptoms may occur.

Psychiatric and paradoxical reactions

When benzodiazepines are used it is known that reactions such as restlessness, agitation, irritability, aggression, delirium, 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 the elderly.

Use in patients with concomitant diseases

In elderly patients, the use of the lowest effective dose is recommended to avoid the onset of ataxia or excessive sedation, as they may present a problem in elderly and debilitated patients. Likewise, 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 hepatic and / or renal function. In patients with severe hepatic insufficiency, benzodiazepines are not indicated as they can precipitate encephalopathy (see "Dose, method and time of administration"). 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 can be precipitated in such patients). XANAX prolonged-release tablets should not be used in patients with psychomotor difficulties; in patients with endogenous depression , bipolar or with psychotic symptoms. The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected effects from interaction.

Epileptic fits

Patients, particularly those with a history of seizures or epilepsy, should not abruptly stop taking alprazolam. It is recommended that all patients on alprazolam who require dose reduction gradually decrease their dosage under close supervision. doctor.

Status epilepticus

Withdrawal seizures have been reported following discontinuation of alprazolam. A single epileptic episode occurred in most cases, however multiple seizures and seizures were also reported.

Risk associated with dose reduction

Withdrawal reactions may occur when there is a reduction in dosage. For this reason, the dose of XANAX prolonged-release tablets should be gradually reduced or discontinued.

Suicide

Panic disorder has been associated with primary and secondary major depressive disorders and an increase in suicide cases among untreated patients.As with other psychotropic drugs, in severely depressed patients or in those who may be expected to be at risk of suicidal ideation or suicide planning, standard precautions should be taken when administering high doses of alprazolam in patients with panic attacks. and in the number of prescriptions.

Mania

Episodes of hypomania and mania associated with the use of alprazolam have been reported in depressed subjects.

Uricosuric effect

Alprazolam has a weak uricosuric effect. Although other drugs with a weak uricosuric effect have been shown to cause acute renal failure, no cases of acute renal failure have been reported to be attributed to alprazolam therapy.

Azole antifungal agents

Ketoconazole and itraconazole are potent inhibitors of CYP3A which may increase the plasma concentrations of alprazolam. Concomitant administration of alprazolam and ketoconazole, itraconazole or other azole-type antifungals is not recommended (see "Interactions").

Interactions What medications or foods may change the effect of Xanax

Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription. Benzodiazepines produce additional CNS depressant effects when administered concomitantly with alcohol or other CNS depressant drugs. Concomitant intake with alcohol should be avoided. Particular attention, especially in elderly patients, should be used with respiratory depressant drugs such as opioids (analgesics, cough suppressants, replacement treatments). Association with CNS depressants: l "Central depressive effect may be enhanced by concomitant use with anti-psychotics (neuroleptics), hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics, and sedative H1 antihistamines. Molecules that inhibit certain liver enzymes (especially cytochrome P4503A4) may increase the plasma concentration of alprazolam and enhance its activity. Pharmacokinetic interactions may occur when alprazolam is co-administered with drugs that interfere with its metabolism. Co-administration of alprazolam with potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole, posaconazole, vo recazole), protease inhibitors or certain macrolides (erythromycin, clarithromycin, telithromycin) should be done with caution and a substantial dose reduction should be considered.

Interactions with other drugs

The first step in the metabolism of alprazolam is the hydroxylation catalyzed by citrocomo P450 3A (CYP3A). Drugs that inhibit this metabolic process may have a noticeable effect on the clearance of alprazolam. Consequently, administration of alprazolam should be avoided in patients with treatment with very strong CYP3A inhibitors. Alprazolam should be used with CYP3A inhibitor drugs, which have a lower but still significant potency, paying attention and calculating an appropriate dose reduction. For some drugs, the interaction with alprazolam has been quantified through clinical studies; for other drugs interactions are predicted based on in vitro studies and / or experience with similar drugs of the same drug class. Compounds that are potent inhibitors of CYP3A are expected to increase plasma concentrations of alprazolam. Drugs that have been studied in vivo for the ability to increase the area under the curve (AUC) of alprazolam are the following: ketoconazole, 3.98 times; itraconazole, 2.70 times; nefazodone, 1.98 times; fluvoxamine, 1.96 times and erythromycin 1.61 times. CYP3A inducers are expected to decrease alprazolam concentrations and this has indeed been observed in vivo. Oral clearance of alprazolam (taken as a single dose of 0.8 mg) increased 2.40-fold after administration of carbamazepine 300 mg / day for 10 days. Most of the interactions that have been documented with alprazolam relate to drugs that inhibit or induce CYP3A4 (see "Special warnings" and "Precautions for use"). 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.

Potent CYP3A inhibitors

Examples of drugs known as inhibitors of the metabolism of alprazolam and / or related benzodiazepines, presumably by inhibition of CYP3A, are given below. Azole antifungal agents - ketoconazole and itraconazole are potent inhibitors of CYP3A and have been shown in vivo to increase the Alprazolam concentrations 3.98-fold and 2.70-fold, respectively. Co-administration of alprazolam with these two drugs is not recommended. Other azole-type antifungal agents should be considered potent CYP3A inhibitors and co-administration with alprazolam is not recommended (see Section 4.4 - Special Warnings and Precautions for Use). Drugs capable of inhibiting CYP3A based on clinical studies with alprazolam (caution and consideration of appropriate dose reduction of alprazolam during concomitant administration of the following drugs is advised):

Nefazodone - Concomitant intake of nefazodone increases the concentration of alprazolam twice.

Fluvoxamine - Concomitant intake of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71% and reduced psychomotor performance.

Cimetidine - Concomitant intake of cimetidine increased the maximum plasma concentration of alprazolam by 86%, reduced clearance by 42% and increased the half-life by 16%.

Fluoxetine - Concomitant intake of fluoxetine increased the maximum plasma concentration of alprazolam by 46%, reduced clearance by 21%, increased half-life by 17% and reduced psychomotor performance.

Propoxyphene - Concomitant intake of propoxyphene increased the maximum plasma concentration of alprazolam by 6%, reduced clearance by 38% and increased the half-life by 58%.

Oral contraceptives - Concomitant intake of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, reduced clearance by 22% and increased the half-life by 29%.

Co-administration of diltiazem with alprazolam is not recommended.

CYP3A inducers

Carbamazepine - Oral clearance of alprazolam (taken as a single dose of 0.8 mg) increased from 0.90 ± 0.21 mL / min / kg to 2.13 ± 0.54 mL / min / kg and the halving decreased (from 17.1 ± 4.9 to 7.7 ± 1.7 h) after taking 300 mg / day of carbamazepine for 10 days. The dose of carbamazepine used in this study was also quite low than recommended doses (1000-1200 mg / day); the effect observed with usual doses of carbamazepine is unknown.

Use with other CNS inhibitors

If alprazolam is taken together with other psychotropic agents or anticonvulsant drugs, particular attention is advised to the pharmacology of the agents used, especially for those compounds that may potentiate the action of benzodiazepines. Benzodiazepines, including alprazolam, produce additional inhibitory effects charged to the CNS when taken together with other psychotropic drugs, anticonvulsants, anithistamines, alcohol and other drugs that themselves induce CNS inhibition.

Use with imipramine and desipramine

Steady-state plasma concentrations of imipramine and desipramine have been shown to increase on average by 31% and 20%, respectively, when taken together with immediate-release XANAX in doses above 4 mg / day. The clinical significance of these changes is unknown. The interactions between HIV protease inhibitors (eg ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir cause a reduction in alprazolam clearance, prolong its elimination half-life and enhance clinical effects. However, following prolonged exposure to ritonavir, induction of CYP3A compensates for this inhibition. This interaction will require dose adjustment or discontinuation of XANAX treatment.

Interactions with laboratory tests

Although interactions between benzodiazepines and commonly used laboratory tests have been reported occasionally, there are no specific references for a particular drug or test.

Warnings It is important to know that:

Specific groups of patients

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. The usual precautions are recommended when treating patients with impaired renal function and mild or moderate hepatic insufficiency. In elderly and / or debilitated patients it is recommended to always use the lowest dose to avoid the risk of residual sedation or ataxia. 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). A concomitant depressive disorder (primary or secondary) is associated with panic attack disorder with increased cases of suicide in untreated patients. Therefore the same precaution should be taken both when using the higher doses of XANAX 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 not be used alone to treat severe depression or anxiety associated with depression (suicide can be precipitated in such patients). As with other psychotropic drugs, alprazolam in severely depressed or suicidal patients should be administered with due precautions and prescribed in appropriate packaging.

Tolerance

Some loss of the hypnotic effect of benzodiazepines may develop after repeated use for a few weeks.

Amnesia

Benzodiazepines can induce anterograde amnesia. This most often happens several hours after ingestion of the drug (see "Side Effects").

Addiction and withdrawal reactions

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. Certain adverse events, some of which may be life-threatening, are a direct consequence of physical dependence on alprazolam. These include a set of withdrawal symptoms, the most significant of which is epileptic seizure. Addiction can occur at therapeutic doses and / or in patients with no individual risk factors. The risk of addiction increases with concomitant use of different benzodiazepines regardless of anxiolytic or hypnotic indication. Cases of abuse have also been reported. Some patients have experienced considerable difficulty in gradually tapering off and discontinuing alprazolam therapy, especially those taking higher doses for long periods. "relatively short-term use of doses <4 mg / day c" is the risk of dependence. In patients treated with doses above 4 mg / day and for long periods (more than 12 weeks) the risk of dependence and its severity are higher. The risk is further increased in patients with a history of alcohol and drug abuse. People at risk of addiction should be closely monitored. ollo during treatment with alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under direct medical supervision (see "Undesirable Effects"). Following a rapid decrease or abrupt discontinuation of benzodiazepine therapy including alprazolam, withdrawal symptoms have occurred. The latter can range from mild dysphoria, insomnia, headache, extreme anxiety, tension, restlessness, confusion, irritability to more severe symptoms which may include derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or seizures, 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 "Dose, method and time of administration" - Discontinuation of therapy).

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.

The tablets contain lactose; if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Use in 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 treatment with benzodiazepines 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 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. Infants exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit "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, 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 treatment with alprazolam 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 the potential risk of congenital malformations already seen with other benzodiazepines, XANAX prolonged-release tablets should not be administered in the first trimester of pregnancy.

If the product is prescribed to a woman of childbearing age, either if she intends to become pregnant or if she suspects she is pregnant, she should contact her doctor for advice on discontinuing the drug. If XANAX is administered during pregnancy or if the patient discovers that she is pregnant during treatment with XANAX, 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 dosage are strictly respected.

Feeding time

Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers.

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, since impaired attention and reflexes following the drug intake cannot be ruled out, patients under treatment should be warned that it may be dangerous for them to engage in activities that require complete mental attention, such as working on dangerous machinery or driving cars.

Dosage and method of use How to use Xanax: Dosage

XANAX prolonged-release tablets should be administered once daily, preferably in the morning. The tablets must be taken whole; they must not be chewed and must not be crushed or divided.

The optimal dosage of XANAX prolonged-release tablets should be individualized according to the severity of symptoms and the patient's subjective response.

The recommended daily dosage is 3-6 mg / day.

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 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.

Posology in special patient populations

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.

Use in elderly patients

Elderly patients may be more sensitive to the effects of benzodiazepines. Higher plasma concentrations of alprazolam are seen in these patients than in the younger population taking the same drug doses; this is due to the reduced clearance of the drug. In elderly patients, the use of the lowest effective dose of alprazolam is recommended to avoid the onset of ataxia and the possibility of excessive sedation. A lower dose is also recommended in patients with chronic respiratory failure to avoid the risk of respiratory depression.

In patients with advanced hepatic insufficiency or in patients with debilitating disease, the usual starting dose of XANAX prolonged-release tablets is 0.5 mg / day. This dosage can be gradually increased if necessary and tolerated by the patient (see Dosage adjustment).

Dosage adjustment

Treatment with XANAX prolonged-release tablets should be started with a dose of 0.5 mg - 1 mg once daily. Based on the patient's clinical response, the dose can be increased at intervals of 3-4 days up to a maximum of 1 mg / day. A slower dose adjustment is possible to allow for the full manifestation of the pharmacodynamic effect of XANAX prolonged-release tablets. Generally, therapy should be started at a low dose to minimize the risk of adverse reactions in particularly drug sensitive patients. The dose must be increased until an acceptable therapeutic response is obtained (ie a substantial reduction or total elimination of panic attacks), until the onset of intolerance phenomena or until the maximum recommended dose is reached.

Maintaining the dosage

Doses in the range of 1 to 10 mg / day have been used in controlled trials conducted to establish the efficacy of XANAX prolonged-release tablets in panic disorder. Most patients have shown that the treatment is effective at doses of 3-6 mg / day. Occasionally some patients have required a maximum of 10 mg / day to achieve a satisfactory response.

The efficacy of XANAX prolonged-release tablets for longer periods has not been systematically evaluated beyond 8 weeks. The required duration of treatment for panic disorder patients responding to XANAX prolonged-release tablets is not known. However, periodic checks are recommended. After a prolonged period of absence of panic attacks, a gradual withdrawal of the drug under strict control may be tried, but it has been shown that this can often be difficult to achieve without recurring and / or occurring suspension phenomena.

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 ").

Switching from XANAX immediate-release tablets to Xanax prolonged-release tablets.

Patients who are already being treated with split doses of XANAX standard formulation, e.g. 3-4 times a day, may be switched to XANAX prolonged-release tablets at the same total daily dose taken once a day. If the therapeutic response is inadequate, the dosage can be modified as described above.

Overdose What to do if you have taken too much Xanax

Clinical experience

Manifestations of alprazolam overdose include somnolence, dysarthria, impaired coordination, coma, and respiratory depression. As with other benzodiazepines, deaths have been reported in association with alprazolam overdose alone. In addition, accidental deaths have been reported in patients who overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; the alcohol rates seen in some of these patients were lower than those generally associated with alcohol-induced accidental death.

General treatment of overdose

Treatment in cases of overdose is primarily to support respiratory and cardiovascular functions.

As in all overdose cases, breathing, pulse rate and blood pressure should be monitored. Following an overdose of oral benzodiazepines, general supportive treatments should be employed; vomiting should be induced (within one "hour) if patient is conscious or gastric lavage with respiratory protection undertaken if patient is unconscious. If no improvement is observed with stomach emptying, activated charcoal should be given to reduce absorption. Fluids should be administered intravenously and a patent airway maintained. If hypotension occurs, this can be counteracted by the use of vasopressors. Dialysis is of limited support.

As with the treatment of intentional overdose with other drugs, it should be noted that multiple agents may have been ingested. 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, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial nullification of the sedative effects of benzodiazepines and can be used if a benzodiazepine overdose is known or suspected. In the management of respiratory and cardiovascular function associated with overdose it can be used in addition flumazenil.

In case of accidental ingestion / intake of an overdose of XANAX prolonged-release tablets, notify your doctor immediately or go to the nearest hospital.

If you have any questions about the use of XANAX prolonged-release tablets, ask your doctor or pharmacist.

Side Effects What are the side effects of Xanax

Like all medicines, XANAX prolonged-release tablets can cause side effects, although not everybody gets them.
Any side effects of XANAX are usually seen at the start of treatment and usually resolve with continued therapy or reduced doses.

The following information on undesirable effects is based on pooled data from placebo-controlled clinical trials of 5, 6 and 8 weeks duration conducted with XANAX prolonged-release tablets in panic disorder.

The following undesirable effects have been observed and reported during treatment with alprazolam with the following frequencies: very common (≥ 1/10), common (≥ 1/100,

MedDRA Organ systemic class Very common (≥ 1/10) Common (≥ 1/100, Uncommon (≥ 1 / 1,000 a Rare (≥ 1/10, 000 y Very rare ( Not known (cannot be estimated from the available data) Endocrine pathologies Hyperprolactinemia * Metabolism and nutrition disorders Decreased appetite Psychiatric disorders Depression Confusional state, disorientation, decreased libido, anxiety, insomnia, nervousness, increased libido *, irritability. Mania * (see section 4.4 Special warnings and precautions for use), hallucination *, agitation *, anger *, anhedonia, anorgasmia, bradyphrenia, depressive state, derealization, disinhibition, euphoric state, fear, loss of libido, mania, disturbance behavior, nightmares, panic disorder, psychomotor slowdown, sleep disturbances. Hypomania *, aggression *, hostile behavior *, abnormal thoughts *, psychomotor hyperactivity * Nervous system disorders Sedation, somnolence, ataxia, memory impairment, dysarthria, dizziness, headache Impaired balance, coordination problems, attention disturbance, hypersomnia, lethargy, tremor, dizziness, slurred speech, difficulty concentrating Amnesia, clumsiness, convulsions, dysgeusia, abnormal gait, accelerated gait, increased activity, partial seizures, headache, stupor. Autonomic nervous system imbalance *, dystonia * Eye disorders Blurred vision Ear and labyrinth disorders Tinnitus Cardiac pathologies Palpitations Vascular pathologies Flushes Respiratory, thoracic and mediastinal disorders Choking, respiratory distress Gastrointestinal disorders Constipation, dry mouth Nausea Abdominal pain, diarrhea, stomach pain, vomiting, necrotizing enterocolitis Gastrointestinal disease * Hepatobiliary disorders Hepatitis *, liver function abnormalities *, jaundice * Skin and subcutaneous tissue disorders Dermatitis * Increased susceptibility to bruising, rash, increased sweating, itching Angioedema *, photosensitivity reactions * Musculoskeletal and connective tissue disorders Muscle weakness, arthralgia, back problems, muscle cramps, myalgia, pain in the limbs Renal and urinary disorders Incontinence *, enuresis, frequent urination Urinary retention * Diseases of the reproductive system and breast Sexual dysfunction * Menstrual cycle irregularities *, ejaculation disorders, erectile dysfunction, menstrual delay General disorders and administration site conditions Fatigue, irritability Chest pain, altered sensation, drunkenness, nervousness, feeling of relaxation, confusion, flu syndrome, foreign body sensation, sluggishness, thirst, weakness. Peripheral edema * Injury, poisoning and procedural complications Falls, limb injuries, overdose, traffic accidents Diagnostic tests Weight reduction, weight gain Increased blood bilirubin Increased intraocular pressure *

* Undesirable effects identified post-marketing

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 precautions for use). 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 Previous history of aggressive or violent behavior, or abusing alcohol or other substances, may be at risk for such events. Reactions of irritability, hostility and invasive thoughts have been reported following discontinuation of XANAX treatment in patients with post -traumatic from stress.

Post-marketing experience

Several adverse drug reactions have been reported in association with the use of immediate release XANAX since marketing. Due to the spontaneous nature of the reporting of events and the lack of controls, a causal relationship with the use of XANAX immediate release cannot be easily established. In general, the safety profile of XANAX prolonged-release tablets is similar to that immediate-release XANAX Events reported include: elevated liver enzyme levels, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinaemia, gynaecomastia and galactorrhea.

Withdrawal symptoms

Withdrawal symptoms similar to those seen with sedatives / hypnotics and alcohol occurred after discontinuation of benzodiazepines, including alprazolam. Symptoms can range from mild dysphoria and insomnia to more severe symptoms which can include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. It is not always easy to distinguish between new signs and symptoms of discontinuation and disease recurrence in patients undergoing dose reduction. The long-term strategy for treating these phenomena will vary according to their cause and therapeutic goal. If necessary, immediate control of withdrawal symptoms requires resuming treatment at doses of alprazolam sufficient to eliminate symptoms. Failure of other benzodiazepines to completely suppress these withdrawal symptoms has been reported. These failures have been attributed to "incomplete cross tolerance, but may reflect the use of an inadequate dosage regimen of substituted benzodiazepines or the effects of concomitant medications (see "Special Warnings" 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 through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on 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 refers to the product in intact packaging, correctly stored.

This medicinal product does not require any special storage conditions.

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.

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.

More information about Xanax can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other Forms of interaction04.6 Pregnancy and lactation Pregnancy04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE DE THE FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIATION DRUGS, FURTHER DETAILED INSTRUCTIONS ON QUALITY PREPARATION

01.0 NAME OF THE MEDICINAL PRODUCT

XANAX EXTENDED RELEASE TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

XANAX 0.5 mg prolonged-release tablets: each tablet contains: alprazolam 0.5 mg.

XANAX 1 mg prolonged release tablets: each tablet contains: alprazolam 1 mg.

XANAX 2 mg prolonged-release tablets: each tablet contains: 2 mg alprazolam.

XANAX 3 mg prolonged release tablets: each tablet contains: 3 mg alprazolam.

Excipient with known effect: lactose

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Prolonged-release tablets

XANAX 0.5 mg prolonged-release tablets: Round, blue, convex tablets with "P&U 57" written on one side.

XANAX 1 mg prolonged-release tablets: Round, white, convex tablets with "P&U 59" on one side.

XANAX 2 mg prolonged-release tablets: pentagonal, blue tablets with "P&U 66" on one side.

XANAX 3 mg prolonged-release tablets: Triangular, white tablets with "P&U 68" on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

XANAX prolonged-release tablets are indicated for the treatment of panic disorder with or without agoraphobia.

Benzodiazepines are only indicated when the disorder is severe, disabling, or makes the subject very uncomfortable.

04.2 Posology and method of administration

XANAX prolonged-release tablets should be administered once daily, preferably in the morning. The tablets must be taken whole; they must not be chewed and must not be crushed or divided.

The optimal dosage of XANAX prolonged-release tablets should be individualized according to the severity of symptoms and the patient's subjective response.

The recommended daily dosage is 3-6 mg / day.

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 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.

Posology in special patient populations

Pediatric use

The safety and efficacy of alprazolam have not been established in children and adolescents under the age of 18, therefore the use of alprazolam has not been established. recommended.

Use in elderly patients

Elderly patients may be more sensitive to the effects of benzodiazepines. Higher plasma concentrations of alprazolam are seen in these patients than in the younger population taking the same drug doses; this is due to the reduced clearance of the drug. In elderly patients, the use of the lowest effective dose of alprazolam is recommended to avoid the onset of ataxia and the possibility of excessive sedation (see Section 5.2 Pharmacokinetic Properties). A lower dosage is also recommended in patients with chronic respiratory failure. avoid the risk of respiratory depression.

In patients with advanced hepatic insufficiency or in patients with debilitating disease, the usual starting dose of XANAX prolonged-release tablets is 0.5 mg / day. This dosage can be gradually increased if necessary and tolerated by the patient (see Dosage adjustment).

Dosage adjustment

Treatment with XANAX prolonged-release tablets should be started with a dose of 0.5 mg -1 mg once daily. Based on the patient's clinical response, the dose can be increased at intervals of 3-4 days up to a maximum of 1 mg / day. A slower dose adjustment is possible to allow for the full manifestation of the pharmacodynamic effect of XANAX prolonged-release tablets. Generally, therapy should be started at a low dose to minimize the risk of adverse reactions in particularly drug sensitive patients. The dose must be increased until an acceptable therapeutic response is obtained (ie a substantial reduction or total elimination of panic attacks), until the onset of intolerance phenomena or until the maximum recommended dose is reached.

Maintaining the dosage

Doses in the range of 1 to 10 mg / day have been used in controlled trials conducted to establish the efficacy of XANAX prolonged-release tablets in panic disorder. Most patients have shown that the treatment is effective at doses of 3-6 mg / day. Occasionally some patients have required a maximum of 10 mg / day to achieve a satisfactory response.

The efficacy of XANAX prolonged-release tablets for longer periods has not been systematically evaluated beyond 8 weeks. The required duration of treatment for panic disorder patients responding to XANAX prolonged-release tablets is not known. However, periodic checks are recommended. After a prolonged period of absence of panic attacks, a gradual withdrawal of the drug under strict control may be tried, but it has been shown that this can often be difficult to achieve without recurring and / or occurring suspension phenomena.

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).

Switching from XANAX immediate-release tablets to Xanax prolonged-release tablets.

Patients who are already being treated with split doses of XANAX standard formulation, e.g. 3-4 times a day, may be switched to XANAX prolonged-release tablets at the same total daily dose taken once a day. If the therapeutic response is inadequate, the dosage can be modified as described above.

04.3 Contraindications

XANAX prolonged-release tablets are contraindicated in patients with known hypersensitivity to benzodiazepines, alprazolam or 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.

It is also contraindicated in patients with:

• Severe respiratory failure.

• Severe hepatic insufficiency.

• Myasthenia gravis.

• Sleep apnea syndrome.

XANAX prolonged-release tablets are contraindicated in the first trimester of pregnancy and during lactation.

04.4 Special warnings and appropriate precautions for use

Specific groups of patients

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.

The usual precautions are recommended when treating patients with impaired renal function and mild or moderate hepatic insufficiency.

In elderly and / or debilitated patients it is recommended to always use the lowest dose to avoid the risk of residual sedation or ataxia. 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).

A concomitant depressive disorder (primary or secondary) is associated with panic attack disorder with increased cases of suicide in untreated patients. Therefore the same precaution should be taken both when using the higher doses of XANAX 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 not be used alone to treat severe depression or anxiety associated with depression (suicide can be precipitated in such patients).

As with other psychotropic drugs, alprazolam in severely depressed or suicidal patients should be administered with due precautions and prescribed in appropriate packaging.

Tolerance

Some loss of the hypnotic effect of benzodiazepines may develop after repeated use for a few weeks.

Addiction and withdrawal reactions

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. Certain adverse events, some of which may be life-threatening, are a direct consequence of physical dependence on alprazolam. These include a set of withdrawal symptoms, the most significant of which is epileptic seizure. Addiction can occur at therapeutic doses and / or in patients with no individual risk factors. The risk of addiction increases with concomitant use of various benzodiazepines regardless of anxiolytic or hypnotic indication. Cases of abuse have also been reported.

Some patients have found it very difficult to gradually taper off and discontinue alprazolam therapy, especially those taking higher doses for long periods. Even after relatively short-term use of alcohol and drug abuse doses. People at risk of addiction should be closely monitored during treatment with alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those individuals which are under the direct supervision of the physician (See section 4.8 Undesirable effects).

Following a rapid decrease or abrupt discontinuation of benzodiazepine therapy including alprazolam, withdrawal symptoms have occurred. The latter can range from mild dysphoria, insomnia, headache, extreme anxiety, tension, restlessness, confusion, irritability to more severe symptoms which may include derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or seizures, 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).

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. 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 upon discontinuation of the drug.

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.

Amnesia

Benzodiazepines can induce anterograde amnesia. This most often occurs 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, delirium, 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.

Use in patients with concomitant diseases

In elderly patients, the use of the lowest effective dose is recommended to avoid the onset of ataxia or excessive sedation, as they may present a problem in elderly and debilitated patients. Likewise, 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 hepatic and / or renal function. In patients with severe hepatic insufficiency, benzodiazepines are not indicated as they can precipitate encephalopathy (see section 4.2 Posology and method of administration).

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 can precipitate in such patients).

XANAX prolonged-release tablets should not be used in patients with psychomotor difficulties; in patients suffering from endogenous depression, bipolar or with psychotic symptoms.

The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected effects from interaction.

Epileptic fits

Patients, particularly those with a history of seizures or epilepsy, should not abruptly stop taking alprazolam. It is recommended that all patients on alprazolam who require dose reduction gradually decrease their dosage under close supervision. doctor.

Status epilepticus

Withdrawal seizures have been reported following discontinuation of alprazolam. A single epileptic episode occurred in most cases, however multiple seizures and seizures were also reported.

Risk associated with dose reduction

Withdrawal reactions may occur when there is a reduction in dosage. For this reason, the dose of XANAX prolonged-release tablets should be gradually reduced or discontinued.

Suicide

Panic disorder has been associated with primary and secondary major depressive disorders and an increase in suicide cases among untreated patients.

As with other psychotropic drugs in severely depressed patients or those in whom the risk of suicidal ideation or suicide planning can be assumed, standard precautions should be taken when administering high doses of alprazolam in patients with panic attacks. in the number of prescriptions.

Mania

Episodes of hypomania and mania associated with the use of alprazolam have been reported in depressed subjects.

Uricosuric effect

Alprazolam has a weak uricosuric effect. Although other drugs with a weak uricosuric effect have been shown to cause acute renal failure, no cases of acute renal failure have been reported to be attributed to alprazolam therapy.

Azole antifungal agents

Ketoconazole and itraconazole are potent inhibitors of CYP3A which may increase the plasma concentrations of alprazolam. Concomitant administration of alprazolam and ketoconazole, itraconazole or other azole-type antifungals is not recommended (see Section 4.5 - Interactions with other medicinal products and other forms of interaction).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

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.

Particular attention, especially in elderly patients, should be used with respiratory depressant drugs such as opioids (analgesics, cough suppressants, replacement treatments).

Association with CNS depressants: The central depressive effect may be enhanced by concomitant use with anti-psychotics (neuroleptics), hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics, and antihistamines-H1 sedatives.

Molecules that inhibit certain liver enzymes (especially cytochrome P4503A4) can increase the plasma concentration of alprazolam and enhance its activity.

Pharmacokinetic interactions can occur when alprazolam is co-administered with drugs that interfere with its metabolism.

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.

Drug-drug interactions

The first step in the metabolism of alprazolam is hydroxylation catalyzed by citrocomo P450 3A (CYP3A).Drugs that inhibit this metabolic process can have a noticeable effect on the clearance of alprazolam. Consequently, the administration of alprazolam should be avoided in patients treated with very strong CYP3A inhibitors. Alprazolam should be used with CYP3A inhibitors, with lower but still significant potency, paying attention and calculating an appropriate dose reduction. For some drugs, interactions with alprazolam have been quantified through clinical studies; for other drugs, interactions are predicted based on in vitro studies and / or experience with similar drugs of the same drug class.

Compounds that are potent inhibitors of CYP3A are expected to increase the plasma concentrations of alprazolam. The drugs that have been studied in vivo for the ability to increase the area under the curve (AUC) of alprazolam are as follows: ketoconazole, 3.98-fold; itraconazole, 2.70-fold; nefazodone, 1.98-fold; fluvoxamine, 1.96-fold and erythromycin 1 , 61 times. Inducers of CYP3A are expected to decrease alprazolam concentrations and this has actually been observed in vivo. Oral clearance of alprazolam (taken as a single dose of 0.8 mg) increased 2.40-fold after administration of carbamazepine 300 mg / day for 10 days. Most of the interactions that have been documented with alprazolam relate to drugs that inhibit or induce CYP3A4 (for the use of other drugs of this type see Section 4.4 - Special warnings and precautions for use).

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.

Potent CYP3A inhibitors

Examples of drugs known to be inhibitors of the metabolism of alprazolam and / or related benzodiazepines, presumably by inhibition of CYP3A, are given below.

Azole antifungal agents - ketoconazole and itraconazole are potent inhibitors of CYP3A and have shown in vivo the ability 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 (see section 4.4 - Special warnings and precautions for use).

Drugs capable of inhibiting CYP3A based on clinical studies with alprazolam (caution and consideration of appropriate dose reduction of alprazolam during concomitant administration of the following drugs is advised):

Nefazodone - Concomitant intake of nefazodone increases the concentration of alprazolam twice.

Fluvoxamine - Concomitant intake of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71% and reduced psychomotor performance.

Cimetidine - Concomitant intake of cimetidine increased the maximum plasma concentration of alprazolam by 86%, reduced clearance by 42% and increased the half-life by 16%.

Fluoxetine - Concomitant intake of fluoxetine increased the maximum plasma concentration of alprazolam by 46%, reduced clearance by 21%, increased the half-life by 17% and reduced psychomotor performance.

Propoxyphene - Concomitant intake of propoxyphene increased the maximum plasma concentration of alprazolam by 6%, reduced clearance by 38% and increased the half-life by 58%.

Oral contraceptives - Concomitant oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, reduced clearance by 22% and increased the half-life by 29%.

Co-administration of diltiazem with alprazolam is not recommended.

CYP3A inducers

Carbamazepine - Oral clearance of alprazolam (taken as a single dose of 0.8 mg) increased from 0.90 ± 0.21 mL / min / kg to 2.13 ± 0.54 mL / min / kg and the half-life decreased (from 17.1 ± 4.9 to 7.7 ± 1.7 h) after taking 300 mg / day of carbamazepine for 10 days. The dose of carbamazepine used in this study was also quite low compared to at recommended doses (1000-1200 mg / day); the effect observed with usual doses of carbamazepine is unknown.

Use with other CNS inhibitors

If alprazolam is taken together with other psychotropic agents or anticonvulsant drugs, particular attention is advised to the pharmacology of the agents used, especially for those compounds that may potentiate the action of benzodiazepines. Benzodiazepines, including alprazolam, produce additional inhibitory effects charged to the CNS when taken together with other psychotropic drugs, anticonvulsants, anithistamines, alcohol and other drugs that themselves induce CNS inhibition.

Use with imipramine and desipramine

It has been shown that plasma concentrations at steady-state of imipramine and desipramine increase on average by 31% and 20%, respectively, when taken together with immediate-release XANAX in doses above 4 mg / day. The clinical significance of these variations is unknown.

Interactions between HIV protease inhibitors (eg ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir cause decreased clearance of alprazolam, prolong its elimination half-life, and increase clinical effects. following prolonged exposure to ritonavir, induction of CYP3A compensates for this inhibition.

This interaction will require a dose adjustment or "discontinuation of XANAX treatment."

Interactions with laboratory tests

Although interactions between benzodiazepines and commonly used laboratory tests have been reported occasionally, there are no specific references for a particular drug or test.

04.6 Pregnancy and breastfeeding

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 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. Infants exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit 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, 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.

Due to the potential risk of congenital malformations already seen with other benzodiazepines, XANAX prolonged-release tablets should not be administered in the first trimester of pregnancy.

If the product is prescribed to a woman of childbearing age, either if she intends to become pregnant or if she suspects she is pregnant, she should contact her doctor for advice on discontinuing the drug.

If XANAX is administered during pregnancy or if the patient discovers that she is pregnant during treatment with XANAX, 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 dosage are strictly respected.

Pregnancy

Since benzodiazepines are excreted in breast milk, they should not be given to breastfeeding mothers.

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, since impaired attention and reflexes following the drug intake cannot be ruled out, patients under treatment should be warned that it may be dangerous for them to engage in activities that require complete mental attention, such as working on dangerous machinery or driving cars.

04.8 Undesirable effects

Any side effects of XANAX are usually seen at the start of treatment and usually resolve with continued therapy or reduced doses.

The following information on undesirable effects is based on pooled data from placebo-controlled clinical trials of 5, 6 and 8 weeks duration conducted with XANAX prolonged-release tablets in panic disorder.

The following undesirable effects have been observed and reported during treatment with alprazolam with the following frequencies: very common (≥ 1/10), common (≥ 1/100,

MedDRA Organ-systemic class Very common (≥ 1/10) Common (≥ 1/100, Uncommon (≥ 1 / 1,000 a Rare (≥ 1/10, 000 y Very rare Not known (cannot be estimated from the available data) Endocrine pathologies Hyperprolactinemia * Metabolism and nutrition disorders Decreased appetite Psychiatric disorders Depression Confusional state, disorientation, decreased libido, anxiety, insomnia, nervousness, increased libido *, irritability. Mania * (see section 4.4 Special warnings and precautions for use), hallucination *, agitation *, anger *, anhedonia, anorgasmia, bradyphrenia, depressive state, derealization, disinhibition, euphoric state, fear, loss of libido, mania, disturbance behavior, nightmares, panic disorder, psychomotor slowdown, sleep disturbances. Hypomania *, aggression *, hostile behavior *, abnormal thoughts *, psychomotor hyperactivity * Nervous system disorders Sedation, somnolence, ataxia, memory impairment, dysarthria, dizziness, headache Impaired balance, coordination problems, attention disturbance, hypersomnia, lethargy, tremor, dizziness, slurred speech, difficulty concentrating Amnesia, clumsiness, convulsions, dysgeusia, abnormal gait, accelerated gait, increased activity, partial seizures, headache, stupor. Autonomic nervous system imbalance *, dystonia * Eye disorders Blurred vision Ear and labyrinth disorders Tinnitus Cardiac pathologies Palpitations Vascular pathologies Flushes Respiratory, thoracic and mediastinal disorders Choking, respiratory distress Gastrointestinal disorders Constipation, dry mouth Nausea Abdominal pain, diarrhea, stomach pain, vomiting, necrotizing enterocolitis Gastrointestinal disease * Hepatobiliary disorders Hepatitis *, liver function abnormalities *, jaundice * Skin and subcutaneous tissue disorders Dermatitis * Increased susceptibility to bruising, rash, increased sweating, itching Angioedema *, photosensitivity reactions * Musculoskeletal and connective tissue disorders Muscle weakness, arthralgia, back problems, muscle cramps, myalgia, pain in the limbs Renal and urinary disorders Incontinence *, enuresis, frequent urination Urinary retention * Diseases of the reproductive system and breast Sexual dysfunction * Menstrual cycle irregularities *, ejaculation disorders, erectile dysfunction, menstrual delay General disorders and administration site conditions Fatigue, irritability Chest pain, altered sensation, drunkenness, nervousness, feeling of relaxation, confusion, flu syndrome, foreign body sensation, sluggishness, thirst, weakness. Peripheral edema * Injury, poisoning and procedural complications Falls, limb injuries, overdose, traffic accidents Diagnostic tests Weight reduction, weight gain Increased blood bilirubin Increased intraocular pressure *

* Undesirable effects identified post-marketing

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 precautions for use). 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 Previous history of aggressive or violent behavior, or abusing alcohol or other substances, may be at risk for such events. Reactions of irritability, hostility and invasive thoughts have been reported following discontinuation of XANAX treatment in patients with post -traumatic from stress.

Post-marketing experience

Several adverse drug reactions have been reported in association with the use of immediate release XANAX since marketing. Due to the spontaneous nature of the reporting of events and the lack of controls, a causal relationship with the use of XANAX immediate release cannot be easily established. In general, the safety profile of XANAX prolonged-release tablets is similar to that immediate-release XANAX Events reported include: elevated liver enzyme levels, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinaemia, gynaecomastia and galactorrhea.

Withdrawal symptoms

Withdrawal symptoms similar to those seen with sedatives / hypnotics and alcohol occurred after discontinuation of benzodiazepines, including alprazolam. Symptoms can range from mild dysphoria and insomnia to more severe symptoms which can include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. It is not always easy to distinguish between new signs and symptoms of discontinuation and disease recurrence in patients undergoing dose reduction. The long-term strategy for treating these phenomena will vary according to their cause and therapeutic goal. If necessary, immediate control of withdrawal symptoms requires resuming treatment at doses of alprazolam sufficient to eliminate symptoms. Failure of other benzodiazepines to completely suppress these withdrawal symptoms has been reported. These failures have been attributed to "incomplete cross tolerance, but may reflect the use of an inadequate dosage regimen of substituted benzodiazepines or the effects of concomitant medications (see Section 4.4 - Special warnings and precautions for use).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at: "www.agenziafarmaco.gov.it/it/responsabili".

04.9 Overdose

Clinical experience

Manifestations of alprazolam overdose include somnolence, dysarthria, impaired coordination, coma, and respiratory depression. As with other benzodiazepines, deaths have been reported in association with alprazolam overdose alone.In addition, accidental deaths have been reported in patients who overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; the alcohol rates seen in some of these patients were lower than those generally associated with alcohol-induced accidental death.

General treatment of overdose

Treatment in cases of overdose is primarily to support respiratory and cardiovascular functions.

As in all overdose cases, breathing, pulse rate and blood pressure should be monitored. Following an overdose of oral benzodiazepines, general supportive treatments should be employed; vomiting should be induced (within one "hour) if patient is conscious or gastric lavage with respiratory protection undertaken if patient is unconscious. If no improvement is observed with stomach emptying, activated charcoal should be given to reduce absorption. Fluids should be administered intravenously and a patent airway maintained. If hypotension occurs, this can be counteracted by the use of vasopressors. Dialysis is of limited support.

As with the treatment of intentional overdose with other drugs, it should be noted that multiple agents may have been ingested. Benzodiazepine overdose usually results in 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, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial nullification of the sedative effects of benzodiazepines and can be used if a benzodiazepine overdose is known or suspected . Flumazenil additionally may be used in the management of respiratory and cardiovascular function associated with overdose.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Benzodiazepine derivatives, ATC code: N05BA12

XANAX prolonged-release tablets contain alprazolam, a triazole analog of the benzodiazepine class 1.4 of the CNS-acting compounds.

CNS-acting agents of benzodiazepine class 1,4 presumably exert their effects by binding to stereospecific receptors present at various sites of the central nervous system. The exact mechanism of action is not known. From a clinical point of view, all benzodiazepines cause a dose-related depressive activity of the central nervous system ranging from moderate impairment of performance to hypnosis.

05.2 Pharmacokinetic properties

Absorption

The mean absolute bioavailability of aprazolam contained in XANAX prolonged-release tablets is approximately 90% and the relative bioavailability compared to immediate-release XANAX is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of XANAX prolonged-release tablets are similar to those of XANAX immediate-release, except for a slower absorption rate. The slower rate of absorption results in a relatively constant plasma concentration which is maintained between 5 and 11 hours after administration. The pharmacokinetics of alprazolam and two of the major active metabolites (4-hydroxialprazolam and a-hydroxialprazolam) are linear and plasma concentrations are proportional up to a daily dose of 10 mg once daily. Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and prolonged-release formulations.

Food significantly affects the bioavailability of XANAX prolonged-release tablets. A high-fat meal up to 2 hours prior to administration of XANAX Retard increased the mean Cmax by approximately 25%. The effect of the meal on Tmax depended on the time of day the meal was taken, with a reduction in Tmax of about 1/3 for subjects who ate the meal immediately before taking the drug and an increase in Tmax of about 1/3 for subjects who took a meal one hour before or after taking the drug. The extent of exposure (AUC) and the elimination half-life (t ½) are not affected by meals.

Significant differences in the rate of absorption of prolonged-release alprazolam were observed in relation to the time of day the drug was taken, with a 30% increase in Cmax and a 1-hour decrease in Tmax when the drug was taken. was taken in the evening, compared to when it was taken in the morning.

Distribution

Alprazolam in vitro it binds (80%) to human serum proteins. Serum albumin accounts for most of the binding.

Metabolism

Alprazolam is extensively metabolised in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in plasma: 4-hydroxialprazolam and a-hydroxialprazolam. In humans, an alprazolam-derived benzophenone is also detected. metabolites is similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxialprazolam and a-hydroxialprazolam) are similar for the standard formulation of alprazolam and for the prolonged release, indicating that the metabolism of alprazolam is not affected by the rate of absorption. 4-hydroxialprazolam and a-hydroxialprazolam relative to the concentrations of unchanged alprazolam are always lower than 10% and 4%. The relative potencies reported in benzodiazepine receptor binding trials and in animal models of induced seizure inhibition are 0.20 and 0.66 for 4-hydroxialprazolam and a-hydroxialprazolam, respectively. Such low concentrations and the lower potencies of 4-hydroxialprazolam and a-hydroxialprazolam suggest that these metabolites are unlikely to contribute significantly to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Elimination

Alprazolam and its metabolites are mainly excreted in the urine. The mean plasma elimination half-life of alprazolam following administration of XANAX prolonged-release tablets ranges from 10.7-15.8 hours in healthy adult subjects.

Special patient populations

While pharmacokinetic studies with XANAX prolonged-release tablets have not been conducted in special patient populations, it is anticipated that factors (such as age, gender, hepatic or renal impairment) that could modify the pharmacokinetics of alprazolam following administration of Alprazolam tablets XANAX immediate release are no different from those found with XANAX prolonged release tablets.

Alterations in the absorption, distribution, metabolism and excretion of benzodiazepines have been observed in various disease states, including alcoholism, impaired liver and kidney function. Alterations have also been observed in elderly patients. In elderly healthy subjects, alterations have also been observed. a "mean half-life of alprazolam of 16.3 hours (range 9.0-26.9 hours, n = 16) compared to 11.0 hours (range 6.5-15.8 hours, n = 16) found in healthy adult subjects. In patients with alcoholism-related liver disease the half-life of alprazolam ranged from 5.8 to 65.3 hours (mean 19.7 hours, n = 17) compared with 6.3 to 26.9 hours ( mean = 11.4 hours, n = 17) in healthy adult subjects. In a group of obese subjects the half-life of alprazolam ranged from 9.9 to 40.4 hours (mean = 21.8 hours, n = 12) compared to the interval found in healthy subjects equal to 6.3-15.8 hours (mean = 10.6 hours, n = 12).

Due to the similarity to other benzodiazepines, it is assumed that alprazolam passes through the placenta and is excreted in breast milk.

Ethnic group to which they belong - the maximum concentrations and the half-life of alprazolam are approximately 15% and 25% higher in subjects of Asian origin than in those of Caucasian origin.

Pediatric patients - The pharmacokinetics of alprazolam following administration of XANAX Retard in pediatric patients have not been studied.

Gender of belonging - Gender has no effect on alprazolam pharmacokinetics.

Cigarette smoke - Alprazolam concentrations can be reduced by up to 50% in smokers compared to non-smokers.

05.3 Preclinical safety data

Carcinogenesis, Mutagenesis, Impaired fertility and effects on the eyes

No evidence of carcinogenic potential was found during 2-year biological assays 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 treated mice. with doses 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 correspond 500 times the human dose of 10 mg / day.

Alprazolam showed no mutagenic effects in vitro in the DNA Damage / Alkaline Elution Test or in the Ames test.

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.

Other Animal Studies

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 did not appear until 11 months after the start of treatment.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Lactose, hypromellose, colloidal anhydrous silica, magnesium stearate.

The 0.5 and 2 mg tablets also contain Indigo carmine (E132)

06.2 Incompatibility

Not relevant.

06.3 Period of validity

2 years.

06.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package

XANAX 0.5 mg prolonged release tablets: packs of 20, 30, 40, 60, 100 tablets

XANAX 1 mg prolonged-release tablets: packs of 2, 10, 20, 30, 40, 60, 100 tablets

XANAX 2 mg prolonged-release tablets: packs of 10, 20, 30, 60, 100 tablets

XANAX 3 mg prolonged-release tablets: packs of 10, 20, 30, 40, 100 tablets

Alprazolam prolonged-release tablets are packaged in aluminum / PA blisters

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Pfizer Italia S.r.l. - Via Isonzo, 71 - 04100 Latina

08.0 MARKETING AUTHORIZATION NUMBER

Xanax 0.5 mg prolonged-release tablets - 20 tablets AIC n. 025980133

Xanax 0.5 mg prolonged release tablets - 30 tablets AIC n. 025980145

Xanax 0.5 mg prolonged release tablets - 40 tablets AIC n. 025980158

Xanax 0.5 mg prolonged-release tablets - 60 tablets AIC n. 025980160

Xanax 0.5 mg prolonged-release tablets - 100 tablets AIC n. 025980172

Xanax 1 mg prolonged release tablets - 2 tablets AIC n. 025980184

Xanax 1 mg prolonged-release tablets - 10 tablets AIC n. 025980196

Xanax 1 mg prolonged release tablets - 20 tablets AIC n. 025980208

Xanax 1 mg prolonged-release tablets - 30 tablets AIC n. 025980210

Xanax 1 mg prolonged-release tablets - 40 tablets AIC n. 025980222

Xanax 1 mg prolonged-release tablets - 60 tablets AIC n. 025980234

Xanax 1 mg prolonged release tablets - 100 tablets AIC n. 025980246

Xanax 2 mg prolonged-release tablets - 10 tablets AIC n. 025980259

Xanax 2 mg prolonged release tablets - 20 tablets AIC n. 025980261

Xanax 2 mg prolonged-release tablets - 30 tablets AIC n. 025980273

Xanax 2 mg prolonged release tablets - 60 tablets AIC n. 025980285

Xanax 2 mg prolonged-release tablets - 100 tablets AIC n. 025980297

Xanax 3 mg prolonged release tablets - 10 tablets AIC n. 025980309

Xanax 3 mg prolonged release tablets - 20 tablets AIC n. 025980311

Xanax 3 mg prolonged release tablets - 30 tablets AIC n. 025980323

Xanax 3 mg prolonged release tablets - 40 tablets AIC n. 025980335

Xanax 3 mg prolonged release tablets - 100 tablets AIC n. 025980347

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

May 27, 2009

10.0 DATE OF REVISION OF THE TEXT

July 15, 2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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