XANAX is indicated for short-term symptomatic treatment of anxiety in adults.

XANAX is only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

Duration of treatment

XANAX should be used in the lowest possible effective dose, for the shortest possible time and for a maximum of 2-4 weeks. The need for continued treatment should be reassessed frequently. Long-term treatment is not recommended. The risk of dependence may increase with dose and duration of treatment (see section 4.4).

Posology

XANAX divisible tablets: The optimum dosage should be determined individually based on the severity of the symptoms and individual patient response. In the event of severe adverse effects with the initial dose, a dose reduction is necessary.

In the few patients who require a higher dose, the dosage should be increased gradually, starting with a higher dose in the evening, to avoid adverse effects. In general, patients who have not previously taken psychotropic agents will require a lower dose compared to those who have previously been treated with tranquillizers, antidepressants or hypnotics or compared to chronic alcoholics.

In order to prevent ataxia and oversedation, it is advisable to use the lowest effective dose. This is particularly important in elderly and/or debilitated patients.

Paediatric population

Safety and efficacy of alprazolam in children and adolescents below the age of 18 years have not been established; therefore use of alprazolam is not recommended.

SYMPTOMATIC TREATMENT OF ANXIETY

XANAX Tablets

Usual starting dose: varies from 0.25 mg to 0.5 mg three times daily.

Usual dose: The dose can be increased to suit the patient’s needs to a maximal daily dose of 4 mg divided over multiple administrations.

TREATMENT OF GERIATRIC OR DEBILITATED PATIENTS

XANAX tablets

Usual starting dose: 0.25 mg twice to three times daily.

Usual dose: If necessary, the dose can be increased gradually depending on tolerance.

The starting dose should be reduced if side-effects occur.

DISCONTINUATION OF TREATMENT

Since the treatment is symptomatic, the original symptoms may recur after discontinuation of treatment.

The dose must be gradually reduced to avoid withdrawal symptoms. The patient should be re-assessed regularly and the need to prolong treatment should be evaluated, certainly when the patient’s symptoms are milder and might not require medicinal treatment. The general period of treatment should not exceed 2 to 4 weeks

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including XANAX, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe XANAX concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of XANAX than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking XANAX, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when XANAX is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions].

Duration of treatment

The duration of treatment should be as short as possible and not more than 2-4 weeks (see section 4.2). An extension of the treatment time beyond this must not be made without a reassessment of the situation.

It may be appropriate to inform the patient on initiation of treatment that the treatment is time-limited and to explain exactly how the dosage will be gradually decreased. There is evidence to suggest that withdrawal symptoms may occur within the dosage interval when using short-acting benzodiazepines, especially at high doses. When long-acting benzodiazepines are used it is important to inform the patient that he/she should not change to a short-acting benzodiazepine, as withdrawal symptoms may then develop.

Dependence

Addiction and physical and psychic dependence can occur with the use of benzodiazepines, including alprazolam. The risk of dependence increases with dose and duration of treatment; this risk is also greater in patients with a history of alcohol or drug abuse. Pharmacodependency may occur at therapeutic doses and/or in patients with no individualised risk factor. There is an increased risk of pharmacodependency with the combined use of several benzodiazepines regardless of the anxiolytic or hypnotic indication. Cases of abuse have also been reported.

Withdrawal symptoms

Once dependence has developed, rapid tapering off or abrupt discontinuation of benzodiazepines, including alprazolam, can result in undesirable effects such as rebound phenomena or withdrawal symptoms (see section 4.8).  These symptoms appear under the form of headaches, muscle pain, extreme anxiety, tension, agitation, confusion, irritability and insomnia.  In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. These signs and symptoms, and the more severe forms in particular, are generally observed most frequently in patients after long-term treatment with excessive doses. However, withdrawal symptoms have also been reported after abrupt discontinuation of therapeutic doses of benzodiazepines.

During discontinuation of treatment, the dosage should be reduced therefore slowly in keeping with good medical practice (see section 4.2 Posology and method of administration – Discontinuation of treatment), particularly in epileptic patients.

Amnesia

Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product.

Psychiatric and paradoxical reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural effects are known to occur when using benzodiazepines (see section 4.8). Should this occur, use of alprazolam should be discontinued. These reactions are more likely to occur in children and elderly.

Tolerance

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

Tolerance or dose increase are rarely observed with alprazolam, but can occur. Tolerance has been demonstrated for the sedative action, but not for the anxiolytic effect of alprazolam.

Elderly patients

Benzodiazepines and related products should be used with caution in elderly, due to the risk of sedation and/or musculoskeletal weakness that can promote falls, often with serious consequences in this population.

In geriatric and debilitated patients it is advisable to use the lowest effective dose to prevent ataxia or oversedation.

In patients with impaired renal or hepatic function the usual precautions should be taken.

Safety and efficacy of alprazolam in children and adolescents below the age of 18 years have not been established; therefore use of alprazolam is not recommended.

Suitable precautions should be taken in patients with acute closed angle glaucoma.

Benzodiazepines and benzodiazepine-like agents should not be prescribed alone to treat depression as they may precipitate or increase the risk of suicide. Therefore XANAX should be used with caution and the prescription size should be limited in patients with signs and symptoms of a depressive disorder or suicidal tendencies. Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see 4.5 Interaction with other medicinal products and other forms of interactions).

Lactose: the tablets and prolonged-release tablets contain lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption (rare hereditary problems) should not take this medicine.

Benzodiazepines, including alprazolam, have an additive depressant effect on the central nervous system (CNS) when used in combination with other psychotropic agents, anticonvulsives, antihistaminics, alcohol and other agents with an effect on the CNS.

Concomitant intake with alcohol is not recommended. Alprazolam should be used with caution when combined with CNS depressants. Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic products, anesthetics and sedative antihistamines. In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

No effects on prothrombin time and warfarin plasma levels have been observed.

Increased digoxin concentrations have been reported when alprazolam was given, especially in elderly (>65 years of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.

Pharmacokinetic interactions can occur when alprazolam is administered in combination with drugs that interfere with its metabolism.

CYP3A4 inhibitors

Drugs that inhibit certain hepatic enzymes (in particular the cytochrome P450 3A4 enzyme system) can increase the concentration of alprazolam and potentiate its effect. Data from clinical studies with alprazolam, in vitro studies with alprazolam, and clinical studies with drugs metabolized similarly to alprazolam provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs. Based on the degree of interaction and the type of data available, the following recommendations are made:

·         Combined use with ketoconazole, itraconazole or other azole-like antifungal agents is not recommended.

·         Caution and possibly a dose reduction are recommended in case of combined use with nefazodon, fluvoxamine and cimetidine.

·         Caution is required in the event of combined use with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem or macrolide antibiotics such as erythromycin and clarithromycine.

CYP3A4 Inducers

Since alprazolam is metabolized by CYP3A4, inducers of this enzyme (e.g, carbamazepine, phenobarbital, phenytoin, rifampicin and St John’s Wort) could cause decreased effect of alprazolam

Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are complex and time dependent. Short term, low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-reduction or discontinuation of alprazolam treatment.

Mean increases of respectively 31 % and 20 % of the steady-state plasma levels of imipramine and desipramine have been reported during concurrent administration of XANAX up to 4 mg daily. The clinical significance of these changes has not yet been established.

Interactions with isoniazide or rifampicin have not been evaluated.

No changes in alprazolam kinetics have been noted during concurrent administration of propranolol or disulfiram.

Although it has never been described with alprazolam, there is an increased risk of psychosis when benzodiazepines are used in combination with valproic acid.

Theophyllin antagonizes the effect of benzodiazepines

Pregnancy

Alprazolam should not be used during pregnancy unless the clinical condition of the woman requires treatment with alprazolam. If alprazolam is used during pregnancy, or the patient becomes pregnant while taking alprazolam, the patient should be apprised of the potential hazard to the fetus.

When alprazolam is prescribed to a woman of childbearing age, she should be warned to notify her physician if she wishes to become pregnant or if she is pregnant, so the physician can decide to discontinue treatment.

Benzodiazepines pass the foetoplacental barrier. Children of patients who have taken benzodiazepines during pregnancy may present malformations. This has not been quantified for alprazolam.

Benzodiazepine treatment at high dose, during the second and/or the third trimester of pregnancy, has revealed a decrease of fetal active movements and a variability of fetal cardiac rhythm.

When the product is administered for medical reasons during the last phase of pregnancy or during delivery, hypothermia, axial hypotonia, sucking troubles leading to a poor weight gain may be observed. At high doses, respiratory depression or apnea and hypothermia may appear in the newborn. These signs are reversible but they may last from 1 up to 3 weeks, according to the half life of the product. Since infants whose mother took benzodiapines chronically during pregnancy may have developed physical dependence, withdrawal symptoms can occur in the postnatal development. They result in hyperexcitability, agitation and tremor observed a few days after birth. The apparition of withdrawal symptoms after birth depends on the half life of the substance.

The data concerning teratogenicity and effects on postnatal development and behavior following benzodiazepine treatment are inconsistent. A large amount of data based on cohort studies indicate that first trimester exposure to benzodiazepines is not associated with an increase in the risk of major malformation. However, some early case-control epidemiological studies have found a twofold increased risk of oral clefts.

If alprazolam treatment is necessary during the last part of pregnancy, high doses should be avoided and withdrawal symptoms and/or floppy infant syndrome should be monitored in newborn,

Breast-feeding

Alprazolam is excreted in breast milk. A risk for newborns/infants cannot be excluded. Although the use of benzodiazepines is not recommended during lactation, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from alprazolam therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman please refer to Section 4.4 for information on the discontinuation of alprazolam therapy.

Fertility

Alprazolam did not impair fertility in rats up to the highest dose tested of 5 mg/kg (Human Equivalent Dose of 0.8 mg/kg), about 5 times the maximum recommended daily human exposure (see section 5.3 Preclinical Safety Data)

As with other substances that act on the central nervous system, patients receiving treatment with XANAX should be warned not to drive a vehicle or operate dangerous machinery until it has been established that they do not become impaired while receiving the drug. For the same reason these patients should be warned not to combine the use of alcohol and CNS depressants during treatment with XANAX.

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see section 4.5 Interaction with other medicinal products and other forms of interactions).

The most annoying adverse effects of XANAX are due to an extension of the pharmacological activity of alprazolam.

Whether or not certain undesirable effects occur depends totally on the patient’s individual sensitivity and the dose administered. Potential adverse effects are usually observed at the start of treatment and usually disappear when the treatment is continued or when the dose is reduced.

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10000) and not known (cannot be estimated from available data).

Undesirable effects associated with alprazolam therapy in patients participating in controlled clinical studies and with post-marketing experience are as follows:

Symptoms of XANAX overdosage is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Although a benzodiazepine overdose is not usually life-threatening, it is always necessary to bear in mind the possibility that CNS depressants such as alcohol or barbiturates have been taken and the potential underlying pathology should be considered. In the management of any overdose, it should be borne in mind that other agents may have been taken simultaneously. Treatment should be adapted accordingly and consists mainly in induction of vomiting (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Afterwards, an osmotic laxative can be administered. Special attention should be paid to supporting respiratory and cardiovascular functions in intensive care. In case of coma, treatment is mainly symptomatic, thereby avoiding complications such as asphyxiation due to ptosis of the tongue or aspiration of gastric contents. Intravenous fluid administration is required to prevent dehydration. When other sedatives have been taken in combination, it is of primordial importance to support vital functions. It is known that the effect due to ingestion of a very large dose can persist for a long time. Forced diuresis or haemodialysis is of limited use.

In case of a severe intoxication with coma or respiratory insufficiency, IV administration of flumazenil can be used as an antidote. The use of flumazenil as an antidote is contra-indicated in the following situations:

- Use of tricyclic antidepressants

- Concurrent use of drugs that induce seizures

- ECG anomalies such as a prolonged QRS interval or QT interval (suggestive of concurrent use of tricyclic antidepressants).

Pharmacotherapeutic group: derivatives of benzodiazepines, ATC code: N05B A12.

XANAX contains triazolobenzodiazepine. All benzodiazepines have qualitatively similar properties: anxiolysis, hypnosedation, myorelaxation, anticonvulsion. However, there are quantitative pharmacokinetic differences, which have resulted in various fields of application.

In general it is accepted that the action of benzodiazepines is based upon potentiation of neural inhibition, mediated by gamma-aminobutyric acid.

XANAX tablets

Maximal plasma levels are reached one to two hours after oral administration of XANAX tablets.

ALPRAZOLAM

The half-life of alprazolam is between 12 and 15 hours and is 16 hours on average in elderly patients.

Alprazolam is mainly oxidized. The principal metabolites of alprazolam are alpha-hydroxy-alprazolam and a benzophenone derivative. The plasma levels of these metabolites are extremely low. The biological activity of alpha-hydroxy-alprazolam is about the half of that of alprazolam. Their half-lives are of the same order of magnitude as that of alprazolam.

The benzophenone derivative is almost inactive.

Alprazolam and its metabolites are mainly eliminated via urine.

In vitro, 80 % of alprazolam is bound to serum proteins

Mutagenesis, Carcinogenesis, Fertility, and Ocular Effects

Alprazolam was not mutagenic in the in vitro Ames test.  Alprazolam did not produce chromosomal aberrations in the in vivo micronucleus assay in rats up to the highest dose tested of 100 mg/kg.

No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg (Human Equivalent Dose of 4,8 mg/kg) and in mice at doses up to 10 mg/kg (Human Equivalent Dose of 0,8 mg/kg, values that are about 28 times and 5 times, respectively, the maximum recommended daily human exposure of 10 mg (0,17 mg/kg).

Alprazolam did not impair fertility in rats up to the highest dose tested of 5 mg/kg (Human Equivalent Dose of 0.8 mg/kg), about 5 times the maximum recommended daily human exposure.

When rats were treated orally with alprazolam at 3, 10, and 30 mg/kg (Human Equivalent Dose range of 0,5 mg/kg to 4,8 mg/kg) for 2 years, which is 3 to 28 times the maximum daily human exposure, a tendency for a dose related increase in the number of cataracts (females) and corneal vascularization (males) was observed.  These lesions did not appear until after 11 months of treatment.

During toxicity studies with repeated dosing over 12 months in dogs, seizures appeared with doses of 3 mg/kg (Human Equivalent Dose of 1,7 mg/kg) or more, corresponding to about 10 times the maximum daily human exposure.  Duration and incidence of the seizure episodes were dose-dependent and some of them were fatal.  The significance for humans is not evident.

XANAX 0.25 mg, 0.5 mg and 1 mg tablets

The excipients are: lactose, microcrystalline cellulose, colloidal anhydrous silica, maize starch, magnesium stearate and sodium docusate (85 %) - sodium benzoate (15 %) powder. The tablets with 0.5 mg alprazolam also contain the colouring agent erythrosine aluminium laque (E 127). The tablets with 1 mg also contain the colouring agents erythrosine (E 127) aluminium laque and carmin indigo (E 132).

Not applicable.

Keep out of the sight and reach of children.

Store below 25ºC.

XANAX divisible tablets:

- tablets containing 0.25 mg: 50 tablets

- tablets containing 0.5 mg: 50 tablets

- tablets containing 1.0 mg: 30 tablets

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.