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Xanax Tablets 250 micrograms & 500 micrograms

1. Name Of The Medicinal Product

Xanax® Tablets 250 and 500 micrograms

2. Qualitative And Quantitative Composition

Alprazolam 250 and 500 micrograms

3. Pharmaceutical Form

White, oval, biconvex tablets containing 250 microgram (0.25 mg) alprazolam, scored on one side and marked "Upjohn 29" on the other.

Pink, oval, biconvex tablets containing 500 microgram (0.5 mg) alprazolam, scored on one side and marked "Upjohn 55" on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Xanax is indicated for the short-term treatment of moderate or severe anxiety states and anxiety associated with depression. It is only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

Xanax should not be used to treat short-term mild anxiety, such as anxiety or tension associated with the stress of everyday life. As the efficacy of Xanax in depression and in phobic or obsessional states has yet to be established, specific treatment may have to be considered.

4.2 Posology And Method Of Administration

Treatment should be as short as possible. It is recommended that the patient be reassessed at the end of no longer than 4 weeks' treatment and the need for continued treatment established, especially in case the patient is symptom free. The overall duration of treatment should not be more than 8-12 weeks, including a tapering off process.

In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status with special expertise. As with all benzodiazepines, physicians should be aware that long-term use might lead to dependence in certain patients.

The optimum dosage of Xanax should be based upon the severity of the symptoms and individual patient response. The lowest dose which can control symptoms should be used. Dosage should be reassessed at intervals of no more than 4 weeks. The usual dosage is stated below; in the few patients who require higher doses, the dosage should be increased cautiously to avoid adverse effects. When higher dosage is required, the evening dose should be increased before the daytime doses. In general, patients who have not previously received psychotropic medications will require lower doses than those so treated, or those with a history of chronic alcoholism.

Treatment should always be tapered off gradually. During discontinuation of alprazolam treatment, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction

There is a reduced clearance of the drug and, as with other benzodiazepines, an increased sensitivity to the drug in elderly patients.

Anxiety: 250 micrograms (0.25 mg) to 500 micrograms (0.5 mg) three times daily increasing if required to a total of 3 mg daily.

Geriatric patients or in the presence of debilitating disease: 250 micrograms (0.25 mg) two to three times daily to be gradually increased if needed and tolerated.

Children: Not recommended.

If side-effects occur, the dose should be lowered. It is advisable to review treatment regularly and to discontinue use as soon as possible. Should longer term treatment be necessary, then intermittent treatment may be considered to minimize the risk of dependence.

4.3 Contraindications

Myasthenia gravis Hypersensitivity to benzodiazepines or any of the other constituents of the tablet Severe respiratory insufficiency Sleep apnoea syndrome Severe hepatic insufficiency

4.4 Special Warnings And Precautions For Use

Tolerance

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

Dependence

Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol and drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealization, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually by no more than 0.5 mg every three days. Some patients may require an even slower dose reduction.

Duration of treatment

The duration of treatment should bed as short as possible (see posology) depending on the indication, but should not exceed eight to twelve weeks including tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

There are indications, that in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Amnesia

Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 ours (see also undesirable effects).

Psychiatric and 'paradoxical' reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued.

They are more likely to occur in children and the elderly.

Specific patient groups

Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. The elderly should be given a reduced dose (see posology). A lower dose is also recommended for patients with chronic respiratory insufficiency due to risk of respiratory depression.

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. Caution is recommended when treating patients with impaired renal or hepatic function.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Benzodiazepines should not be used alone to treat depression of anxiety associated with depression (suicide may be precipitated in such patients). Administration to severely depressed or suicidal patients should be done with appropriate precautions and appropriate size of the prescription.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended: Concomitant intake with alcohol

The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Take into account: Combination 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 drugs, anaesthetics and sedative antihistamines.

Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) may increase the concentration of alprazolam and enhance it's activity. Data from clinical studies with alprazolam, in-vitro studies with alprazolam and clinical studies with drugs metabolised 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:

The co-administration of alprazolam with ketoconazole, itraconazole, or other azole-type antifungals is not recommended.

Caution and consideration of dose reduction is recommended when alprazolam is co-administered with nefazodone, fluvoxamine and cimetidine.

Caution is recommended when alprazolam is co-administered with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.

Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are complex and time dependent. 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-adjustment or discontinuation of alprazolam.

4.6 Pregnancy And Lactation

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant. The data concerning teratogenicity and effects on postnatal development and behaviour following benzodiazepine treatment are inconsistent. There is evidence from some early studies with other members of the benzodiazepine class that in utero exposure may be associated with malformations. Later studies with the benzodiazepine class of drugs have provided no clear evidence of any type of defect.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy or during labour, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also interactions).

These effects are potentiated by alcohol (see also interactions).

Patients should be cautioned about operating motor vehicles or engaging in other dangerous activities while taking Xanax.

4.8 Undesirable Effects

Sedation/drowsiness, light-headedness, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, double or blurred vision, insomnia, nervousness/anxiety, tremor, change in weight. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. Other side effects like gastrointestinal disturbances, changes in libido or skin reactions have been reported occasionally.

In addition, the following adverse events have been reported in association with the use of alprazolam: dystonia, anorexia, slurred speech, jaundice, musculoskeletal weakness, sexual dysfunction/changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal liver function and hyperprolactinaemia. Increased intraocular pressure has been rarely reported.

Withdrawal symptoms have occurred following rapid decrease or abrupt discontinuance of benzodiazepines including alprazolam. These can range from mild dysphoria and insomnia to a major syndrome, which may include abdominal and muscle cramps, vomiting, sweating, tremor and convulsions. In addition, withdrawal seizures have occurred upon rapid decrease or abrupt discontinuation of therapy with alprazolam.

Amnesia

Anterograde amnesia may occur at therapeutic dosages, the risk increasing at higher dosages. Amnesic effects may be associated with inappropriate behaviour (see warnings and precautions).

Depression

Pre-existing depression may be unmasked during benzodiazepam use.

Psychiatric and 'paradoxical' reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and the elderly.

In many of the spontaneous case reports of adverse behavioural effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Patients who have borderline personality disorder, a prior history of violent or aggressive behaviour, or alcohol or substance abuse may be at risk of such events. Instances of irritability, hostility and intrusive thoughts have been reported during discontinuance of alprazolam in patients with post-traumatic stress disorder.

Dependence

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see warnings and precautions). Psychic dependence may occur. Abuse of benzodiazepines have been reported.

4.9 Overdose

As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol). In the management of overdose with any medicinal product, it should be borne in mind that multiple agents have been taken.

Following overdose with any medicinal product, vomiting may be induced (within 1 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.

Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Symptoms of overdose are extensions of its pharmacological activity and usually manifested by slurring of speech, motor incoordination and 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.

Flumazenil may be useful as an antidote.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Alprazolam, like other benzodiazepines, has a high affinity for the benzodiazepine binding site in the brain. It facilitates the inhibitory neurotransmitter action of gamma-aminobutyric acid, which mediates both pre- and post synaptic inhibition in the central nervous system (CNS).

5.2 Pharmacokinetic Properties

Alprazolam is readily absorbed. Following oral administration peak concentration in the plasma occurs after 1 - 2 hours.

The mean half-life is 12 - 15 hours. Repeated dosage may lead to accumulation and this should be borne in mind in elderly patients and those with impaired renal or hepatic function. Alprazolam and its metabolites are excreted primarily in the urine.

In vitro alprazolam is bound (80%) to human serum protein.

5.3 Preclinical Safety Data

None given

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica, maize starch, magnesium stearate and docusate sodium with sodium benzoate.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Blister pack: Keep container in the outer carton.

Bottle pack only: Store in the original container.

6.5 Nature And Contents Of Container

Clear PVC/aluminium foil blister strips of 10 tablets, packed 6 strips to a box. Glass bottle with metal screw cap or HDPE bottle with LDPE tamper evident cap containing 100 or 1000 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00032/0092 and 0093

9. Date Of First Authorisation/Renewal Of The Authorisation

27 August 1982/23 January 2003

10. Date Of Revision Of The Text

June 2006

Legal category: POM

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