Xanax Tablets 250 micrograms

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1. Name of the medicinal product

Xanax Tablets 250 micrograms

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2. Qualitative and quantitative composition

Alprazolam 250 micrograms

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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.

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4. Clinical particulars
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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.

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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. (See section 4.4 Special warnings and precautions for use)

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.

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

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4.3 Contraindications

Alprazolam is contraindicated in patients with known hypersensitivity to benzodiazepines, alprazolam, or to any component of the product's formulation. Benzodiazepines are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, sleep apnoea syndrome, severe hepatic insufficiency.

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4.4 Special warnings and precautions for use

Caution is recommended when treating patients with impaired renal function or mild to moderate hepatic insufficiency.

In patients presenting with major depression or anxiety associated with depression benzodiazepines and benzodiazepine-like agents should not be prescribed alone to treat depression as they may precipitate or increase the risk of suicide. Therefore alprazolam 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.

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

It is recommended that general principle of using the lowest effective dose to be followed in elderly and /or debilitated patients to preclude development of ataxia or oversedation (See section 4.2 Posology and method of administration). A lower dose is also recommended for patients with chronic respiratory insufficiency due to risk of respiratory depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (See section 4.5 Interactions with other medicinal products and other form of interactions).

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. 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 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, irritability and insomnia. 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. (See section 4.2 Posology and method of administration)

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 that 0.5 mg every three days. Some patients may require even slower dosage reduction.

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. (See section 4.2 Posology and method of administration)

Duration of treatment

The duration of treatment should be as short as possible (See section 4.2 Posology and method of administration) 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 hours. (See section 4.8. 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 medicinal product should be discontinued. They are more likely to occur in children and the elderly.

Tolerance

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

Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.

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

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

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4.5 Interaction with other medicinal products and other forms of interaction

Benzodiazepines produce an additive effect when co-administered with alcohol or other CNS depressants. 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 drugs, anaesthetics and sedative antihistamines. In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

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

CYP3A Inhibitors

Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) may increase the concentration of alprazolam and enhance its 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.

• The co-administration of nefazodone or fluvoxamine increases the AUC of alprazolam by approximately 2-fold. 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, clarithromycin and troleandomycin.

CYP3A4 Inducers

Since alprazolam is metabolized by CYP3A4, inducers of this enzyme may enhance the metabolism 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-adjustment or discontinuation of alprazolam.

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4.6. Fertility, pregnancy and lactation

Pregnancy

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 benzodiazepine 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.

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 treatment has to be administered for medical reasons during the last part of pregnancy, even at low doses, floppy infant syndrome such as axial hypotonia, sucking troubles leading to a poor weight gain may be observed. These signs are reversible but they may last from 1 up to 3 weeks, according to the half life of the product. At high doses, respiratory depression or apnoea and hypothermia in newborn may appear. Moreover, neonatal withdrawal symptoms with hyperexcitability, agitation and tremor may be observed a few days after birth, even if no floppy infant syndrome is observed. The apparition of withdrawal symptoms after birth depends on the half life of the substance.

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 of the patient becomes pregnant while taking alprazolam, the patient should be apprised of the potential hazard to the fetus.

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

Breastfeeding

Alprazolam is excreted in breast milk at low level. However, alprazolam is not recommended during breastfeeding.

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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 section 4.5 Interactions with other Medical Products and other forms of Interaction).

These effects are potentiated by alcohol (See section 4.5 Interactions with other Medical Products and other forms of Interaction).

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

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4.8 Undesirable effects

Adverse events, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage.

The following undesirable effects have been observed and reported during treatment with alprazolam with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

MedDRA System Organ ClassFrequencyUndesirable Effects
Endocrine disordersUncommon Hyperprolactinaemia
Metabolism and nutrition disordersCommon Decreased appetite
Psychiatric disordersCommon Confusional state, depression, disorientation, libido decreased
Uncommon Anxiety, insomnia, nervousness, hypomania, mania (see section 4.4 Special warnings and precautions for use), hallucination, anger, aggression, hostility, agitation, libido disorder, thinking abnormal, psychomotor hyperactivity
Nervous system disordersVery common Sedation, somnolence
Common Ataxia, balance disorder, coordination abnormal, memory impairment, dysarthria, disturbance in attention, hypersomnia, lethargy, dizziness, headache
Uncommon Amnesia, tremor, dystonia
Not Known Autonomic nervous system imbalance
Eye disordersCommon Vision blurred
Gastrointestinal disordersCommon Constipation, dry mouth, nausea
Uncommon Gastrointestinal disorder
Hepatobiliary disordersUncommon Hepatitis, hepatic function abnormal, jaundice
Skin and subcutaneous tissue disordersUncommon Dermatitis
Not Known Angioedema
Musculoskeletal and connective tissue disordersUncommon Muscular weakness
Renal and urinary disordersUncommon Incontinence, urinary retention
Reproductive system and breast disordersUncommon Sexual dysfunction, menstruation irregular
General disorders and administration site conditionsCommon Fatigue, irritability
Not Known Peripheral oedema
InvestigationsUncommon Change in weight, intraocular pressure increased

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 section 4.4 Special warnings and precautions for use).

Depression

Pre-existing depression may be unmasked during benzodiazepine 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 section 4.4 Special warnings and precautions for use). Psychic dependence may occur. Abuse of benzodiazepines has been reported.

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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 oral benzodiazepines, 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.

Overdose of benzodiazepines 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.

Flumazenil may be useful as an antidote.

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5. Pharmacological properties
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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).

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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.

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5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

When rats were treated orally with alprazolam for 2 years, 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.

In reproductive toxicity studies administration of alprazolam in rats and rabbits is associated at very high doses with developmental delay and an increased incidence of fetal death and skeletal malformations. In fertility studies, treatment of male rats at high doses prior to mating resulted in a decrease in the percentage of dams conceiving.

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6. Pharmaceutical particulars
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6.1 List of excipients

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

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6.2 Incompatibilities

None known.

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6.3 Shelf life

5 years.

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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.

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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.

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6.6 Special precautions for disposal and other handling

Not applicable.

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7. Marketing authorisation holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

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8. Marketing authorisation number(s)

PL 00057/1058

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9. Date of first authorisation/renewal of the authorisation

27 August 1982/23 January 2003

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10. Date of revision of the text

Nov/2012

Company information
Pfizer Limited
Ramsgate Road, Sandwich, Kent, CT13 9NJ
Telephone : +44 (0)1304 616 161
Fax : +44 (0)1304 656 221
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