4.2 Posology and method of administration

Posology

Anxiety:
Treatment should be as short as possible. The overall duration of treatment generally should not be more than 8 - 12 weeks, including a tapering off process. The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in case the patient is symptom free.

The recommended starting dose is 500 micrograms to 1 mg daily in divided doses, with increments (no greater than 1 mg every 3 - 4 days), to the level of optimal control usually 3 to 4 mg daily.

To discontinue 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 3 days. Some patients may require an even slower dosage reduction (see section 4.4).

Elderly patients:
In elderly or debilitated patients a regimen of 250 micrograms twice daily should be used initially with gradual increments if required and tolerance is assured.

Treatment should be started with the lower recommended dose. The maximum dose should not be exceeded.

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.

Paediatric patients population:
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.

Method of administration

For oral use

Treatment should be started with the lower recommended dose. The maximum dose should not be exceeded.

Initial doses may be given at bedtime to minimise daytime lethargy. If side effects occur with the starting dose, the dose should be lowered.

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.

4.3 Contraindications

• Hypersensitivity to the active substance, alprazolam or to any of the excipients listed in section 6.1, or to any other benzodiazepine.
• Myasthenia gravis
• Severe respiratory insufficiency
• Sleep apnoea syndrome
• Severe hepatic insufficiency

4.4 Special warnings and precautions for use

Specific patient groups

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 used 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.

Paediatric population
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.

Elderly Ppatients
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.

It is recommended that the general principle of using the lowest effective dose be followed in older and/or debilitated patients to preclude the development of ataxia or over-sedation.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see section 4.5).

In patients presenting with major depression or anxiety associated with depression, benzodiazepines and benzodiazepine-like agents should not be used 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.

A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy (see section 4.3).

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

Paediatric population
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.

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.

Dependence
Use of benzodiazepines may lead to the development of physical and psychological 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 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 physical or psychological 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: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures (see section 4.2).

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.

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, mild dysphoria, anxiety or sleep disturbances, abdominal and muscle cramps, vomiting, sweating, tremor and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually (see section 4.2).

Duration of treatment
The duration of treatment should be as short as possible (see section 4.2) but should not exceed 8 to 12 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 an uninterrupted sleep of 7-8 hours.

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 older peoplethe elderly.

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 an uninterrupted sleep of 7-8 hours.

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

Administration to severely depressed or suicidal patients should be done with appropriate precautions and appropriate size of the prescription.

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

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

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.

Special care should be made with drugs depressing respiratory function such as opioids (analgesics, antitussives, substitutive treatments), notably in older people the elderly. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Alprazolam should be used with caution when combined with other CNS depressants. Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, some antidepressant agents, opioids, anticonvulsants, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative H1-antihistamines. In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychological dependence.

Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that inhibit the hepatic enzyme CYP3A4 by increasing the plasma levels of alprazolam.

The co-administration of alprazolam with strong CYP3A4 inhibitors like azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), protease inhibitors or some macrolides (erythromycin, clarithromycin, telithromycin) should be made with caution and a substantial dose reduction considered.

CYP3A inhibitors Inhibitors
Compounds which 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. To a lesser degree this also applies to benzodiazepines that are metabolised only by conjugation. Based on the degree of interaction and the data available currently, 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. The co-administration of nefazodone or fluvoxamine increases the AUC of alprazolam by approximately 2 fold.
• Caution is recommended when alprazolam is co-administered with fluoxetine, dextropropoxyphene, oral contraceptives, diltiazem, or macrolide antibiotics such as erythromycin, clarithromycin and troleandomycin.

CYP3A4 inducers 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.

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

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).

Withdrawal symptoms
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 using therapeutic dosages, the risk increasing at higher dosages. Amnesic effects may be associated with inappropriate behaviour (see section 4.4).

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 benzodiazepine or benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and older people the elderly .

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. Psychic dependence may occur. Abuse of benzodiazepines has been reported (see section 4.4).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anxiolytics, benzodiazepine Benzodiazepine derivatives, ATC code: N05BA12

Mechanism of action
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).

4.2 Posology and method of administration
Elderly:
In older elderly or debilitated patients a regimen of 250 micrograms twice daily should be used initially with gradual increments if required and tolerance is assured.

4.4 Special warnings and precautions for use
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. It is recommended that the general principle of using the lowest effective dose be followed in older and/or debilitated patients to preclude the development of ataxia or over-sedation. Use alprazolam with caution in older patients as there is a risk of falls and consequently of hip fractures secondary to the myorelaxant effects of benzodiazepines.