4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

Duration of treatment

Prior to starting treatment with Xanax, a discussion should be held with patients to put in place a strategy for ending treatment with Xanax in order to minimise the risk of dependence, addiction and drug withdrawal syndrome (see section 4.4).

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).

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.

The elderly 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.

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.

Paediatric population

The safety and efficacy of alprazolam in children and adolescents below the age of 18 years have not been established. No data are available.

Method of administration

For oral use.

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 frequently. The usual dosage is stated above; 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.

The dose must be gradually reduced to avoid withdrawal symptoms (see section 4.4). The risk of dependence may increase with dose and duration of treatment, therefore, the lowest possible effective dose and duration should be used and the need for continued treatment reassessed frequently (see section 4.4).

Elderly patients

There is a reduced clearance of the drug and, as with other benzodiazepines, an increased sensitivity to the drug in elderly patients. See section 5.2.

4.3. Contraindications

Hypersensitivity to benzodiazepines, alprazolam, or to any of the excipients listed in section 6.1. Benzodiazepines are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, sleep apnoea syndrome and severe hepatic insufficiency.

4.4. Special warnings and precautions for use

Duration of treatment

The length 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.

Renal and hepatic impairment

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

Depression/anxiety

Benzodiazepines and benzodiazepine-like agents should not be prescribed alone to treat depression as they may precipitate or increase the risk of suicide. 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.

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 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.

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 over-sedation (see section 4.2). 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).

Risk from concomitant use of opioids

Concomitant use of Xanax and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as Xanax with opioids should be reserved for patients for whom alternative treatment options are not possible.

If a decision is made to prescribe Xanax concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms (see section 4.5).

Drug dependence, tolerance and potential for abuse

Drug addiction comprises behavioural, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use and possible tolerance or physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, which manifests as withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Addiction and dependence are related but distinct presentations and in discussing these themes, terminology that apportion blame to the individual should be avoided.

For all patients, prolonged use of this product may lead to drug dependence and addiction but can occur with short-term use at recommended therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

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. Alprazolam may be subject to diversion. There have been reports of overdose-related deaths when alprazolam is abused with other central nervous system (CNS) depressants including opioids, other benzodiazepines, and alcohol. These risks should be considered when prescribing or dispensing alprazolam. Additional support and monitoring may be necessary when prescribing for patients at risk of drug misuse. To reduce these risks the smallest appropriate quantity should be used and patients should be advised on the proper storage and disposal of unused drug (see section 4.2, 4.8 and 4.9).

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of symptom control as initially experienced. Patients may also supplement their treatment with additional medications to achieve the same effect. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for treatment with Xanax should be reviewed regularly, with frequent assessments of patients being undertaken during the course of their treatment.

Drug withdrawal syndrome

Prior to starting treatment with Xanax, a discussion should be held with patients to explain the risk of dependence, addiction, and drug withdrawal syndrome. A withdrawal strategy for ending treatment with Xanax should also be put in place with the patient before starting treatment (there may be exceptions to this in specific clinical situations such as symptom management in end of life palliative care).

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: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take in excess of weeks or months. Patients should be informed of this when the medication is first prescribed.

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, the dose must be gradually reduced to avoid withdrawal symptoms (see section 4.2). The reduction schedule for a patient should be tailored to the individual and should be modified to allow intolerable withdrawal symptoms to improve before making the next reduction. If using a published withdrawal schedule, apply it flexibly to accommodate the person's preferences, changes to their circumstances and the response to dose reductions. Suggest a slow stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed.

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).

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.

Excipients with known effect information

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

This medicine contains 0.11 mg Sodium Benzoate in each tablet.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Opioids

The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Xanax with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4). 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.

Digoxin

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.

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 hyper excitability, 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.

Breast-feeding

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

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 and use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see section 4.5).

These effects are potentiated by alcohol (see section 4.5).

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

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

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 Class

Frequency

Undesirable Effects

Endocrine disorders

Not known

Hyperprolactinaemia*

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Very common

Depression

Common

Confusional state, disorientation, libido decreased, anxiety, insomnia, nervousness, libido increased*

Uncommon

Mania* (see section 4.4), hallucination*, anger*, agitation*, drug dependence (see section 4.4)

Not known

Hypomania*, aggression*, hostility*, thinking abnormal*, psychomotor hyperactivity*, drug abuse*

Nervous system disorders

Very common

Sedation, somnolence, ataxia, memory impairment, dysarthria, dizziness, headache

Common

Balance disorder, coordination abnormal, disturbance in attention, hypersomnia, lethargy, tremor

Uncommon

Amnesia

Not Known

Autonomic nervous system imbalance*, dystonia*

Eye disorders

Common

Vision blurred

Gastrointestinal disorders

Very common

Constipation, dry mouth

Common

Nausea

Not known

Gastrointestinal disorder*

Hepatobiliary disorders

Not known

Hepatitis*, hepatic function abnormal*, jaundice*

Skin and subcutaneous tissue disorders

Common

Dermatitis*

Not Known

Angioedema*, photosensitivity reaction*

Musculoskeletal and connective tissue disorders

Uncommon

Muscular weakness

Renal and urinary disorders

Uncommon

Incontinence*

Not known

Urinary retention*

Reproductive system and breast disorders

Common

Sexual dysfunction*

Uncommon

Menstruation irregular*

General disorders and administration site conditions

Very common

Fatigue, irritability

Uncommon

Drug withdrawal syndrome*(see 4.4 Special warnings and precautions)

Not Known

Oedema peripheral*

Investigations

Common

Weight decreased, weight increased

Not known

Intraocular pressure increased*

* ADR identified post-marketing

Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of “rebound” phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form (see section 4.4). These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

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.

In severe cases the following symptoms may occur: derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, convulsions. Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

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).

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.

Abuse, dependence and withdrawal

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). Psychic dependence may occur. Abuse of benzodiazepines has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur. 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.