Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
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.
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.
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).
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).
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: 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 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).
The duration of treatment should be as short as possible (see section 4.2) 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.
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).
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.
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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 central nervous system (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.
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:
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.
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.
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.
Alprazolam is excreted in breast milk at low level. However, alprazolam is not recommended during breast-feeding.
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:
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).
Not known: Hyperprolactinaemia*
Common: Decreased appetite
Very common: Depression
Common: Confusional state, disorientation, libido decreased, anxiety, insomnia, nervousness, libido increased*
Uncommon: Mania* (see section 4.4), hallucination*, anger*, agitation*
Not known: Hypomania*, aggression*, hostility*, thinking abnormal*, psychomotor hyperactivity*
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*
Common: Vision blurred
Very common: Constipation, dry mouth
Common: Nausea
Not known: Gastrointestinal disorder*
Not known: Hepatitis*, hepatic function abnormal*, jaundice*
Common: Dermatitis*
Not Known: Angioedema*, photosensitivity reaction*
Uncommon: Muscular weakness
Uncommon: Incontinence*
Not known: Urinary retention*
Common: Sexual dysfunction*
Uncommon: Menstruation irregular*
Very common: Fatigue, irritability
Not Known: Oedema peripheral*
Common: Weight increased, weight decreased
Not known: Intraocular pressure increased*
* ADR identified post-marketing
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.
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).
Pre-existing depression may be unmasked during benzodiazepine use.
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.
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 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.
Not applicable.
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