Alprazolam Stada
Summary of Product Characteristics
1. NAME OF THE MEDICINAL PRODUCT
Alprazolam Stada 0.25 mg tablets
Alprazolam Stada 0.5 mg tablets
Alprazolam Stada 1 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Alprazolam Stada 0.25 mg tablet: 1 tablet contains 0.25 mg alprazolam
Excipient with known effect: Each tablet contains 92.46 mg lactose.
Alprazolam Stada 0.5 mg tablet: 1 tablet contains 0.5 mg alprazolam
Excipient with known effect: Each tablet contains 92.15 mg lactose.
Alprazolam Stada 1 mg tablet: 1 tablet contains 1 mg alprazolam
Excipient with known effect: Each tablet contains 91.71 mg lactose.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
Alprazolam Stada 0.25 mg: white, oblong, scored tablets
Alprazolam Stada 0.5 mg: pink, oblong, scored tablets
Alprazolam Stada 1 mg: light blue, oblong, scored tablets
The tablet can be divided into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Short-term symptomatic treatment of anxiety.
Alprazolam is only indicated when disorder is severe, disabling or subjecting the individual to extreme distress.
4.2 Posology and method of administration
Treatment should be as short as possible. The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in case the patient is symptom free. The overall duration of the 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.
The optimal dose of alprazolam should be individually determined in accordance with the severity of the symptoms and the patient’s response.
The duration of the treatment should be agreed with the patient, and the patient should be made aware of the potential initial undesirable effects and that rebound phenomena may occur at withdrawal (see section 4.4). There is a reduced clearance and an increased sensitivity to alprazolam in older people.
In most patients, the symptoms of anxiety can generally be effectively treated with a dose of between 0.5 mg per day and 3 mg per day, divided up into separately administered measures. Under no circumstances should the maximum dose of 3 mg per day be exceeded. Chronic alcoholics and patients who have never previously taken psychotropic medications generally require lower doses than patients who have already been treated with tranquillisers, antidepressants or hypnotic medicinal products. In order to avoid ataxia and over sedation it is recommended that the lowest effective dose be used.
Adults
Initial dosage*: 0.25 to 0.5 mg three times daily.
Maintenance Dosage*: 0.5 to a maximum of 3 mg daily in divided doses (increasing at intervals of 3-4 days).
Older people, sensitive, weakened patients or patients with kidney or liver functions disorders
Initial dosage*: 0.25 mg, two to three times daily
Maintenance Dosage: 0.5 to 0.75 mg per day in divided doses: The dose should gradually be increased by no more than 0.5 mg every three days when needed and if the disease permits.
Maximum dose: 0.75 mg if physically frail to 1.5 mg daily if physically robust.
* If side-effects occur, the dose should be reduced.
If required the evening dose should be increased before the daytime dose.
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.
Discontinuation of treatment
The dose should be reduced gradually in order to avoid the discontinuation phenomenon. The phasing out should be made by 0.5 mg per three days or in some cases even more slowly.
The treatment should be started, followed up and completed by the same physician, if possible.
Method of administration
For oral use.
The tablets should be taken together with some fluid and may be taken with or without food.
4.3 Contraindications
-
Hypersensitivity to the active substance, other benzodiazepines or to any of the excipients listed in section 6.1
-
Sleep apnoea syndrome
-
Myasthenia gravis
-
Severe respiratory insufficiency
-
Severe hepatic insufficiency
-
Acute intoxication brought about by alcohol or other CNS active agents
4.4 Special warnings and precautions for use
Specific patient groups
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.
Caution is recommended when treating patients with impaired renal function or mild to moderate hepatic insufficiency (see section 4.2).
Benzodiazepines are not indicated for the treatment of patients with severe liver disorders, since benzodiazepines can promote the development of encephalopathy (see section 4.3).
It is recommended that the general principle of using the lowest effective dose be followed in older people and/or debilitated patients to preclude the development of ataxia or oversedation (see section 4.2). Use Alprazolam with caution in older people as there is a risk of falls secondary to the myorelaxant effects of benzodiazepines.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol, drug or medicinal product abuse (see section 4.5).
In patients with chronic respiratory insufficiency a lower dose should be used, given the possibility of respiratory depression.
Benzodiazepines should not be used for the primary treatment of psychoses.
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.
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 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
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. 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. Withdrawal symptoms can appear several days after the end of treatment.
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 is decreased gradually (tapering off).
Duration of treatment
The duration of the treatment should be as short as possible (see section 4.2) depending on the indication, but should not exceed 8-12 weeks in case of anxiety, including the 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 short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
When benzodiazepines with long duration of action are being used it is important to warn against changing in benzodiazepine with short duration of action, as withdrawal symptoms may develop.
Abrupt cessation of benzodiazepines can lead to paraesthesia, perception changes and depersonalisation during one or several weeks. In some cases convulsions have been reported.
Psychiatric and paradoxical reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, aggravated insomnia, delirium, 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 people. Extreme caution should be used in prescribing benzodiazepines in patients with borderline or antisocial personality disorders.
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.
Alprazolam Stada contains lactose monohydrate. 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
Pharmacodynamic interactions
Alcohol
Benzodiazepines produce an additive effect when co-administered with alcohol. Therefore, concomitant intake with alcohol is not recommended. Combination with alcohol potentates the sedative effect of alprazolam.
Psychotropic Pharmaceuticals
Special care should be made with drugs depressing respiratory function such as opioids (analgesics, antitussives, substitutive treatments), notably in older people.
Alprazolam should be used with caution when combined with other CNS depressants. Enhancement of the central depressive effect may occur and benzodiazepines produce an additive effect when co-administered with other CNS depressants or psychotropic medicinal products, such as antipsychotics (neuroleptics), anxiolytics/sedatives, some antidepressant agents, hypnotics, narcotic analgesics (opioids), anticonvulsants, anaesthetics and sedating H1-antihistamines.
However, when taking the tablets in combination with narcotic analgesics, potentiation of euphoria can occur which may lead to an increased psychic dependence.
Clozapine
With clozapine there is an increased risk of respiratory and/or cardiac arrest.
Muscle relaxants
One should be prepared for an increase of the muscle relaxing effect (risk of falls) when alprazolam is used during therapy with a muscle relaxant, especially during the beginning of treatment.
Pharmacokinetic interactions
CYP3A4 inhibitors
Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that inhibit the hepatic enzyme CYP3A4 by increasing the plasma levels of alprazolam. Alprazolam should therefore be used with caution in patients taking these medicines and a reduction of dosage may be necessary when such pharmaceuticals are concomitantly used.
Itraconazole, a potent CYP3A4-inhibitor, increases AUC and prolongs the elimination half-life for alprazolam. In a study where healthy volunteers were given itraconazole 200 mg/day and 0.8 mg alprazolam, the AUC was increased two-three fold, and the elimination half-life was prolonged to about 40 hours. Alterations have also been seen on psychomotor function affected by alprazolam. Itraconazole may enhance the CNS-depressant effects of alprazolam and withdrawal of itraconazole may attenuate the therapeutic efficacy of alprazolam.
Concomitant use with potent CYP3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors or some macrolides (clarithromycin, telithromycin) is not recommended. However, if concomitant use of alprazolam and a potent CYP3A4 inhibitor is considered necessary, the alprazolam dose should be reduced to one half or one third.
Erythromycin inhibits the metabolism of alprazolam. The alprazolam concentration in plasma increases by about 50 %. The combination may require adjustment of the dose.
Nefazodone inhibits CYP3A4 mediated oxidation of alprazolam, which results in a doubling of the plasma concentration of alprazolam and risk of intensified CNS effects.
In combination, it is therefore recommended to reduce the alprazolam dosage to one half of the dose.
Fluvoxamine treatment extends the half-life for alprazolam from 20 hours to 34 hours and doubles the alprazolam concentration in plasma.
When used in combination, half of the dosage of alprazolam is recommended.
Fluoxetine has a moderate inhibitory effect on alprazolam-metabolism resulting in increased plasma concentrations. During concomitant use, the psychomotor effects of alprazolam are therefore intensified. Adjustment of the dose may be required.
Other CYP3A4 inhibitors that are expected to increase the plasma concentration of alprazolam are diltiazem and fluconazole. A dose reduction may be needed.
Cimetidine reduces the clearance of alprazolam which may possibly intensify the effect. The clinical significance of the interaction has not yet been determined.
CYP3A4 inducers
Patients on concomitant treatment of alprazolam and theophylline get a significantly lower alprazolam concentration in plasma than patients only treated with alprazolam, possibly caused by induced metabolism. The clinical significance of this interaction has not yet been determined.
Carbamazepine seems to induce the alprazolam-metabolism resulting in a reduced effect. The clinical significance of this interaction has not yet been determined.
The effect of alprazolam on the pharmacokinetics of other medicinal products
Increase of digoxin plasma levels has been reported with concomitant use of 1 mg alprazolam daily, particularly in older people. Therefore patients receiving alprazolam and digoxin concurrently should be closely monitored for signs and symptoms of digoxin toxicity.
4.6 Fertility, pregnancy and lactation
Pregnancy
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 an increased risk of oral clefts. The data indicated that the risk of having an infant with an oral cleft after maternal benzodiazepine exposure is less than 2/1,000 compared with an expected rate for such defects of approximately 1/1,000 in the general population.
Benzodiazepine treatment at high dose, during the second and/or the third trimester of pregnancy, has revealed a decrease of foetal active movements and a variability of foetal 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.
Taking into account these data, the use of alprazolam during pregnancy may be considered, if therapeutic indications and posology are strictly respected.
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. Accordingly, its use during birth is only permissible, if there is a critical indication.
Breastfeeding
Alprazolam is excreted in breast milk at low level. However, alprazolam is not recommended during breastfeeding.
4.7 Effects on ability to drive and use machines
Alprazolam has major influence on the ability to drive and use machines.
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or use machines. Patients should be warned of this hazard and advised not to drive or operate machinery during treatment. These effects are potentiated by alcohol. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see section 4.5).
4.8 Undesirable effects
Adverse reactions have been ranked under headings of frequency using the following convention:
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).
Endocrine disorders
Uncommon: Hyperprolactinaemia.
Metabolism and nutrition disorders
Common: Decreased appetite.
Not known: Anorexia, stimulation of appetite.
Psychiatric disorders
Common: Confusion, depression.
Uncommon: Hallucinations, rage, aggressive behaviour, hostile behaviour, anxiety, agitation, changes in libido, sleep disorders (e.g. insomnia), thinking abnormal, nervousness, stimulation
Nervous system disorders
Very common: Sedation, drowsiness (occurs initially in about 30 % of the patients, but it usually decreases after a few days or after a dose reduction).
Common: Ataxia, coordination disorders, memory impairment, slurred speech, concentration difficulties, dizziness, headache, light-headedness
Uncommon: Amnesia, dystonia, tremor
Not known: Reduced alertness, autonomic manifestations (such as increased salivation, nasal congestion and tachycardia).
Eye disorders
Common: Blurred vision.
Vascular disorders
Not known: Hypotension.
Gastrointestinal disorders
Common: Constipation, diarrhoea, nausea.
Uncommon: Vomiting.
Rare: Xerostomia.
Not known: Dysphagia.
Hepatobiliary disorders
Uncommon: Abnormal liver function, jaundice.
Not known: Hepatitis.
Skin and subcutaneous tissue disorders
Uncommon: Skin reactions, dermatitis.
Musculoskeletal and connective tissue disorders
Uncommon: Musculoskeletal weakness (risk of falls).
Renal and urinary disorders
Uncommon: Incontinence, urinary retention.
Reproductive system and breast disorders
Uncommon: Sexual dysfunction, menstrual irregularities.
General disorders and administration site conditions
Common: Asthenia, irritability.
Not known: Fatigue, peripheral oedema.
Investigations
Uncommon: Change in weight, increased intraocular pressure.
Depression
Previously unnoticed depressions may become apparent, in susceptible individuals, during benzodiazepine use.
Psychiatric and “paradoxical” reactions
Reactions such as restlessness, agitation, irritability, aggression, delusions, fits of rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural disorders can occur; they are more likely in older people.
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).
Amnesia
Anterograde amnesia can occur even at therapeutic doses and the risk increases at higher doses. Amnesia may be accompanied by inappropriate behaviour (see also section 4.4).
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 national reporting system listed in Appendix V.
4.9 Overdose
Symptoms:
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.
Likewise dizziness, dysarthria and unconsciousness, but also some paradox reactions as agitation, aggressiveness, and hallucinations have been reported.
Agitation and hallucinosis are more common with alprazolam than for other benzodiazepines. Mydriasis and miosis may occur.
Convulsions, arrhythmia and AV-block may also occur as well as tachycardia, hypothermia, nausea and vomiting.
Toxicity:
A dose of 25 – 50 mg in combination with alcohol (2 per mille in blood), given to adults, showed lethal intoxication. After a dose of 0.3 mg/kg was given to an eight years old child, the intoxication was moderate to serious. A dose of 10 mg to a thirteen year old showed a moderate intoxication. A serious intoxication was seen after administering 15 mg (in combination with alcohol) in an adult, whereas 20-40 mg only showed moderate intoxication. 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 born in mind that multiple agents may have been taken. Treatment should be adjusted accordingly.
Treatment:
Following overdose with oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. Patients with slight signs of intoxication should sleep it off under medical observation. If there is no advantage in emptying the stomach, the use of activated charcoal is generally indicated to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care.
Treatment with benzodiazepine antagonists (i.e. flumazenil) could be considered in severe cases, but due to the longer effect of benzodiazepines, a continuous infusion is recommended (for adults for example 0.3-1.0 mg/min.). Flumazenil can increase the risk of convulsions. Forced diuresis or haemodialysis is of no value.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anxiolytics, benzodiazepine derivatives.
ATC-code: N05BA12
Alprazolam is a benzodiazepine with a triazolo-ring added to the structure. Alprazolam binds to the benzodiazepine-receptors and thereby gives potentiation of the GABA-system. The medicinal product has a rapid onset on the common anxiety symptoms such as agitation, restlessness, and tension. Alprazolam gives an anxiolytic effect when treating depression. Drowsiness is not unusual at therapeutic doses initially, but usually passes with continued treatment. In anxiolytic doses, alprazolam gives no or slight muscular weakness.
Alprazolam gives a dose-dependent reduction of the REM sleep and a prolongation of REM latency.
The development of tolerance has been seen for the sedative effect, but not for the anxiolytic effect of alprazolam.
5.2 Pharmacokinetic properties
The bioavailability of alprazolam is approx. 90 %. Food ingestion at the same time delays the absorption of alprazolam, but has not influence on the absorbed quantity. The time taken for peak concentration in plasma after ingestion is 1-2 hours and the plasma concentration is proportional to the ingested dose. The protein-binding level for alprazolam is approx. 70 % whereas the clearance is approx.
1 ml/min/kg body weight and the volume of distribution approx. 1 litre/kg. Alprazolam gives no or only slight enzyme induction.
Alprazolam undergoes considerable metabolism in the liver, mainly by hydroxylation to alpha-hydroxy-alprazolam and 4-hydroxyalprazolam. These metabolites are glucuronised before elimination in the urine. Several studies indicate that the enzyme CYP3A4 catalyses the metabolism of alprazolam. The elimination half-life for alprazolam is approx. 12 hours. The main metabolites are biologically active. Their half-lives are comparable with alprazolam and they occur in low concentrations so that they hardly contribute to the pharmacological effect.
In older men there can be a prolonged elimination half-life (approx. 19 h).
The half-life is increased with impaired liver function.
5.3 Preclinical safety data
In rats given alprazolam for 24 months a tendency for dose-related increases in number of cataracts and in corneal vascularisation was evident in females and males respectively.
In a repeated dose toxicity study (12 months) with high dosages p.o. convulsions were observed in dogs, some of which were lethal. Relevance for man is not clear.
There was no evidence of carcinogenic potential in rats and mice.
Alprazolam administered to rats and rabbits at high doses caused an increase in birth defects and foetal death.
Prenatal exposure of mice and rats to benzodiazepines, including alprazolam, has been associated with behavioural changes in the offspring. The possible significance of these changes to the human situation is unclear.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Docusate sodium
Sodium benzoate (E211)
Starch, pregelatinised
Cellulose, microcrystalline
Lactose monohydrate
Magnesium stearate
Silica, colloidal anhydrous.
Alprazolam Stada 0.5 mg tablet: additionally contains erythrosine aluminium lake* (E127) (*consists of erythrosine and aluminium hydroxide).
Alprazolam Stada 1 mg tablet: additionally contains indigo carmine aluminium lake (E132) (*consists of indigotin and aluminium hydroxide).
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30 °C.
6.5 Nature and contents of container
Aluminium/PVC blister.
0, 25 /0,5 mg:
Packs containing 7, 10, 14, 20, 21, 28, 30, 40, 50, 60, 70, 80, 84, 90, 100, 200, 250, 500 and 1000 tablets.
1 mg:
Packs containing 10, 14, 20, 21, 28, 30, 40, 50, 60, 70, 80, 84, 90, 100, 200, 250, 500 and 1000 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 15 December 2000
Date of last renewal: 15 December 2010
10. DATE OF REVISION OF THE TEXT
2015-05-19
11