The format of this leaflet was determined by the Ministry of Health and its content was checked and approved by it.

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1 The format of this leaflet was determined by the Ministry of Health and its content was checked and approved by it. Prescribing Information XANAGIS Tablets Composition Each tablet contains: 0.25, 0.5, or 1 mg of alprazolam. יש להוסיף לעלון:פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר עלון מאושר מאי 2009 Indications For the management of anxiety and anxiety associated with depression. Treatment of panic disorder with or without phobic avoidance. Contraindications Xanagis is contraindicated in: Myasthenia gravis Hypersensitivity to the active substance or to any of the excipients Severe respiratory insufficiency Sleep apnoea syndrome Severe hepatic insufficiency The safety and efficacy of the product have not been studied in patients under eighteen years of age. Benzodiazepines are contra-indicated in children under 6 years of age. Special warnings and precautions for use Rapid tapering off or abrupt discontinuation of benzodiazepines, including alprazolam, can result in undesirable effects such as rebound phenomena or withdrawal symptoms. Consequently, the dose should be tapered off gradually (see 4.2), particularly in epileptic patients. These signs and symptoms, and the more severe forms in particular, are generally observed most frequently in patients after long-term treatment with excessive doses. However, withdrawal symptoms have also been reported after abrupt discontinuation of therapeutic doses of benzodiazepines. When treatment is discontinued in patients with panic disorders or related conditions, the recurring symptoms often closely resemble withdrawal symptoms. Addiction and emotional/physical dependence can occur with the use of benzodiazepines, including alprazolam. Caution is required, in particular when benzodiazepines are prescribed for patients who are prone to drug abuse (e.g.

2 alcoholics, drug addicts), since these patients are predisposed to addiction and dependence. In geriatric and debilitated patients it is advisable to use the lowest effective dose to prevent ataxia or oversedation. In patients with impaired renal or hepatic function the usual precautions should be taken. The safety and efficacy of the product have not been studied in patients under eighteen years of age. In various cases benzodiazepines are administered to meet occasional or transient requirements. The period of administration will therefore be brief. In some cases the patient's health requires prolonged administration. With long-term use of benzodiazepines, the need for treatment should be reviewed periodically by the physician in each individual case. Prolonged use can undeniable result in psychic dependence. When Xanagis is combined with alcohol, other hypnotics or tranquillizers, it is necessary to bear in mind the additive effect. Restlessness, agitation, irritability, aggression, delusions, anger, nightmares, hallucinations, psychosis, inappropriate behaviour and other behavioural disorders can occur with the use of benzodiazepines (see section 4.8). In this event treatment should be discontinued. Tolerance or dose increase are rarely observed with alprazolam, but can occur. Tolerance has been demonstrated for the sedative action, but not for the anxiolytic effect of alprazolam. Suitable precautions should be taken in patients with acute closed angle glaucoma. Administration to severely depressed patients with suicidal tendency should be done with appropriate precautions and appropriate size of prescriptions. Lactose: Tablets contain lactose and should not be used in patients with galactose intolerance, Lapp lactates deficiency or glucose-galactose malabsorption (rare hereditary problems). SPECIAL PRECAUTIONS FOR PATIENTS TREATED FOR PANIC DISORDERS Panic disorders or related conditions have been associated with major primary or secondary depressions in untreated patients and with an increase in the number of suicide cases. Consequently, the same precautions are required as with the use of other psychotropic agents for the treatment of patients suffering from depression or in patients suspected of harbouring occult suicide ideas or plans. Interactions with other medicinal products and other forms of interaction Benzodiazepines, including alprazolam, have an additive depressant effect on the central nervous system (CNS) when used in combination with other psychotropic agents, anticonvulsives, antihistamines, alcohol and other agents with an effect on the CNS. No effects on prothrombin time and warfarin plasma levels have been observed. 2

3 Pharmacokinetic interactions can occur when alprazolam is administered in combination with drugs that interfere with its metabolism. Drugs that inhibit certain hepatic enzymes (in particular the cytochrome P450 IIIA4 enzyme system) can increase the concentration of alprazolam and potentiate its effect. The following recommendations are based on several studies: Combined use with ketoconazole, itraconazole or other azole-like antifungal agents is not recommended. Caution and possibly a dose reduction are recommended in case of combined use with nefazodon, fluvoxamine and cimetidine. Caution is required in the event of combined use with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem or macrolide antibodies such as erythromycin and claritromycin. Interactions between HIV-protease inhibitors (e.g. ritonavir) and alprazolam are complex and time-dependent. Low doses of ritonavir resulted in a considerable reduction in the clearance of alprazolam, a prolonged half-life and increase clinical effects. However, after prolonged ritonavir exposure this inhibition is counteracted by CYP3A induction. The interaction requires dose adjustment or discontinuation of treatment with alprazolam. Mean increases of respectively 31% and 20% of the steady-state plasma levels of imipramine and desipramine have been reported during concurrent administration of Xanagis up to 4 mg daily. The clinical significance of these changes has not yet been established. Interactions with isoniazide or rifampicin have not been evaluated. No changes in alprazolam kinetics have been noted during concurrent administration of propranolol or disulfiram. Alprazolam does not affect the plasma levels of phenytoin, but the effect of phenytoin on the levels of alprazolam has not been studied. Although it has never been described with alprazolam, there is an increased risk of psychosis when benzodiazepines are used in combination with valproic acid. Theophyllin antagonizes the effect of benzodiazepines. Pregnancy and lactation When alprazolam is prescribed to a woman of childbearing age, she should be warned to notify her physician if she wishes to become pregnant or if she is pregnant, so the physician can decide to discontinue treatment. Benzodiazepines pass the foetoplacental barrier and are excreted in breast milk. Children of patients who have taken benzodiazepines during pregnancy may present malformations. This has not been quantified for alprazolam. When the product is administered for medical reasons during the first phase of pregnancy or during delivery, hypothermia, hopotonia and respiratory depression may occur in the newborn. Since infants whose mother took benzodiazepines chronically during pregnancy may have developed physical dependence, withdrawal symptoms can occur in the postnatal development. The use of benzodiazepines is not recommended in case of suspected or confirmed pregnancy and during lactation. 3

4 Undesirable effects The most annoying adverse effects of Xanagis are due to an extension of the pharmacological activity of alprazolam. Whether or not certain undesirable effects occur depends totally on the patient's individual sensitivity and the dose administered. potential adverse effects are usually observed at the start of treatment and usually disappear when the treatment is continued or when the dose is reduced. Nervous system disorders - Drowsiness and light headedness/dizziness are reported frequently. - Less common adverse effects are headache, depression, tremor, weight changes, memory disorders, amnesia, concentration disorders, confusion, co-ordination disorders and autonomic manifestations. - Other effects associate with benzodiazepines: Paradoxical reactions such as irritability, stimulation, anger, aggressive or hostile behaviour, increased agitation, nervousness, anxiety or insomnia. In many cases the patients were also taking other centrally acting drugs and/or suffered from an underlying psychiatric disorder. In one case it was suggested that patients with borderline personality disorders, a history of aggressive behaviour, alcohol of drug abuse, patients suffering from post-traumatic stress were possibly more at risk of developing these adverse effects. - The following adverse effects of benzodiazepines have been reported rarely or very exceptionally: dystonia, fatigue, ataxia, muscle weakness, motor disorders, epilepsy, speech disorders, memory disorders, signs of paranoia, depersonalization, hallucinations. Hepatobiliary disorders Abnormal hepatic function, cholestasis or jaundice are rare. Blood and lymphatic system disorders Agranulocytosis is rare. Respiratory, thoracic and mediastinal disorders Allergic reactions or anaphylaxis are rare. Renal and urinary disorders Sexual dysfunction, sporadic menstrual and ovulation disorders, gynaecomastia, incontinence or urinary retention are rare. Gastrointestinal disorders Reports of various digestive disorders are less frequent, anorexia is rare. Eye disorders Blurred vision has not been reported frequently, increased intra-ocular pressure is rare. Endocrine disorders Hyperprolactinomia. 4

5 During treatment with high doses, as is recommended for panic disorders and related conditions, the following adverse reactions were noted more frequently compared to placebo: sedation, somnolence, fatigue, ataxia, impaired co-ordination, speech disorders. The following adverse reactions were observed less frequently: mood changes, gastrointestinal symptoms, dermatitis, memory disorders, sexual dysfunction, cognitive disorders and confusion. OTHER EFFECTS DUE TO THE USE OF BENZODIAZEPINES - psychic and physical dependence; - withdrawal symptoms: Once physical dependence has developed, abrupt cessation of treatment can be associated with withdrawal symptoms. These can vary from headache, muscle pain, extreme anxiety, tension, agitation, confusion, irritability to derealization, depersonalization, impaired hearing, stiffening and tingling of the limbs, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. Rebound phenomena such as insomnia and anxiety can occur when treatment is discontinued. Mood changes, anxiety, sleep disorders and agitation may also occur in these circumstances. Benzodiazepines abuse has been reported. Severe symptoms in particular are observed more frequently on long-term high dose treatment. These withdrawal symptoms have also been observed when treatment was withdrawn rapidly or discontinued abruptly. Gradual dose reduction is therefore advisable when treatment is discontinued. It is advisable to reduce the daily dose of Xanagis tablets with no more than 0.5 mg every three days. Some patients require an even more gradual dose reduction. Posology and method of administration The optimum dosage of Xanagis (alprazolam) should be determined individually based on the severity of the symptoms and individual patient response. In the event of severe adverse effects with initial dose, a dose reduction is necessary. The recommended daily dose will be sufficient in most patients. In the few patients who require a higher dose, the dosage should be increased gradually, starting with a higher dose in the evening, to avoid adverse effects. In general, patients who have not previously taken psychotropic agents will require a lower dose compared to those who have previously been treated with tranquillizers, antidepressants or hypnotics or compared to chronic alcoholics. In order to prevent ataxia and oversedation, it is advisable to use the lowest effective dose. This is particularly important in elderly and/or debilitated patients. SYMPTOMATIC TREATMENT OF ANXIETY Recommended starting dose: varies from 0.25 mg to 0.5 mg three times daily. Recommended dose: The dose can be increased to suit the patient's needs to a maximal daily dose of 4 mg divided over the day. 5

6 SYMPTOMATIC TREATMENT OF PANIC DISORDERS Recommend starting dose: varies from 0.5 to 1 mg at bedtime. Recommended dose: The dose should be adjusted according to the patient's response. The maximal dose increase should be 1 mg every three to four days. Additional doses may be given to reach 3 or 4 administrations daily. In clinical studies the mean dose was 6 ± 2 mg. Exceptionally, a maximum dose of 10 mg daily was required in a few patients. TREATMENT OF GERIATRIC OR DEBILITATED PATIENTS Recommended starting dose: 0.25 mg twice to three times daily. Recommended dose: If necessary, the dose can be increased gradually depending on tolerance. The starting dose should be reduced if side-effects occur. DISCONTINUATION OF TREATMENT Since the treatment is symptomatic, the original symptoms may recur after discontinuation of treatment. The dose should be tapered off gradually. It is advisable to reduce the daily dose of Xanagis with maximum decrements of 0.5 mg every three days. In some patients, it may even be necessary to reduce the dose more gradually. Treatment should be as short as possible. The patient should be re-assessed regularly and the need to prolong treatment should be evaluated, certainly when the patient's symptoms are milder and might not require medicinal treatment. The general period of treatment should not exceed 8 to 12 weeks, including the tapering off process. As mentioned above, treatment is symptomatic, and is applied episodically, considering the agreed maximum duration of 8 to 12 weeks. In case of long-term use, there is a risk of dependence (unfavourable benefit/risk). In certain cases, it may be necessary to prolong the period of treatment. However, this should only be done after re-assessment of the patient by a specialist. Overdose Symptoms of Xanagis overdosage include extensions of its pharmacological activity, such as ataxia, somnolence, speech disorders, coma and respiratory depression. Although a benzodiazepine overdose is not usually life-threatening, it is always necessary to bear in mind the possibility that agents such as alcohol and barbiturates have been taken and the potential underlying pathology should be considered. Treatment should be adapted accordingly. Treatment of overdosage consists mainly in supporting respiratory and cardiovascular functions. In case of coma, treatment is mainly symptomatic, hereby avoiding complications such as asphyxiation due to ptosis of the tongue or aspiration pf gastric contents. Intravenous fluid administration is required to prevent dehydration. When other sedatives have been taken in combination, it is of primordial importance to support vital functions. Shortly after ingestion, gastric lavage and/or activated charcoal can be indicated. Afterwards, an osmotic laxative can be administered. It is known that the 6

7 effect due to ingestion of a very large dose can persist for a long time. Forced diuresis or haemodialysis is of limited use. In case of a severe intoxication with coma or respiratory insufficiency, IV administration of flumazenil can be used as antidote. The use of flumazenil as an antidote is contra-indicated in the following situations: - Use of tricyclic antidepressants - Concurrent use of drugs that induce seizures - ECG anomalies such as prolonged QRS interval or QT interval (suggestive of concurrent use of tricyclic antidepressants). PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: derivatives of benzodiazepines, ATC code: N05B A12. Xanagis contains triazolobenzodiazepines. All benzodiazepines have qualitatively similar properties: anxiolysis, hypnosedation, myorelaxation, anticonvulsion. However, there arequantitative pharmacokinetic differences, which have resulted in various fields of application. In general it is accepted that the benzodiazepines is based upon potentiation of neural inhibition, mediated by gamma-aminobutyric acid. Pharmacokinetic properties Maximal plasma levels are reached one to two hours after oral administration of Xanagis tablets. ALPRAZOLAM The half-life of alprazolam is between 12 and 15 hours and is 16 hours on average in elderly patients. Alprazolam is mainly oxidized. The principal metabolites of alprazolam are alphahydroxy-alprazolam and benzophenone derivatives. The plasma levels of these metabolites are extremely low. The biological activity of alpha-hydroxy-alprazolam is about half of that of alprazolam. The half-lives are of the same order of magnitude as that of alprazolam. The benzophenone derivative is almost inactive. Alprazolam and its metabolites are mainly eliminated via urine. In vitro, 80% of alprazolam is bound to serum proteins. Preclinical safety data It has been shown in rats that alprazolam, when submitted for two years in a dosage of 3, 10 and 30 mg/kg/day (15 to 150 times the maximum recommended human dose), results in a tendency of dose-dependent increase of the incidence of cataract and corneal vascularisation is male and female. In repeated dose-toxicity studies for 12 months in dogs, (sometimes fatal) seizures were observed with doses of 3 mg/kg/day (15 times the maximum recommended human dose). The duration and incidence of the convulsive periods was dosedependent. Relevance of these data for human is not clear yet. Two-year studies in rats and mice gave no evidence for carcinogenic effects. 7

8 PHARMACEUTICAL PARTICULARS List of excipients The adjuvants are: lactose, microcrystalline cellulose, colloidal anhydroussilica, maize starch, magnesium stearate and sodiume docusate (85%) sodiume benzoate (15%) powder. The tablets with 0.5 mg alprazolam also contain the colouring agent erythrosine aluminum laque (E127). The tablets with 1 mg also contain the colouring agents erythrosine (E127) aluminum laque and certain indigo (E132). Incompatibilities Not applicable Shelf life 36 months Special precautions for storage Keep out of reach and sight of children. Store at room temperature (15-25 C). Presentations Box containing 50 tablets of 0.25 mg. Box containing 50 tablets of 0.5 mg. Box containing 50 tablets of 1 mg. Perrigo Israel Pharmaceuticals, Ltd., Yeruham