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  • Zyban
    / GSK


    Active Ingredient
    Bupropion (as HCl) 150 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Prolonged-Release Tablets

    60 X 150 mg

    partial basket chart 25889 26101

    Dosage

    Use in Adults: It is recommended that treatment is started while the patient is still smoking and a “target stop date” set within the first two weeks of treatment with the drug, preferably in the second week. The initial dose is 150 mg to be taken daily for six days, increasing on day seven to 150 mg twice daily. There should be an interval of at least 8 hours between successive doses. The maximum single dose must not exceed 150 mg and the maximum total daily dose must not exceed 300 mg. Insomnia is a very common adverse event which can be reduced by avoiding bedtime doses of the drug (provided there is at least 8 hours between doses).
    Pediatric Population: Use in patients under 18 years of age is not recommended as the safety and efficacy of the drug have not been evaluated in these patients.
    Older people: This drug should be used with caution in older people. Greater sensitivity in some older individuals cannot be ruled out. The recommended dose in older people is 150 mg once a day.
    Patients with hepatic impairment: This drug should be used with caution in patients with hepatic impairment. Because of increased variability in the pharmacokinetics in patients with mild to moderate impairment the recommended dose in these patients is 150 mg once a day.
    Patients with renal impairment: This drug should be used with caution in patients with renal insufficiency. The recommended dose in these patients is 150 mg once a day.
    See prescribing information for full details.


    Indications

    The drug is indicated as an aid to smoking cessation in combination with motivational support in nicotine-dependent patients.


    Contra-Indications

    Hypersensitivity to bupropion or any of the excipients. Current seizure disorder or any history of seizures. Known central nervous system (CNS) tumour. Patients who, at any time during treatment, are undergoing abrupt withdrawal from alcohol or any medicinal product known to be associated with risk of seizures on withdrawal (in particular benzodiazepines and benzodiazepine-like agents). Current or previous diagnosis of bulimia or anorexia nervosa. Severe hepatic cirrhosis. Concomitant use of the drug and monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 14 days should elapse between discontinuation of irreversible MAOIs and initiation of treatment with this drug. For reversible MAOIs, a 24 hour period is sufficient.
    Patients with a history of bipolar disorder as it may precipitate a manic episode during the depressed phase of their illness. The drug should not be administered to patients being treated with any other medicinal product containing bupropion as the incidence of seizures is dose dependent and to avoid overdosage.


    Special Precautions

    Seizures: The recommended dose of the drug must not be exceeded, since bupropion is associated with a dose-related risk of seizure. At doses up to the maximum recommended daily dose (300 mg daily), the incidence of seizures is approximately 0.1% (1/1,000). There is an increased risk of seizures occurring with the use of the drug in the presence of predisposing risk factors which lower the seizure threshold. The drug must not be used in patients with predisposing risk factors unless there is a compelling clinical justification for which the potential medical benefit of smoking cessation outweighs the potential increased risk of seizure. In these patients, a maximum dose of 150 mg daily should be considered for the duration of treatment.
    All patients should be assessed for predisposing risk factors, which include: Concomitant administration of other medicinal products known to lower the seizure threshold (e.g., antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones and sedating antihistamines). For patients prescribed such medicinal products whilst taking this drug, a maximum dose of 150 mg daily for the remainder of their treatment should be considered. Alcohol abuse. History of head trauma. Diabetes treated with hypoglycaemics or insulin. Use of stimulants or anorectic products. The drug should be discontinued and not recommenced in patients who experience a seizure while on treatment.
    Interactions: Due to pharmacokinetic interactions plasma levels of bupropion or its metabolites may be altered, which may increase the potential for undesirable effects (e.g. dry mouth, insomnia, seizures). Therefore care should be taken when bupropion is given concomitantly with medicinal products which can induce or inhibit the metabolism of bupropion. Bupropion inhibits metabolism by cytochrome P450 2D6. Caution is advised when medicinal products metabolised by this enzyme are administered concomitantly. In the literature it has been shown that medications that inhibit CYP2D6 may lead to reduced concentrations of endoxifen which is the active metabolite of tamoxifen. Therefore the use of bupropion, which is an inhibitor of CYP2D6, should whenever possible be avoided during tamoxifen treatment.
    Neuropsychiatry: This drug is a centrally-acting noradrenaline/dopamine reuptake inhibitor. Neuropsychiatric reactions have been reported. In particular, psychotic and manic symptomatology have been reported mainly in patients with a known history of psychiatric illness. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation and behaviour (including suicide attempt), has been reported in patients undergoing a smoking cessation attempt. These symptoms have also been reported during treatment with this drug, and generally occurred early during the treatment course. Bupropion is indicated for the treatment of depression in some countries. A meta-analysis of placebo controlled clinical trials of antidepressant drugs in adults with major depressive disorder and other psychiatric disorders showed an increased risk of suicidal thinking and behaviour associated with antidepressant use compared to placebo in patients less than 25 years old. Clinicians should be aware of the possible emergence of significant depressive symptomatology in patients undergoing a smoking cessation attempt, and should advise patients accordingly. Data in animals suggest a potential for drug abuse. However, studies on abuse liability in humans and extensive clinical experience show that bupropion has low abuse potential.
    Hypersensitivity: This drug should be discontinued if patients experience hypersensitivity reactions during treatment. Clinicians should be aware that symptoms may progress or recur following the discontinuation of the drug and should ensure symptomatic treatment is administered for an adequate length of time (at least one week). Symptoms typically include skin rash, pruritus, urticaria or chest pain but more severe reactions may include angioedema, dyspnoea/bronchospasm, anaphylactic shock, erythema multiforme or Stevens-Johnson Syndrome. Arthralgia, myalgia and fever have also been reported in association with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness. In most patients symptoms improved after stopping bupropion and initiating treatment with antihistamine or corticosteroids, and resolved over time.
    Hypertension: In clinical practice, hypertension, which in some cases may be severe and require acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. This has been observed in patients with and without pre-existing hypertension. A baseline blood pressure should be obtained at the start of treatment with subsequent monitoring, especially in patients with pre-existing hypertension. Consideration should be given to discontinuation of this drug if a clinically significant increase in blood pressure is observed. Limited clinical trial data suggest that higher smoking cessation rates may be achieved by the combination use of this drug together with Nicotine Transdermal System (NTS). However, a higher rate of treatment-emergent hypertension was noted in the combination therapy group. If combination therapy with a NTS is used, caution must be exercised and weekly monitoring of blood pressure is recommended. Prior to initiation of combination therapy prescribers should consult the prescribing information of the relevant NTS.
    Specific patient groups
    Older people: Clinical experience with bupropion has not identified any differences in tolerability between older and other adult patients. However, greater sensitivity of some older individuals cannot be ruled out; hence 150 mg once a day is the recommended dose in these patients.
    Patients with hepatic impairment: Bupropion is extensively metabolised in the liver to active metabolites, which are further metabolised. No statistically significant differences in the pharmacokinetics of bupropion were observed in patients with mild to moderate hepatic cirrhosis compared with healthy volunteers, but bupropion plasma levels showed a higher variability between individual patients. Therefore this drug should be used with caution in patients with mild to moderate hepatic impairment and 150 mg once a day is the recommended dose in these patients. All patients with hepatic impairment should be closely monitored for possible undesirable effects (e.g., insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels.
    Patients with renal impairment: Bupropion is mainly excreted into urine as its metabolites. Therefore 150 mg once a day is the recommended dose in patients with renal impairment, as bupropion and its active metabolites may accumulate to a greater extent than usual. The patient should be closely monitored for possible undesirable effects that could indicate high drug or metabolite levels.
    Interference with urine testing: Having an amphetamine-like chemical structure, bupropion interferes with the assay used in some rapid urine drug screens, which can result in false positive readings, particularly for amphetamines. A positive result should usually be confirmed with a more specific method.
    Angle-closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including bupropion may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Patients should be advised that taking this drug can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
    Inappropriate routes of administration: This drug is intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported, and may lead to a rapid release, faster absorption and a potential overdose. Seizures and/or cases of death have been reported when bupropion has been administered intra-nasally or by parenteral injection.
    See prescribing information for full details.


    Side Effects

    The most common side effects are: Hypersensitivity reactions, such as urticaria, insomnia, depression, tremor, concentration disturbance, headache, dizziness, taste disorders, dry mouth, gastrointestinal disturbance including nausea and vomiting, abdominal pain, constipation, rash, pruritus, sweating, fever.
    See prescribing information for full details.


    Drug interactions

    In patients receiving medicinal products known to lower the seizure threshold, this drug must only be used if there is a compelling clinical justification for which the potential medical benefit of smoking cessation outweighs the increased risk of seizure.
    The effect of bupropion on other medicinal products: Although not metabolised by the CYP2D6 isoenzyme, bupropion and its main metabolite, hydroxybupropion, inhibit the CYP2D6 pathway. Co-administration of bupropion hydrochloride and desipramine to healthy volunteers known to be extensive metabolisers of the CYP2D6 isoenzyme resulted in large (2- to 5-fold) increases in the Cmax and AUC of desipramine. Inhibition of CYP2D6 was present for at least 7 days after the last dose of bupropion hydrochloride.
    Concomitant therapy with medicinal products with narrow therapeutic indices that are predominantly metabolised by CYP2D6 should be initiated at the lower end of the dose range of the concomitant medicinal product. Such medicinal products include certain antidepressants (e.g. desipramine, imipramine, paroxetine), antipsychotics (e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), and Type 1C antiarrhythmics (e.g. propafanone, flecainide). If this drug is added to the treatment regimen of a patient already receiving such a medicinal product, the need to decrease the dose of the original medicinal product should be considered. In these cases the expected benefit of treatment with this drug should be carefully considered compared with the potential risks.
    Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g. tamoxifen), may have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion.
    Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.
    The effect of other medicinal products on bupropion: Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6. Co-administration of medicinal products that may affect the metabolism of bupropion via CYP2B6 isoenzyme (e.g. CYP2B6 substrates: cyclophosphamide, ifosfamide, and CYP2B6 inhibitors: orphenadrine, ticlopidine, clopidogrel), may result in increased bupropion plasma levels and lower levels of active metabolite hydroxy-bupropion. The clinical consequences of the inhibition of the metabolism of bupropion via CYP2B6 enzyme and the consequent changes in the bupropion-hydroxybupropion ratio are currently unknown.
    Since bupropion is extensively metabolised, caution is advised when bupropion is co-administered with medicinal products known to induce metabolism (e.g. carbamazepine, phenytoin, ritonavir, efavirenz) or inhibit metabolism (e.g. valproate), as these may affect its clinical efficacy and safety.
    In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20 to 80%. Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers. Patients receiving any of these drugs with bupropion may need increased doses of bupropion but the maximum recommended dose of bupropion should not be exceeded.
    Nicotine, administered transdermally by patches, did not affect the pharmacokinetics of bupropion and its metabolites.
    Co-administration of digoxin with bupropion may decrease digoxin levels. Digoxin AUC 0–24 h was decreased and renal clearance was increased in healthy volunteers, based on a cross-study comparison. Clinicians should be aware that digoxin levels may rise on discontinuation of bupropion and the patient should be monitored for possible digoxin toxicity.
    Other interactions: Smoking is associated with an increase in CYP1A2 activity. After cessation of smoking, reduced clearance of medicinal products metabolised by this enzyme, with subsequent increases in plasma levels, may occur. This may be particularly important for those medicinal products primarily metabolised by CYP1A2 with narrow therapeutic windows (e.g. theophylline, tacrine and clozapine). The clinical consequences of smoking cessation on other medicinal products that are partially metabolised by CYP1A2 (e.g., imipramine, olanzapine, clomipramine, and fluvoxamine) are unknown. In addition, limited data indicate that the metabolism of flecainide or pentazocine may also be induced by smoking.
    Administration of this drug to patients receiving either levodopa or amantadine concurrently should be undertaken with caution. Limited clinical data suggest a higher incidence of undesirable effects (e.g. nausea, vomiting, and neuropsychiatric events) in patients receiving bupropion concurrently with either levodopa or amantadine. Although clinical data do not identify a pharmacokinetic interaction between bupropion and alcohol, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during treatment with this drug. The consumption of alcohol during treatment with this drug should be minimised or avoided. Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by a different mechanism from bupropion, concomitant use of this drug and monoamine oxidase inhibitors (MAOIs) is contraindicated as there is an increased possibility of adverse reactions from their co-administration. At least 14 days should elapse between discontinuation of irreversible MAOIs and initiation of treatment with this drug. For reversible MAOIs, a 24 hour period is sufficient. Studies suggest that exposure to bupropion may be increased when sustained release bupropion tablets are taken with a high fat meal.
    Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 subjects and had only a slight increase in the AUC of lamotrigine glucuronide.  


    Pregnancy and Lactation

    Pregnancy: Some epidemiological studies of pregnancy outcomes following maternal exposure to bupropion in the first trimester have reported an association with increased risk of certain congenital cardiovascular malformations specifically ventricular septal defects and left outflow tract heart defects. These findings are not consistent across studies. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. This drug should not be used in pregnancy. Pregnant women should be encouraged to quit smoking without the use of pharmacotherapy.
    Lactation: Bupropion and its metabolites are excreted in human breast milk. A decision on whether to abstain from breast-feeding or to abstain from therapy with this drug should be made taking into account the benefit of breast-feeding to the newborn/infant and the benefit of therapy with this drug to the mother.
    See prescribing information for full details.


    Overdose

    Acute ingestion of doses in excess of 10 times the maximum therapeutic dose has been reported. In addition to those events reported as Undesirable Effects, overdose has resulted in symptoms including drowsiness, loss of consciousness and/or ECG changes such as conduction disturbances (including QRS prolongation), arrhythmias and tachycardia. QTc prolongation has also been reported but was generally seen in conjunction with QRS prolongation and increased heart rate. Although most patients recovered without sequelae, deaths associated with bupropion have been reported rarely in patients ingesting large overdoses of the drug.
    Treatment: In the event of overdose, hospitalisation is advised. ECG and vital signs should be monitored. Ensure an adequate airway, oxygenation and ventilation. The use of activated charcoal is recommended. No specific antidote for bupropion is known. Further management should be as clinically indicated.


    Important notes

    Storage: Should be stored above 25°C, in the original package.


    Manufacturer
    Glaxo Wellcome SA, SPAIN
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