Central Nervous System-Antidepressants
= Additional active ingredients
Bupropion HCl 150 mg, 300 mg.
PRESENTATION AND DOSSAGE
TABS: 30 X 150 mg
TABS: 30 X 300 mg
The drug is indicated for the treatment of major depressive episodes. Following satisfactory response, continuation of therapy with the drug is effective in preventing relapse.
Hypersensitivity to bupropion or any of the excipients. Patients taking any other medicdbinal product containing bupropion, as the incidence of seizures is dose dependent. Patients with a current seizure disorder or any history of seizures. Patients with a known central nervous system tumor. Patients who, at any time during treatment, are undergoing abrupt withdrawal from alcohol or any medicdbinal product known to be associated with a risk of seizures on withdrawal (in particular benzodiazepines and benzodiazepine-like agents). Patients with severe hepatic cirrhosis. Patients with a current or previous diagnosis of bulimia or anorexia nervosa. Concomitant use with MAOI’s. At least 14 days should elapse between discontinuation of irreversible MAOI’s and initiation of treatment. For reversible MAOI’s, a 24 hour period is sufficient.
Seizures: The recommended dose of modified release bupropion tablets should not be exceeded, since bupropion is associated with a dose-related risk of seizure. The overall incidence of seizure with modified release bupropion tablets in clinical trials at doses up to 450 mg/day was approximately 0.1%. There is an increased risk of seizures occurring with the use of this drug in the presence of predisposing risk factors which lower the seizure threshold. Therefore, the drug should be administered with caution to patients with one or more conditions predisposing to a lowered seizure threshold. 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), Alcohol abuse, History of head trauma, Diabetes treated with hypoglycaemics or insulin, Use of stimulants or anorectic products. This drug should be discontinued and not recommenced in patients who experience a seizure while on treatment.
Neuropsychiatry: Suicide/suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Neuropsychiatric symptoms including mania and bipolar disorder: Neuropsychiatric symptoms have been reported. In particular, psychotic and manic symptomatology has been observed, mainly in patients with a known history of psychiatric illness. Additionally a major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Limited clinical data on use of bupropion in combination with mood stabilisers in patients with a history of bipolar disorder suggests a low rate of switch to mania. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Data in animals suggest a potential for abuse. However, studies on abuse liability in humans and extensive clinical experience show that bupropion has low abuse potential. Clinical experience with bupropion in patients receiving electroconvulsive therapy (ECT) is limited. Caution should be exercised in patients receiving ECT therapy concomitantly with bupropion treatment.
Hypersensitivity: This drug should be discontinued promptly if patients experience hypersensitivity reactions during treatment. Clinicians should be aware that symptoms may progress or recur following the discontinuation of this 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 . In most patients symptoms improved after stopping bupropion and initiating treatment with antihistamine or corticosteroids, and resolved over time.
Cardiovascular disease: There is limited clinical experience of the use of bupropion to treat depression in patients with cardiovascular disease. Care should be exercised if it is used in these patients. However, bupropion was generally well tolerated in studies for smoking cessation in patients with ischaemic cardiovascular disease.
Blood pressure: Bupropion has been shown not to induce significant increases in blood pressure in non-depressed patients with Stage I hypertension. However, in clinical practice, hypertension, which in some cases may be severe and require acute treatment, has been reported in patients receiving bupropion. 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. Concomitant use of bupropion and a nicotine transdermal system may result in elevations of blood pressure.
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including this drug 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.
Specific patient groups: Pediatric population – Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders.
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. All patients with hepatic impairment should be monitored closely 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 the urine as its metabolites. Therefore in patients with renal impairment, bupropion and its active metabolites may accumulate to a greater extent than usual. The patient should be closely monitored for possible undesirable effects (e.g. insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels.
Older people – Efficacy has been shown equivocally in older people. In a clinical trial, older people followed the same dose regimen as for the adults. Greater sensitivity in some older individuals cannot be ruled out.
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.
Inappropriate routes of administration: This product 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.
Hypersensitivity reactions such as urticaria. anorexia. Insomnia, agitation, anxiety. Headache, tremor, dizziness, taste disorders. Visual disturbance, tinnitus. Increased blood pressure (sometimes severe), flushing, dry mouth, GI disturbance including nausea and vomiting. Abdominal pain, constipation, rash pruritus, sweating. Fever, chest pain, asthenia.
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.
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 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. 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), antipsychotics (e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), serotonin selective reuptake inhibitors (SSRIs) and Type 1C antiarrhythmics (e.g. propafenone, 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 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 (a SSRI) 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 hydroxybupropion. 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 coadministered 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. The clinical consequences of the reduced exposure are unclear, but may include decreased efficacy in the treatment of major depression. 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.
Other interaction information: 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 bupropion treatment. The consumption of alcohol during treatment with this drug should be minimised or avoided.
Use in Adults: The recommended starting dose is 150 mg, given once daily. An optimal dose was not established in clinical studies. If no improvement is seen after 4 weeks treatment at 150 mg, the dose may be increased to 300 mg, given once daily. There should be an interval of at least 24 hours between successive doses. The onset of action for bupropion has been noted 14 days after starting therapy. As with all antidepressants the full antidepressant effect of the drug may not be evident until after several weeks of treatment. Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.
Pediatric Population: The drug is not indicated for use in children or adolescents aged less than 18 years. The safety and efficacy of this drug in patients under 18 years of age have not been established.
Older people: Efficacy has been shown equivocally in older people. In a clinical trial, older people followed the same dose regimen as for the adults. Greater sensitivity in some older individuals cannot be ruled out.
Patients with hepatic impairment: The 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: The recommended dose in these patients is 150mg once a day, as bupropion and its active metabolites may accumulate in such patients to a greater extent than usual.
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 electrocardiogram (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.
PREGNANCY & 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 during pregnancy unless the clinical condition of the woman requires treatment with bupropion and alternative treatments are not an option.
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.
MANUFACTURER & DISTRIBUTER:
License Holder: GlaxoSmithKline Israel Ltd.