Bupyra Xl 150mg & 300mg Tablets

BUPYRA XL is indicated for the treatment of depression as defined by DSM IV Criteria. Following a satisfactory response, continuation with BUPYRA XL therapy is effective in preventing relapse and preventing recurrence of further depressive episodes.

Therapy should be initiated by medical practitioners experienced in the treatment of depression. BUPYRA XL tablets should be swallowed whole. The tablets should not be cut, crushed or chewed as this may lead to an increased risk of adverse effects including seizure. There should be an interval of at least 24 hours between successive doses. Insomnia is a very common adverse event which is often transient. Insomnia may be reduced by avoiding dosing at bedtime (provided there is at least 24 hours between doses) or, if clinically indicated, dose reduction.

Posology:

Initial treatment: The initial dose of BUPYRA XL is 150 mg taken as a single daily dose in the morning. Patients who are not responding adequately to a dose of 150 mg/day may benefit from an increase to the usual adult target dose of 300 mg/day, given once daily.

Switching patients from sustained release tablets: When switching patients from sustained release tablets to extended release tablets; give the same total daily dose when possible. Patients who are currently being treated with sustained release tablets at 300 mg/day (e.g. 150 mg twice daily) may be switched to extended release tablets 300 mg once daily.

Special populations:

Children and adolescents: BUPYRA XL is not indicated for use in children or adolescents aged less than 18 years (see section 4.3).

Elderly: Greater sensitivity of some elderly individuals to BUPYRA XL cannot be ruled out; hence a reduced frequency and/or dose may be required (see section 4.4).

Renal impairment: Treatment of patients with renal impairment should be initiated at a reduced frequency and/or dose as bupropion and its metabolites may accumulate in such patients to a greater extent than usual (see section 4.4).

Hepatic impairment: BUPYRA XL should be used with caution in patients with mild liver impairment. Because of increased variability in the pharmacokinetics in patients with mild hepatic cirrhosis, a reduced frequency of dosing should be considered (see section 4.4). BUPYRA XL is contraindicated in patients with moderate to severe hepatic cirrhosis (see section 4.3).

• Hypersensitivity to bupropion hydrochloride or to any of the excipients listed in section 6.1.
• Patients younger than 18 years.
• BUPYRA XL is contraindicated in patients with a seizure disorder or any history of seizures.
• BUPYRA XL is contraindicated in patients with a known central nervous system tumour.
• Patients being treated with any other preparation containing bupropion should not receive BUPYRA XL, as the incidence of seizures is dose dependent.
• Patients undergoing abrupt discontinuation of alcohol or sedatives (benzodiazepines and benzodiazepine-like medicines) should not receive BUPYRA XL.
• Patients with a current or previous diagnosis of bulimia or anorexia nervosa should not receive BUPYRA XL as a higher incidence of seizures was seen in this patient population when BUPYRA XL was administered.
• BUPYRA XL is contraindicated with concomitant administration with monoamine oxidase inhibitors (MAOIs). At least 14 days should elapse between the discontinuation of MAOIs and initiation of treatment with BUPYRA XL.
• Liver disease, Child-Pugh grades B and C, range 7 - 13.
• Women of child-bearing potential not using contraception.

Seizures: The recommended dose of BUPYRA XL should not be exceeded, since BUPYRA XL 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 BUPYRA XL in the presence of predisposing risk factors, which lower the seizure threshold. Therefore, BUPYRA XL should not be administered to patients with one or more conditions predisposing to a lowered seizure threshold, which include:

• history of head trauma
• central nervous system (CNS) tumour
• history of seizures
• concomitant administration of other medicines known to lower the seizure threshold (e.g. antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones and sedating antihistamines)
• excessive use of alcohol or sedatives (see section 4.3)
• diabetes treated with hypoglycaemics or insulin
• use of stimulants or anorectic medicines.

BUPYRA XL treatment should be stopped and is not recommended for patients who experience a seizure while on treatment.

Interactions (see section 4.5): 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 BUPYRA XL is given concomitantly with medicines which can induce or inhibit the metabolism of bupropion. BUPYRA XL inhibits metabolism by cytochrome P450 2D6. Caution is advised when medicines metabolised by this enzyme are administered concurrently.

Neuropsychiatry: Suicide/suicidal thoughts or clinical worsening: Patients with major depressive disorder may experience worsening of their depression and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medicines. This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients being treated with BUPYRA XL should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of therapy, or at the time of dose changes, either increases or decreases. Patients with a history of suicidal behaviour or thoughts, young adults and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia, hypomania and mania.

A meta-analysis of placebo controlled clinical trials of antidepressant medicines 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.

Close supervision of patients and in particular those at high risk should accompany medicine therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

It should be recognised that the onset of some neuropsychiatric symptoms could be related either to the underlying disease state or the medicine therapy and an appropriate patient assessment should be undertaken (see Neuropsychiatric symptoms including mania and bipolar disorder below; see section 4.8).

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing BUPYRA XL, in patients who experience the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patientu2019s presenting symptoms.

Neuropsychiatric symptoms including mania and bipolar disorder: Neuropsychiatric symptoms have been reported (see section 4.8). In particular, psychotic and manic symptomatology has been observed, mainly in patients with a known history of psychiatric illness. Aggression, rage and violent behaviour may occur. 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 the 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 BUYPRA XL, 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.

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: BUPYRA XL should be promptly discontinued if patients experience hypersensitivity reactions during treatment (see section 4.3). Healthcare providers should be aware that the symptoms may progress or recur following the discontinuation of BUPYRA XL 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 (see section 4.8). In most patients symptoms improved after stopping bupropion and initiating treatment with antihistamines or corticosteroids, and resolved over time.

Cardiovascular disease: There is limited clinical experience of the use of bupropion as contained in BUPYRA XL to treat depression in patients with cardiovascular disease. Care should be exercised if it is used in these patients. However, bupropion as contained in BUPYRA XL was generally well tolerated in studies for smoking cessation in patients with ischaemic cardiovascular disease (see section 5.1).

Blood pressure: Bupropion as contained in BUPYRA XL 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 (see section 4.8) 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 BUPYRA XL if a clinically significant increase in blood pressure is observed. Concomitant use of BUPYRA XL and a nicotine transdermal system may result in elevations of blood pressure.

Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by a different mechanism from bupropion, concomitant use of BUPYRA XL and monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.3) 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 BUPYRA XL. For reversible MAOIs a 24-hour period is sufficient.

The effect of bupropion on other medicines:

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 C max and AUC of desipramine. Inhibition of CYP2D6 was present for at least 7 days after the last dose of bupropion. Concomitant therapy with medicines with narrow therapeutic indices that are predominantly metabolised by CYP2D6 should be initiated at the lower end of the dose range of the concomitant medicine. Such medicines 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 antidysrhythmics (e.g. propafenone, flecainide). If BUPYRA XL is added to the treatment regimen of a patient already receiving such a medicine, the need to decrease the dose of the original medicine should be considered.

There have been post-marketing reports of serotonin syndrome, a potentially life-threatening condition, when bupropion is co-administered with a serotonergic medicine, such as Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.4).

Medicines 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 BUPYRA XL (see section 4.4). Although citalopram (a SSRI) is not primarily metabolised by CYP2D6, in one study, bupropion increased the C max and AUC of citalopram by 30% and 40%, respectively. Co-administration of digoxin with bupropion may decrease digoxin levels. Digoxin AUC 0u201324 h was decreased and renal clearance was increased in healthy volunteers, based on a cross-study comparison.

Medical practitioners should be aware that digoxin levels may rise on discontinuation of BUPYRA XL and the patient should be monitored for possible digoxin toxicity.

The effect of other medicines on bupropion:

BUPYRA XL is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6 (see section 5.2). Co-administration of medicines 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 as contained in BUPYRA XL is extensively metabolised, caution is advised when BUPYRA XL is co-administered with medicines 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. It has been reported 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% (see section 5.2). 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 medicines with BUPYRA XL may need increased doses, but the maximum recommended dose of BUPYRA XL should not be exceeded.

Other interaction information:

Administration of BUPYRA XL 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 u2013 see section 4.8) in patients receiving BUPYRA XL 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 BUPYRA XL treatment should be minimised or avoided. There have been no pharmacokinetic studies with BUPYRA XL and co-administered benzodiazepines. Based on in vitro metabolic pathways, there is no basis for such an interaction. After co-administration of bupropion with diazepam in healthy volunteers, there was less sedation than when diazepam was administered alone. There has been no systematic evaluation of the combination of bupropion as contained in BUPYRA XL with antidepressants (other than desipramine and citalopram), benzodiazepines (other than diazepam), or neuroleptics. There has also been limited clinical experience with St Johnu2019s Wort. Concomitant use of BUPYRA XL and a nicotine transdermal system (NTS) may result in elevations of blood pressure.

Pregnancy: Safety in pregnancy has not been established. Epidemiological studies of pregnancy outcomes following maternal exposure to bupropion in the first trimester have reported an association with increased risk of some congenital cardiovascular malformations, including ventricular septal defects and left ventricular outflow tract defects. These findings are not consistent across studies.

Lactation: Safety in lactation has not been established. As bupropion and its metabolites are excreted in human breast milk, mothers should be advised not to breastfeed while taking BUPYRA XL.

Fertility: There are no data on the effect of bupropion on human fertility. A reproductive study in rats revealed no evidence of impaired fertility.

BUPYRA XL may affect the ability to perform tasks that require judgement or motor and cognitive skill. Patients should exercise caution before driving or use of any machinery until they are reasonably certain BUPYRA XL does not adversely affect their performance.

SOC: FREQUENCY:

Blood and lymphatic system disorders: Frequency unknown: Anaemia, leukopenia and thrombocytopenia

Immune system disorders: Frequent: Hypersensitivity reactions such as urticaria

Less frequent: More severe hypersensitivity reactions including angioedema, dyspnoea/bronchospasm and anaphylactic shock. 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.

Metabolism and nutrition disorders: Frequent: Anorexia

Less frequent: Weight loss, blood glucose disturbances

Frequency unknown: Hyponatraemia

Psychiatric disorders: Frequent: Insomnia (see section 4.2), agitation, anxiety

Less frequent: Depression, confusion, aggression, hostility, irritability, restlessness, hallucinations, abnormal dreams including nightmares, delusions, depersonalisation, paranoid ideation

Frequency unknown: Suicidal ideation and suicidal behaviour***, psychosis

Nervous system disorders: Frequent: Headache, tremor, dizziness, taste disorders

Less frequent: Concentration disturbance, seizures**, dystonia, ataxia, parkinsonism, incoordination, memory impairment, paraesthesia, syncope

Frequency unknown: Serotonin syndrome****

Eye disorders: Frequent: Visual disturbance

Ear and labyrinth disorders: Frequent: Tinnitus

Cardiac disorders: Less frequent: Tachycardia, palpitations

Vascular disorders: Frequent: Increased blood pressure (sometimes severe), flushing

Less frequent: Vasodilation, postural hypotension

Gastrointestinal disorders: Frequent: Dry mouth, gastrointestinal disturbance including nausea and vomiting, abdominal pain, constipation

Hepato-biliary disorders: Less frequent: Elevated liver enzymes, jaundice, hepatitis

Skin and subcutaneous tissue disorders: Frequent: Rash, pruritis, sweating

Less frequent: Erythema multiforme, Stevens Johnson syndrome, exacerbation of psoriasis

Frequency unknown: Systemic lupus erythematosus syndrome aggravated, cutaneous lupus erythematosus, acute generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders: Less frequent: Twitching

Renal and urinary disorders: Less frequent: Urinary frequency and/or retention, urinary incontinence

General disorders and administration site conditions: Frequent: Fever, chest pain, asthenia

* Hypersensitivity may manifest as skin reactions. Refer to u2018Immune system disordersu2019 and u2018Skin and subcutaneous tissue disordersu2019.

** The incidence of seizures is approximately 0.1% (1/1,000). The most frequent type of seizures is generalised tonic-clonic seizures, a seizure type which can result in some cases, in postictal confusion or memory impairment (see section 4.4).

*** Cases of suicidal ideation and suicidal behaviour have been reported during bupropion therapy or early after treatment discontinuation (see section 4.4).

**** Serotonin syndrome may occur as a consequence of an interaction between BUPYRA XL and a serotonergic medicine such as Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.4).

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u20186.04 Adverse Drug Reaction Reporting Formu2019, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In addition to those events reported as undesirable effects, overdose has resulted in symptoms including drowsiness, loss of consciousness and ECG changes such as conduction disturbances (including QRS prolongation), dysrhythmias 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 BUPYRA XL have been rarely reported in patients ingesting large overdoses of the medicine. Acute ingestion of doses in excess of 10 times the maximum therapeutic dose has been reported. Serotonin syndrome has also been reported.

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 BUPYRA XL is known. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.