Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use
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 WELLBUTRIN XR in the presence of predisposing risk factors which lower the seizure threshold. Therefore WELLBUTRIN XR 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 (see also section 4.3)
• History of head trauma
• Diabetes treated with hypoglycaemics or insulin
• Use of stimulants or anorectic products 
WELLBUTRIN XR should be discontinued and not recommenced in 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 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 concurrently.

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 (see section 4.5).

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.

A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug 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 drug therapy (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 the medicinal product, 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 patient’s 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. 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
WELLBUTRIN XR 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 WELLBUTRIN XR 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 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 (see section 5.1).

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 (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 WELLBUTRIN XR 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.

Brugada syndrome

Bupropion may unmask Brugada syndrome, a rare hereditary disease of the cardiac sodium channel with characteristic ECG changes ST segment elevation and T wave abnormalities in the right precordial leads), which may lead to cardiac arrest and/or sudden death. Caution is advised in patients with Brugada syndrome or risk factors such as a family history of cardiac arrest or sudden death.


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.

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 WELLBUTRIN XR should be used with caution in patients with mild to moderate hepatic impairment (see section 4.2).

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.

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 (see section 4.2).

Elderly – Efficacy has been shown equivocally in older people. In a clinical trial, older people followed the same dose regimen as for the adults (see sections 4.2 Adults and 5.2). 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

WELLBUTRIN XR 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.

Serotonin Syndrome

There have been post-marketing reports of serotonin syndrome, a potentially life-threatening condition, when WELLBUTRIN XR is co-administered with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.5). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Serotonin syndrome may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.




Effects on Driving

4.7         Effects on ability to drive and use machines
As with other CNS acting drugs bupropion may affect ability to perform tasks that require judgement or motor and cognitive skill. Patients should therefore exercise caution before driving or use of machinery until they are reasonably certain WELLBUTRIN XR does not adversely affect their performance.