Zyban 150 mg prolonged release tablets

Update section 4.8 to add alopecia as a very rare side effect.

Update section 4 of the PIL - Very rare side effects - To add alopecia.

Change to section 2 - what you need to know - warnings and precautions

Change to section 6 - date of revision

In section 4.4 (Special warnings and precautions), information on Brugada syndrome have been added and minor editorial changes.

In section 4.2, 4.8, 5.2 and 6.1, minor editorial changes to align to the QRD template latest version. 

In section 10 (Date of revision), updated with the latest date of revision.

Update to section 4.8 - addition of Dysphemia to psychiatric disorders under frequency not known.

Update to SPC:
Section 4.8 – addition of Systemic lupus erythematosus syndrome aggravated, cutaneous lupus erythematosus under frequency not known

Section 4.4 – addition of serotonin syndrome when Zyban is co-administrated with SSRI and SNRIs
Section 4.5 – addition of interaction with SSRI and SNRIs
Section 4.8 - addition of serotonin syndrome to nervous system disorders under frequency not known
Section 4.8 - reporting of suspected adverse reactions section
Section 4.9 - addition of serotonin syndrome

4.5          Interaction with other medicinal products and other forms of interaction - 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.

NAME OF THE MEDICINAL PRODUCT – removal of ‘film coated’

PHARMACEUTICAL FORM - removal of ‘film coated’

Posology and method of administration – QRD and layout of text changes

Special warnings and precautions for use – QRD and new text regarding inappropriate routes of administration

Undesirable effects – addition of anaemia, leuocpenia and thrombocytopenia with frequency of unknown. Contact information for reporting of AE.

Pharmacokinetic properties – QRD changes

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

For a the full list of excipients, see section 6.1.

4.2       Posology and method of administration

Zyban 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 seizures.

4.3       Contraindications

Zyban is contraindicated in patients with hypersensitivity to bupropion or any of the excipients listed in section 6.1.

4.4       Special warnings and precautions for use

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.

4.5       Interaction with other medicinal products and other forms of interaction

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 (Kaletra) 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. 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.

6.6       Special precautions for disposal

No special requirements for disposal.

1.         NAME OF THE MEDICINAL PRODUCT

Zyban 150 mg prolonged release film-coated tablets.

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4.         CLINICAL PARTICULARS

4.3       Contraindications

Zyban 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.

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4.4       Special warnings and precautions for use

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 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 (see section 4.5).

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4.5       Interaction with other medicinal products and other forms of interaction

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 C_max 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 Zyban 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 Zyban 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 (see section 4.4).

Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.

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4.6       Fertility, Ppregnancy and lactation

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10.       DATE OF REVISION OF THE TEXT

December 2010May 2011

1.         NAME OF THE MEDICINAL PRODUCT

Zyban 150 mg prolonged release film-coated tablets.

4.         CLINICAL PARTICULARS

4.5       Interaction with other medicinal products and other forms of interaction

The effect of other medicinal products on bupropion:

Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6 (see section 5.2).  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 interaction with 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 (Kaletra®) 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.  This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir 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.

10.       DATE OF REVISION OF THE TEXT

February December 2010

SPC UPDATES

Section 4.4 Special warnings and precautions for use

Update to paragraph regarding the elderly under the subheading ‘Specific patient groups’, removing the statement regarding decreased renal function in elderly patients, i.e:

Elderly – Clinical experience with bupropion has not identified any differences in tolerability between elderly and other adult patients. However, greater sensitivity of some elderly individuals cannot be ruled out. Elderly patients are more likely to have decreased renal function, hence 150 mg once a day is the recommended dose in these patients (see sections 4.2 and 5.2).

Section 4.6 Pregnancy and lactation

Statement regarding use in breast feeding mothers updated from advising against using Zyban when breast feeding to a risk-benefit appraoch, i.e.

As bBupropion and its metabolites are excreted in human breast milk mothers should be advised not to breast feed while taking Zyban. A decision on whether to abstain from breast-feeding or to abstain from therapy with Zyban should be made taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Zyban therapy to the mother.

Section 4.8 Undesirable effects

Updated the description of the frequency categories from ‘greater than’ (>) to ‘great than and equal to’ (≥).

Included additional frequency category ‘not known (cannot be estimated from the available data).’

Added ‘psychosis’ as an additional side effect, with unknown frequency and in system order class ‘psychiatric disorders’.

Although not formally studied, cConcomitant 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 Zyban 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 Zyban should be carefully considered compared with the potential risks.

In vitro findings indicate that bBupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6 (see 5.2 Pharmacokinetic Properties). Care should therefore be exercised when Zyban is co-administered with Co-administration of medicinal products that may affect the CYP2B6 isoenzyme (e.g.: CYP2B6 substrates: orphenadrine, 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 interaction with CYP2B6 enzyme and the consequent changes in the bupropion-hydroxybupropion ratio are currently unknown.

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. Experimental and clinical data do not rule out potential for QT prolongation and widening of QRS at supra-therapeutic levels. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion have been reported rarely in patients ingesting massive large overdoses of the drug.

Treatment: In the event of overdose, hospitalisation is advised. ECG and vital signs should be monitored.