4.1. Therapeutic indications

Zyban tablets are indicated as an aid to smoking cessation in combination with motivational support in nicotine-dependent patients.

4.2. Posology and method of administration

Posology

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 Zyban, preferably in the second week. The initial dose is 150mg to be taken daily for six days, increasing on day seven to 150mg twice daily.

There should be an interval of at least 8 hours between successive doses.

The maximum single dose must not exceed 150mg and the maximum total daily dose must not exceed 300mg.

Insomnia is a very common adverse event which can be reduced by avoiding bedtime doses of Zyban (provided there is at least 8 hours between doses).

Paediatric population

Use in patients under 18 years of age is not recommended as the safety and efficacy of Zyban tablets have not been evaluated in these patients.

Elderly

Zyban 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 150mg once a day (see section 4.4).

Hepatic impairment

Zyban 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 150mg once a day.

Renal impairment

Zyban should be used with caution in patients with renal insufficiency. The recommended dose in these patients is 150mg once a day (see section 4.4).

Method of administration

Zyban should be used in accordance with smoking cessation guidelines.

Prescribers should assess the patient's motivation to quit. Smoking cessation therapies are more likely to succeed in those patients whom are motivated to quit and have motivational support.

Patients should be treated for 7-9 weeks. If at seven weeks no effect is seen, treatment should be discontinued.

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.

Zyban can be taken with or without food (see sections 4.5 and 5.2).

Discontinuing therapy

Although discontinuation reactions are not expected with Zyban, a tapering-off period may be considered.

4.3. Contraindications

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

Zyban is contraindicated in patients with a current seizure disorder or any history of seizures.

Zyban is contraindicated in patients with a known central nervous system (CNS) tumour.

Zyban is contraindicated in 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).

Zyban is contraindicated in patients with a current or previous diagnosis of bulimia or anorexia nervosa.

Zyban is contraindicated for use in patients with severe hepatic cirrhosis.

Concomitant use of Zyban and monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 14 days should elapse between discontinuation of irreversible MAOIs and initiation of treatment with Zyban. For reversible MAOIs, a 24 hour period is sufficient.

Zyban is contraindicated in patients with a history of bipolar disorder as it may precipitate a manic episode during the depressed phase of their illness.

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.

4.4. Special warnings and precautions for use

Seizures

The recommended dose of Zyban must not be exceeded, since bupropion is associated with a dose-related risk of seizure. At doses up to the maximum recommended daily dose (300mg of Zyban daily), the incidence of seizures is approximately 0.1% (1/1,000).

There is an increased risk of seizures occurring with the use of Zyban in the presence of predisposing risk factors which lower the seizure threshold. Zyban 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 150mg daily should be considered for the duration of treatment.

All patients should be assessed for predisposing risk factors, which include:

1. 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 Zyban, a maximum dose of 150 mg daily for the remainder of their treatment should be considered.

2. alcohol abuse (see also section 4.3)

3. history of head trauma

4. diabetes treated with hypoglycaemics or insulin

5. use of stimulants or anorectic products.

Zyban 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 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).

Neuropsychiatry

Zyban is a centrally-acting noradrenaline/dopamine reuptake inhibitor. Neuropsychiatric reactions have been reported (see section 4.8). 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 Zyban treatment, 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

Zyban should be discontinued if patients experience hypersensitivity reactions during treatment.

Clinicians should be aware that symptoms may progress or recur following the discontinuation of Zyban 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 (see section 4.8). 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 (see section 4.8) 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 Zyban 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 Zyban 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.

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

Elderly – 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 (see sections 4.2 and 5.2).

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 Zyban 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.

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 (see sections 4.2 and 5.2). 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.

Inappropriate routes of administration

Zyban 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 Zyban 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.

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

In patients receiving medicinal products known to lower the seizure threshold, Zyban 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 (see section 4.4).

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 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.

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

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.

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.

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 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% (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.

Nicotine, administered transdermally by patches, did not affect the pharmacokinetics of bupropion and its metabolites.

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 Zyban 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 – see section 4.8) 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 Zyban treatment. The consumption of alcohol during Zyban treatment 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 Zyban 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 Zyban. 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 (see section 5.2).

4.6. Fertility, 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 (see section 5.3). Zyban should not be used in pregnancy. Pregnant women should be encouraged to quit smoking without the use of pharmacotherapy.

Breast-feeding

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 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.

Fertility

There are no data on the effect of bupropion on human fertility. A reproductive study in rats revealed no evidence of impaired fertility (see section 5.3).

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 skills. Zyban has also been reported to cause dizziness and lightheadedness. Patients should therefore exercise caution before driving or use of machinery until they are reasonably certain Zyban does not adversely affect their performance.

4.8. Undesirable effects

The list below provides information on the undesirable effects identified from clinical experience, categorised by incidence and System Organ Class body system. It is important to note that smoking cessation is often associated with nicotine withdrawal symptoms (e.g. agitation, insomnia, tremor, sweating), some of which are also recognised as adverse events associated with Zyban.

Undesirable effects are ranked under headings of frequency using the following convention; very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10000, <1/1,000); very rare (<1/10000); not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Not known

Anaemia, leucopenia and thrombocytopenia

Immune system disorders*

Common

Hypersensitivity reactions such as urticaria

Rare

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

Uncommon

Anorexia

Rare

Blood glucose disturbances

Not known

Hyponatraemia

Psychiatric disorders

Very common

Insomnia (see section 4.2)

Common

Depression (see section 4.4), agitation, anxiety

Uncommon

Confusion

Rare

Irritability, hostility, hallucinations, depersonalisation, abnormal dreams including nightmares

Very rare

Delusions, paranoid ideation, restlessness, aggression

Not known

Suicidal ideation and suicidal behaviour***, psychosis, dysphemia, panic attack

Nervous system disorders

Common

Tremor, concentration disturbance, headache, dizziness, taste disorders

Rare

Seizures (see below)**, dystonia, ataxia, Parkinsonism, incoordination, memory impairment, paraesthesia, syncope

Not known

Serotonin syndrome****

Eye disorders

Uncommon

Visual disturbance

Ear and labyrinth disorders

Uncommon

Tinnitus

Cardiac disorders

Uncommon

Tachycardia

Rare

Palpitations

Vascular disorders

Uncommon

Increased blood pressure (sometimes severe), flushing

Rare

Vasodilation, postural hypotension

Gastrointestinal disorders

Common

Dry mouth, gastrointestinal disturbance including nausea and vomiting, abdominal pain, constipation

Hepatobiliary disorders

Rare

Elevated liver enzymes, jaundice, hepatitis

Skin and subcutaneous tissue disorders*

Common

Rash, pruritus, sweating.

Rare

Erythema multiforme and Stevens Johnson syndrome have also been reported. Exacerbation of psoriasis

Very rare

Alopecia

Not known

Systemic lupus erythematosus syndrome aggravated, cutaneous lupus erythematosus, acute generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders

Rare

Twitching

Renal and urinary disorders

Rare

Urinary frequency and/or retention

Very rare

Urinary incontinence

General disorders and administration site conditions

Common

Fever

Uncommon

Chest pain, asthenia

* Hypersensitivity may manifest as skin reactions. See “Immune system disorders” and “Skin and subcutaneous tissue disorders”.

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

***Cases of suicidal ideation and suicidal behaviour have been reported during bupropion therapy (see section 4.4).

****Serotonin syndrome may occur as a consequence of an interaction between bupropion and a serotonergic medicinal product such as Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRI) (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. 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. 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 bupropion is known. Further management should be as clinically indicated.